[Senate Hearing 117-395]
[From the U.S. Government Publishing Office]


                                                    S. Hrg. 117-395

                        FDA USER FEE AGREEMENTS:
                       ADVANCING MEDICAL PRODUCT
                     REGULATION AND INNOVATION FOR
                        THE BENEFIT OF PATIENTS,
                          FDA CENTER DIRECTORS

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

                                HEARING

                                OF THE

                    COMMITTEE ON HEALTH, EDUCATION,
                          LABOR, AND PENSIONS

                          UNITED STATES SENATE

                    ONE HUNDRED SEVENTEENTH CONGRESS

                             SECOND SESSION

                                   ON

EXAMINING FOOD AND DRUG ADMINISTRATION USER FEE AGREEMENTS, FOCUSING ON 
ADVANCING MEDICAL PRODUCT REGULATION AND INNOVATION FOR THE BENEFIT OF 
       PATIENTS AND FOOD AND DRUG ADMINISTRATION CENTER DIRECTORS

                               __________

                             APRIL 26, 2022

                               __________

 Printed for the use of the Committee on Health, Education, Labor, and 
                                Pensions
                                
[GRAPHIC NOT AVAILABLE IN TIFF FORMAT] 


                               __________

                                
                    U.S. GOVERNMENT PUBLISHING OFFICE                    
48-906 PDF                  WASHINGTON : 2023


     Available via the World Wide Web: http://www.govinfo.gov          
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          COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS

                    PATTY MURRAY, Washington, Chair
BERNIE SANDERS (I), Vermont          RICHARD BURR, North Carolina, 
ROBERT P. CASEY, JR., Pennsylvania       Ranking Member
TAMMY BALDWIN, Wisconsin             RAND PAUL, M.D., Kentucky
CHRISTOPHER S. MURPHY, Connecticut   SUSAN M. COLLINS, Maine
TIM KAINE, Virginia                  BILL CASSIDY, M.D., Louisiana
MAGGIE HASSAN, New Hampshire         LISA MURKOWSKI, Alaska
TINA SMITH, Minnesota                MIKE BRAUN, Indiana
JACKY ROSEN, Nevada                  ROGER MARSHALL, M.D., Kansas
BEN RAY LUJAN, New Mexico            TIM SCOTT, South Carolina
JOHN HICKENLOOPER, Colorado          MITT ROMNEY, Utah
                                     TOMMY TUBERVILLE, Alabama
                                     JERRY MORAN, Kansas

                     Evan T. Schatz, Staff Director
               David P. Cleary, Republican Staff Director
                  John Righter, Deputy Staff Director
                           
                           C O N T E N T S

                              ----------                              

                               STATEMENTS

                        TUESDAY, APRIL 26, 2022

                                                                   Page

                           Committee Members

Murray, Hon. Patty, Chair, Committee on Health, Education, Labor, 
  and Pensions, Opening statement................................     1
Burr, Hon. Richard, Ranking Member, a U.S. Senator from the State 
  of North Carolina, Opening statement...........................     3

                               Witnesses

Cavazzoni, Patrizia, M.D., Director, Center for Drug Evaluation 
  and Research, United States Food and Drug Administration, 
  Silver Spring, MD..............................................     7

Marks, Peter, M.D., Ph.D., Director, Center for Biologics 
  Evaluation and Research, United States Food and Drug 
  Administration, Silver Spring, MD..............................     8

Shuren, Jeffrey, M.D., J.D., Director, Center for Devices and 
  Radiological Health, United States Food and Drug 
  Administration, Silver Spring, MD..............................    10

                          ADDITIONAL MATERIAL

    Joint prepared statement of Patrizia Cavazzoni, Peter Marks, 
      and Jeffrey Shuren.........................................    31

                         QUESTIONS AND ANSWERS

Response by Patrizia Cavazzoni to questions of:
    Sen. Casey...................................................    72
    Sen. Hassan..................................................    73
    Sen. Smith...................................................    74
    Sen. Paul....................................................    76
    Sen. Cassidy.................................................    77
    Sen. Scott...................................................    81
    Sen. Tuberville..............................................    92
Response by Peter Marks to questions of:
    Sen. Casey...................................................    98
    Sen. Collins.................................................   100
    Sen. Cassidy.................................................   101
    Sen. Scott...................................................   101
    Sen. Tuberville..............................................   103
Response by Jeffrey Shuren to questions of:
    Sen. Scott...................................................   104
    Sen. Tuberville..............................................   105

 
                        FDA USER FEE AGREEMENTS:
                       ADVANCING MEDICAL PRODUCT
                     REGULATION AND INNOVATION FOR
                        THE BENEFIT OF PATIENTS,
                          FDA CENTER DIRECTORS

                              ----------                              


                        Tuesday, April 26, 2022

                                       U.S. Senate,
       Committee on Health, Education, Labor, and Pensions,
                                                    Washington, DC.

    The Committee met, pursuant to notice, at 10:02 a.m., in 
room 430, Dirksen Senate Office Building, Hon. Patty Murray, 
Chair of the Committee, presiding.

    Present: Senators Murray [presiding], Baldwin, Hassan, 
Rosen, Hickenlooper, Burr, Collins, Cassidy, Braun, and 
Marshall.

                  OPENING STATEMENT OF SENATOR MURRAY

    The Chair. The Senate, Education, Labor, and Pensions 
Committee will please come to order. Today, we are having the 
second of two hearings on reauthorizing four Food and Drug 
Administration user fee programs. I will have an opening 
statement, followed by Ranking Member Burr, and then we will 
introduce our witnesses.

    After the witnesses give their testimony, Senators will 
each have 5 minutes for a round of questions. And while again, 
while we were unable to have this hearing fully open to the 
public or media for in-person attendance, live video is 
available on our Committee website at help.senate.gov. And if 
you are in need of accommodations, including closed captioning, 
you can reach out to the Committee of the Office of 
Congressional Accessibility Service.

    Before we discuss the importance of the user fee programs 
to FDA's drug and device work, recent reporting has put a 
spotlight on issues with the FDA's food, safety, and nutrition 
efforts, including several that have frustrated me for a long 
time.

    While some important steps on nutrition and safety have 
been stalled for years, we have also seen more recent threats 
met with a frustratingly slow response, like arsenic and other 
heavy metals in baby food or contaminated infant formula, which 
FDA first received complaints about last September but was only 
recalled earlier this year.

    I am going to keep pressing for answers from FDA leadership 
on how they will end the pattern of delay and dysfunction here, 
because FDA's mission, when it comes to ensuring our food is 
safe and healthy, is too important to be on the agency's back 
burner. Because people in Washington State and across the 
country depend on the FDA doing its job quickly and carefully 
every single day in more ways than even they realize.

    Whether they are getting a meal or a prescription or an 
ultrasound or almost anything in between, they are putting the 
well-being of themselves and their families in FDA's hands. We 
owe it to them to make sure the FDA has everything it needs and 
is doing everything it can to live up to that huge 
responsibility.

    The user fee programs have an important role to play when 
it comes to FDA's work ensuring the safety and effectiveness of 
medical products families rely on to stay healthy. These 
programs make sure that as FDA gets more new drugs or devices 
to consider for approval, and as it gets more critical work to 
do, it also gets more resources to support that work.

    Given the importance of these programs for keeping families 
safe, Congress has regularly reauthorized them in a bipartisan 
way, and I am glad to be working with Senator Burr and our 
colleagues on this Committee to get this done once again in a 
timely manner. Because it should be unthinkable that after 2 
years, when lefties work has become more important than ever, 
we would fail to get this done or force the agency to send pink 
slips. But it should also be unthinkable that we would let this 
moment slip by without looking carefully at what is and is not 
working at FDA.

    That starts with looking back at this pandemic, from FDA's 
incredible work to quickly review and approve safe, effective 
vaccines, to the challenges it faced like misinformation and 
political interference from the previous administration, to 
other issues we saw, like the constant struggle with testing 
shortages, the hydroxychloroquine debacle, and the ongoing 
frustration parents are dealing with because of unclear 
timelines for vaccines for young children, which I am expecting 
to hear answers about at today's hearing.

    We need to learn from these challenges, something Senator 
Burr and I have already started to work on in our Prevent 
Pandemics Act. But we need to look beyond this pandemic as 
well, because there are countless issues right now that 
families in Washington State are struggling with, but which FDA 
is struggling to address. We have to make sure the approval 
process works for families, not just pharmaceutical companies' 
bottom lines, and that patients are having their voices heard 
and concerns addressed by FDA.

    That means better steps to ensure drugs work for everyone, 
such as increased diversity in clinical trials and pediatric 
drug research and means ensuring the accelerated approval 
pathway benefits patients. And it absolutely means lowering 
drug costs that have been skyrocketing for years and leaving 
patients with impossible choices. Which is why I want to cap 
insulin costs at $35 a month.

    It is also why I want to take steps so FDA can do more to 
bring down barriers that block cheaper generics and biosimilars 
from getting to market and stop pharmaceutical companies who 
game the FDA system to block competition from cheaper drugs. I 
also want FDA to make good on the promise of a law we worked in 
this Committee to pass half a decade ago. And finally, let 
hearing aids be sold over-the-counter and at lower cost to 
millions of people.

    There is no good reason we are still waiting for FDA to 
implement this step and save millions of people thousands of 
dollars. We also need to be looking at what more we can do to 
address substance use disorders and the opioid crisis, as 
overdose deaths keep setting record highs and fentanyl is 
wreaking havoc in our communities. And while there is clearly 
more we can do to strengthen the FDA's oversight of drugs and 
devices, there is also an alarming number of products that 
currently get no meaningful oversight.

    When it comes to cosmetics, we have discovered known 
carcinogens like asbestos and formaldehyde in baby powder, 
children's makeup kits, and hair products. And when it comes to 
dietary supplements, people across the country are faced with a 
shelf full of products that make health claims but lack 
oversight.

    FDA does not have the authority to collect basic 
information about these products or even to know what is on the 
market. People buy, use, and entrust their health to these 
items every day, and they deserve to know these products are 
safe, vetted, and subject to careful FDA oversight. So I hope 
we will be able to make progress on all of these issues and 
more as we work to reauthorize the user fee programs.

    I look forward to hearing from our witnesses today about 
these challenges, thank you for being here, and to working with 
my colleagues on both sides of the aisle to address them in a 
bipartisan way. And as we look at how to support FDA's work, I 
hope we can also make progress soon on the urgently needed 
funding for our COVID response.

    We have got to get that done because families are counting 
on us to provide communities the tests, treatments, and 
vaccines they need to keep people healthy, protect our hard won 
progress against this pandemic, and keep our Country ready for 
whatever comes next.

    With that, I will turn it over to Ranking Member Burr for 
his opening remarks.

                   OPENING STATEMENT OF SENATOR BURR

    Senator Burr. Thank you, Madam Chair. And if I could take a 
point of personal privilege for a moment, I want to reflect on 
the passing of Senator Orrin Hatch. When the Reagan revolution 
came to the Senate, Orrin Hatch became the Committee's Chair. 
He was a remarkable Senator and a good friend to many of us on 
this Committee. His work in this Committee and others is 
something we should all be proud of. Without Orrin, we wouldn't 
have a generic drug industry. Think of how many lives have been 
saved because of that and how many billions have been saved 
with lower cost drugs.

    He was also the author of the Americans With Disabilities 
Act, helping improve the lives of millions of Americans with 
disabilities, giving them opportunities and freedoms to live 
quality lives. The list of what he accomplished could go on and 
on.

    I am saddened by his passing, and my heart and prayers go 
out to his beloved Elaine and their children, and to his 
friends and the staff who worked for him because I know they 
are hurting today as well. And I thank the Chair.

    Madam Chair, I thank you for holding this second hearing 
today on FDA's user fee program, and for working with my staff 
and me on policies that have the potential to go along with the 
legislation as we reauthorize them. The user fee 
reauthorization provides one of those rare opportunities in 
Congress for true bipartisanship and should be seen as a time 
to take a hard look at the policies that affect the daily lives 
of the American people.

    I would bet that each person watching or participating in 
this hearing has already used several products today that are 
regulated by the FDA. That is why it is so important for the 
agency to keep pace with the advancements in these products 
that they regulate. If today's hearing had a theme, it would be 
accountability. You are here today to be held accountable to 
the Congress and to the American people.

    During COVID-19 pandemic, FDA leveraged its authorities and 
responded swiftly to help private sector partners develop and 
bring test, treatments, and vaccines to the American people in 
record time. I was thrilled that the agency embraced the 
letter, and more importantly, the spirit of the law. But this 
seems to be the exception, reserved for emergencies, and not 
the rule.

    COVID was a crisis and you acted fast. But a diagnosis of 
cancer or Alzheimer's is also a crisis for families facing that 
news day in and day out. The agency needs to apply practices 
that used during COVID response to its everyday operations to 
help speed not only the review of products, but their 
development as well. Why shouldn't we expect you to treat more 
things with the same urgency you applied to the pandemic?

    We learned during the pandemic, FDA has a fractured 
framework for clinical tests. It has blind spots where some of 
the most important tests for patients and their doctors are 
concerned, like genetic tests. I want to work on updating FDA's 
regulation for diagnostic tests, and in working with the Chair 
to update the regulations of other products like cosmetics and 
dietary supplements.

    I am glad the Chair's interested in rolling up her sleeves 
and joining with me on this. But there is an elephant in the 
room. The FDA has a responsibility to meet the terms of the 
commitments it has made under the user fee programs. Based on 
my evaluation, you have not fully delivered. During the last 
two decades, I have legislated major reforms at FDA across 
almost all of its programs. The 1997 user fee bill was my bill 
for FDAMA.

    It brought needed reforms to streamline drug review, 
establish risk based regulation of medical devices, and 
required the agency to be more flexible with types of evidence 
it considered for the products it regulates. In 2010, I worked 
with Senator Judd Gregg, Ted Kennedy, Lamar Alexander, and 
others to write the Food Safety Modernization Act aimed at 
reducing food borne illnesses and deaths and modernizing the 
food safety programs at the agency.

    In 2012, I worked with Tom Coburn to hold FDA more 
accountable, reduce product review times, address cultural 
changes at the agency to reinforce that review speed matters, 
especially to patients with a ticking clock. In 2013, this 
Committee worked to provide regulatory certainty for compounded 
drugs, and I worked to ensure the agency had the track and 
trace authorities it needed to improve its ability to detect 
unsafe, counterfeit medicines.

    However, I have also been the roadblock to many proposals 
when I feared that the agency was not ready for the role 
Congress wanted it to play or the mission was at risk. I have 
also objected to giving FDA new and expanded authorities that, 
quite frankly, I didn't think they should have, especially when 
FDA fails to address my concerns about accountability.

    I fought against the passage of the 2009 tobacco law 
because I knew the FDA didn't have what it takes to regulate 
these products. Safe and effective applies everywhere in the 
FDA except CTP. It should have been at ATF all alone. 13 years 
and more than $7.5 billion and its authorized only one vapor 
product, only one. Only one potentially less harmful 
alternative for lifelong smokers.

    I held the 2012 user fee bill on the Senate floor and spoke 
for hours to run through my longstanding concerns with the user 
fee programs and the FDA posture that a user fee bill could be 
dropped in the lap of the U.S. Senate and passed without 
question. I fought to uphold FDA's gold standard of review, 
including when other agencies thought they could perform FDA's 
function better.

    I deeply value and believe in the mission of the Food and 
Drug Administration, which is why the commitments that FDA 
makes are so important and the goals it misses are so 
concerning. The user fee legislation that will come before this 
Committee for a vote in just a few weeks must hold the FDA 
accountable for its actions and inactions. Accountability is 
not an option. You don't get to set goals you can't meet and 
pretend that is accountability. Each of the new agreements this 
Committee is evaluating reflect major new commitments, more 
money, more staff, more Government.

    But what we do about previous commitments that went or 
remain on--what do we do with commitments that went or remain 
unfulfilled? For the drugs program, in Fiscal Year 2019 and 
2020, FDA missed 12 out of the 14 user fee goals in the new 
drug program related to product development meetings with 
sponsors, leaving the innovators in limbo. Meeting 2 of 14 
goals is a 15 percent success rate.

    I believe that would pretty much be an F by anybody's 
grading curve. For the biosimilars program, in Fiscal Year 
2020, FDA only reviewed 50 percent of the applications on time, 
and FDA missed 7 out of 15 goals related to biosimilar product 
development meeting. I am quoting you the facts here of things 
that you committed to do, not Congress imposed on you.

    50 percent of 7 out of 15, that would also be an F under 
anybody's grading. And for the medical device program, not only 
will FDA be 3 months late in finalizing the agreement, it took 
so long because it refused to acknowledge that the agency 
didn't meet all of its goals from the last round.

    Now FDA wants double the money for mediocre performance 
improvements, and for certain devices, longer review times. But 
the missed commitments don't stop there. Missing explanations 
on deficiency letters, a carryover balance the size of a whole 
year of user fee, and the failure to finalize guidance critical 
to some of the most important advanced products in the field.

    More money, lower expectations of accountability, no 
accountability for past failures, and on top of this, a new, 
costly program aimed at shepherding certain devices through the 
review process for which FDA has zero clear deliverables, when 
you already essentially have this authority because I have 
already given it to you. And you expect Congress to rubber 
stamp these agreements? My friends, I don't think so.

    After two transformative, challenging years at FDA, I know 
you can do better. The American people saw you do better. And 
you have an opportunity today to convince me that the agency is 
on the right track for patients. The more you use the user fee 
process to bully dollars out of an industry, holding them 
hostage in the negotiating room, the less accountable FDA is to 
the American people and their elected representatives, period.

    American patients deserve user free programs that bring 
medicines to them on time, that keep pace with technology, that 
reduce the time and cost of development and treatment, and that 
do not grow just to put more Government in between patients and 
cures. I come to this process as a good faith partner to my 
colleagues and as long--as a long standing advocate of the FDA, 
but not as a doormat.

    This Committee has never shied away from difficult FDA 
policy discussions. I promise this process will be thorough and 
critical, so that the agency can rise to the challenge of the 
next generation of scientific advancements to improve the lives 
of the American people. I know you can do it.

    With just a little more accountability added to these 
programs, I am optimistic that my colleagues and I will be able 
to get these agreements signed into law. But if there is more--
if there is not more accountability, I see no reason why I 
shouldn't stand in the way.

    Madam Chair, I thank you.

    The Chair. Thank you, Senator Burr. And thank you for 
beginning with a tribute to Senator Orrin Hatch. Those of us 
who served with him remember his tremendous contributions to 
this Committee, to this Country, to the people of America.

    My condolences as well go to his family, his friends, and 
his staff, and everyone who knew him and didn't know him 
because his legacy will live on. So thank you. Thank you for 
that. I will now introduce today's witnesses. Our first witness 
today is Dr. Patricia Cavazzoni. She is Director of FDA's 
Center for Drug Evaluation and Research. We will also be 
hearing from Dr. Peter Marks. He is the Director of the Center 
for Biologics Evaluation and Research.

    Our final witness is Dr. Jeffrey Shuren. He is the Director 
of the Center for Devices and Radiological Health. Thank you 
all for being here with us today to share your time and 
expertise, and I look forward to hearing from each of you.

    Dr. Cavazzoni, we will begin with your testimony.

  STATEMENT OF PATRIZIA CAVAZZONI, M.D., DIRECTOR, CENTER FOR 
   DRUG EVALUATION AND RESEARCH, UNITED STATES FOOD AND DRUG 
               ADMINISTRATION, SILVER SPRING, MD

    Dr. Cavazzoni. Thank you, Madam Chair, Ranking Member Burr, 
and Members of the Committee. I am Dr. Patricia Cavazzoni, 
Director of the Center for Drug Evaluation and Research at the 
FDA.

    I appreciate the opportunity to appear before you today, 
along with my colleagues Dr. Marks and Dr. Shuren, to discuss 
reauthorization of the user fee programs covering brand name 
drugs, generic drugs, biosimilars, and devices. We appreciate 
the efforts of Congress, and this Committee in particular, in 
reauthorizing these programs in previous cycles, and look 
forward to continuing our partnership this year.

    Dr. Marks will speak about PDUFA in his testimony, I will 
focus my opening remarks on the generic drug user fee program, 
or GDUFA, and the biosimilar drug user fee program, or BsUFA. 
These programs have allowed FDA to provide access to 
affordable, high quality medicines to millions of Americans who 
otherwise couldn't afford them.

    Since its creation more than 10 years ago, GDUFA has 
allowed the agency to approve thousands of generic medicines, 
resulting in significant cost saving for consumers. By some 
accounts, generic drugs saved the U.S. health care system more 
than $2 trillion over that period. Patients' confidence that 
generic drugs will work the same as brand products and can be 
freely substituted is the foundation for the access and savings 
that generics have produced for the health care system.

    We intend to build on this success by approving more drugs 
in a single round of review, including complex generics with 
little or no competition. With more generic drugs on the 
market, there is a corresponding increase in the need for FDA 
advice over the lifecycle of these products. Indeed, we see a 
steady increase in generic drug applications with post-approval 
actions.

    In addition, as brand name drugs become increasingly 
sophisticated and harder to manufacture, the generic program 
faces increased demand to keep up with innovation. GDUFA III 
would introduce new measures that allow for earlier approvals 
and will ensure that the agency has the appropriate staff 
expertise to deliver on our goals year after year. Let me now 
turn to the biosimilar user fee program, or BsUFA.

    The abbreviated biosimilar approval pathway saves the 
developers time and resources, thus encouraging competition and 
potentially lowering health care costs. Since the enactment of 
BsUFA II 5 years ago, the number of approved biosimilar 
products has grown from 5 to 35 today, including an 
interchangeable insulin product.

    BsUFA III proposes to retain the majority of existing 
review performance goals, with changes to some of the meetings 
between FDA and developers to improve communications. With a 
growing portfolio of approved biosimilar products, the proposal 
seeks to expedite the review of new indications or other 
changes after the initial approval.

    Finally, BsUFA III doubles down on efforts to advance the 
development of interchangeable products that may be switched at 
the pharmacy, like generic drugs, resulting in even greater 
access to lower cost biosimilars.

    To close, I cannot emphasize enough the critical importance 
of reauthorizing these three user fee programs. Without them, 
FDA's medical product programs, which have allowed for hundreds 
of treatments and cures for life threatening diseases, would 
not exist as they are today.

    PDUFA's revolutionary impact on innovation and the flow of 
new medicines is matched by GDUFA's impact in making what might 
otherwise be thousands of unaffordable drugs accessible to 
millions of Americans.

    As the BsUFA program continues to grow, we anticipate that 
it will complement GDUFA by expanding the availability of even 
more high quality, affordable medicines for all those who need 
them. Thank you again for the opportunity to be here today. I 
look forward to your questions.

    [The prepared statement of Patrizia Cavazzoni can be found 
on page 31 in Additional Material.:]

    The Chair. Thank you.

    Dr. Marks.

  STATEMENT OF PETER MARKS, M.D., PH.D. DIRECTOR, CENTER FOR 
BIOLOGICS EVALUATION AND RESEARCH, UNITED STATES FOOD AND DRUG 
               ADMINISTRATION, SILVER SPRING, MD

    Dr. Marks. Chair Murray, Ranking Member Burr, and Members 
of the Committee, I am Peter Marks, Director of the Center of 
Biologics Evaluation and Research at the Food and Drug 
Administration. I am pleased to be here today with my 
colleagues to discuss the reauthorization of the medical 
product user fee programs. For my portion of the testimony, I 
will focus on the Prescription Drug User Fee Program, or PDUFA.

    Both CBER and CDER will implement the commitments contained 
in the PDUFA commitment letter, which will refer to its PDUFA 
VII. So, know that while I am presenting the elements of the 
PDUFA VII letter, both Dr. Cavazzoni and I share the 
responsibility for oversight of the program.

    Since first enacted 30 years ago, PDUFA has revolutionized 
the United States drug approval process. It has reversed the 
lag in drug approvals that prompted its creation, providing 
Americans with more timely access to safe and effective medical 
products. Today, almost two-thirds of new active substances 
approved globally are first launched in the United States.

    It is not an understatement to say that there are many 
people with us today who would not be here without the program, 
which has dramatically reshaped drug development and approval 
in the United States, bringing potentially lifesaving medical 
therapies to patients in a much more timely manner.

    Though it began with a general focus on shortening review 
times, through successive 5 year PDUFA reauthorizations, 
program enhancements have evolved and expanded significantly. 
Enhanced interactions give us the opportunity to provide more 
guidance to sponsors, improving the potential for first cycle 
approvals and getting safe and effective drugs to patients 
sooner.

    These interactions also enable sponsors to incorporate the 
advances in regulatory science into their development programs, 
expediting drug development and facilitating timely regulatory 
interactions and decisions. Reauthorization of PDUFA will 
enable the agency to collect fees to support the review of new 
innovative drugs.

    The PDUFA VII commitment letters' focus includes the 
following categories, among others, it will enhance CBER 
support for development, review, and approval of cell and gene 
therapy products and new allergenic extract products, advance--
apply scientific research to expedite drug development, it will 
continue the enhancement and modernization of the drug safety 
system, advance the utilization of innovative manufacturing 
technologies, and improve FDA's hiring and retention of key 
scientific and technical talent.

    As the Director of CBER, I would like to direct your 
attention for a moment to the PDUFA VII commitment focused on 
new enhancement to CEBR's support for the development, review, 
and approval of cell and gene therapy products and new 
allergenic extract products. FDA has experienced exponential 
growth in cellular and gene therapy submissions over the past 7 
years, with close to 2,000 active development programs.

    We have seen a sustained increase in development program 
activities, including an 85 percent increase in investigational 
new drug applications and a 158 percent increase in formal 
meeting requests.

    A number of these programs, such as regenerative medicine 
advanced therapy, or RMAT designation, which was enacted by 
Congress as part of the 21st Century Cures Act, have the 
potential to bring new therapies to meet unmet medical needs 
for serious and life threatening conditions.

    Since December 2016, 72 of 187 requests that have received 
RMAT designation--have received RMAT designation, with three of 
these designated products having received approval in 2021. 
These include two allogeneic cellular products, one for 
children with a rare immune disorder, one for wound healing, 
and a CAR-T cell therapy for patients with a kind of cancer B-
cell lymphoma.

    To meet the demands of the rapidly expanding cell and gene 
therapy portfolio, PDUFA VII proposes new enhancements to 
CBER's capacity. The proposal will allow the agency to produce 
multiple guidances, to host public meetings to examine new 
technologies and approaches, and to better understand patient 
perspectives on gene therapy products, and to conduct public 
outreach to facilitate product development and approval.

    New allergenic extract products also will be included in 
PDUFA VII, and the program will provide needed resources to 
facilitate the development and approval of new medical products 
critical for the diagnosis and treatment of allergies, 
including serious food allergies.

    The enhancements of cell and gene therapy and allergenics 
are just two examples of the important enhancements proposed 
under PDUFA VII, and we will be happy to answer questions 
regarding the others. Thank you for your time today.

    [The prepared statement of Peter Marks can be found on page 
31 in Additional Material.:]

    The Chair. Thank you. Dr. Shuren.

 STATEMENT OF JEFFREY SHUREN, M.D., J.D., DIRECTOR, CENTER FOR 
 DEVICES AND RADIOLOGICAL HEALTH, UNITED STATES FOOD AND DRUG 
               ADMINISTRATION, SILVER SPRING, MD

    Dr. Shuren. Chair Murray, Ranking Member Burr, Members of 
the Committee, thank you for the opportunity to testify today 
about the fifth reauthorization of MDUFA. The investments made 
in previous MDUFA authorizations have paid dividends, as we 
continue to see an increasing number of innovators bringing 
their devices to the U.S. first, and a more robust pipeline of 
innovative technologies.

    I want you to know that I personally regret that we missed 
the statutory deadline to deliver our recommendations to 
Congress, an obligation that I and the entire agency take 
seriously. I am pleased to report, however, that the long 
deliberations that ultimately produced a strong, thoughtful 
agreement on recommendations to Congress that, if enacted, will 
continue to advance medical device innovation, while increasing 
accountability for the program, and maintaining the FDA's 
standards to protect patients.

    CDRH continue to meet and exceed most performance goals 
through the first half of MDUFA IV. However, we missed some 
goals later on. During this time, we saw a rise in our workload 
for which we were not fully funded. For example, so far during 
MDUFA IV, we received over 3,000 more pre-submissions than we 
were resourced to review.

    The number of breakthrough device designations we have 
granted has increased by almost 60 percent. Medical devices 
have and continue to be increasingly more complex, and the 
review of their premarket submissions, more resource intensive. 
While the number of submissions we receive annually has 
increased as well, and we expect these trends to continue. And 
then COVID hit.

    It pushed us into a continuous all hands on deck operation 
in order to facilitate the development and availability of 
pandemic related medical devices. CDRH has received over 8,000 
emergency use and pre-EUA requests, and we are still receiving 
about 120 of these submissions a month. We have granted 
emergency use for full marketing authorization to nearly 2,300 
medical devices for COVID-19, including over 460 tests and 
self-collection kits.

    This has truly been a perfect storm that my center has been 
battling against for over 2 years. Moreover, our efforts to 
grant EUAs are not covered under the scope of MDUFA, and they 
don't count toward that performance. On the other hand, the 
magnitude of the emergency response inevitably led to a backlog 
and delayed review times, and we fell short on some of our 
MDUFA IV goals.

    We know this has had a great impact on companies across the 
country. This is why we have been transparent, communicating 
about impacts publicly and regularly, and we have worked hard 
to address delays for COVID and non-COVID devices through 
hiring more staff and contractors, reallocating current staff, 
and changing policy procedure and practice, with many of my 
staff burning the midnight oil and burning out in the process.

    We greatly appreciate the support from Congress, 
particularly in the form of supplemental funding, and we have 
now turned the corner. We have already reduced the backlog of 
non-COVID device submissions by 45 percent, and we are 
targeting to have most of the center back to normal operations 
by later this year.

    Despite these challenges during MDUFA IV, we continue to 
authorize record numbers of novel devices, over 100 a year, 
even during the pandemic. And we granted almost 600 
breakthrough device designations, with most designations going 
to small startup companies. Even while falling short of some 
goals and facing our most challenging year to date, we have 
continued to provide value to innovators and to patients.

    The MDUFA V proposal takes important steps to address 
resource gaps that began to show before COVID-19 and to support 
improved performance. It also features many new accountability 
mechanisms, one of which is for add-on payments under which FDA 
would receive additional user fees if it meets specified goals.

    These additional funds come with even more ambitious goals 
for the later years MDUFA V. The agreement includes a new 
voluntary pilot, TAP, to provide earlier, more frequent, and 
more strategic engagement with sponsors of breakthrough 
designated devices and those included in the Safer Technologies 
Program to speed device development, and we will be tracking 
over half a dozen metrics for devices in the pilot to make sure 
that TAP provides a return on investment.

    The initiative is another way we are continuing to 
incorporate lessons learned from the pandemic, where we saw how 
engaging with sponsors through the pre-EUA process to problem 
solve and answer their questions in real or near real time was 
critical for facilitating important technologies coming to 
market quickly and safely.

    The MDUFA V proposal would also support advancing the 
patient perspective in regulatory decisions, expanding the use 
of consensus standards, leveraging real world evidence for 
regulatory decisionmaking, and advancing global harmonization, 
among other priorities. We appreciate Congress's patience and 
support.

    Thank you again for the opportunity to testify today.

    [The prepared statement of Jefferey Shuren can be found on 
page 31 in Additional Material.:]

    The Chair. Thank you very much to all of you. We will now 
begin a round of 5 minute questions. And I again ask my 
colleagues, keep track the clock and stay within those 5 
minutes. Dr. Mark, I want to start with you. Families are still 
waiting for a COVID vaccine for children under the age of five. 
And this week there were reports that they may be waiting till 
June.

    Throughout my state, I have had parents talking to me about 
this. They are frustrated, they are confused, and I am, too, 
and they really do deserve some clarity on this.

    For parents back in my home of Washington State, across 
country, can you tell us when you expect a COVID-19 vaccine for 
young children and why it is taking so long, and what we need 
to know in the meantime to keep children safe?

    Dr. Marks. Thank you, Chair. Once we have a fully complete 
emergency use application, we will move quickly, without 
sacrificing our standards, to finish our evaluation of COVID-19 
vaccines for children under 5 years of age. It is one of our 
highest priorities, and we care very deeply about the health 
and well-being of children. But simply making a vaccine 
available doesn't matter if parents don't get their kids 
vaccinated. So it is critically important that we have the 
proper evaluation so that parents will have trust in any 
vaccines that we authorize.

    As we work to complete our reviews, we will bring the 
vaccines before independent advisers to have a discussion of 
the data. And if we authorize the vaccines in young children, 
parents will be able to have access to the information that 
they need to be confident in making their decisions on 
vaccination.

    We are deeply committed to getting a safe and effective 
COVID-19 available for all children, and we will make sure we 
get the job done and get it done correctly. In the next week, 
we will make public a tentative timeline for advisory committee 
meetings for several expected applications.

    But just remember that we can't actually finish our reviews 
until we actually have complete applications in the FDA.

    The Chair. So are the--we don't have complete applications, 
is that why this is taking so long?

    Dr. Marks. You know, unfortunately, we can't comment 
publicly on the state of this, but I would direct you to the 
fact that the manufacturers generally will make an announcement 
when they have a full and complete application in with us for 
emergency use.

    But you can surmise what the situation is because we will 
proceed with all due speed once we have complete applications. 
Some of these are complicated because they are relatively 
larger, covering larger swaths of the pediatric population than 
others.

    The Chair. Dr. Cavazzoni, when it comes to opioids, we have 
seen how FDA failures in the past have really contributed to a 
nationwide crisis, and that continues to tragically grow for 
families and communities across the country. Last year alone, 
we lost over 100,000 people to drug overdoses. That is a 
heartbreaking record.

    More and more of these deaths are due to fentanyl. Fentanyl 
overdose deaths in my home State of Washington have increased 
tenfold in the past 6 years, which is a stunning increase. And 
we really do need an all hands on deck effort to do everything 
possible to get our handle on this problem and save lives. And 
that includes FDA taking decisive action to respond to the 
fentanyl crisis.

    FDA was too slow and too hesitant to address this in the 
past, and I think every Member of this Committee really 
believes we need to be more aggressive and dynamic steps need 
to be taken now and going forward. So while you are here, I 
want to ask you, what is the FDA doing to aggressively work 
with Federal partners to address the use of illicit fentanyl 
related substances and expand access to high quality treatments 
for opioid use disorder and overdose reversal drugs that can 
save lives like naloxone?

    Dr. Cavazzoni. Thank you, Madam Chair. The efforts to fight 
the opioid epidemic are--really need to--FDA as well as all our 
Federal partners, because it is a very complicated situation.

    We are redoubling our efforts when it comes to fighting the 
opioid epidemic, looking at all potential tools that we have. 
And for instance, very recently we have issued a Federal 
register notice indicating that we are considering including 
mailbag envelopes in--with prescriptions as part of the opioid 
grants.

    We are also very, very focused on expanding the access of 
naloxone. Any particular OTC and naloxone, we understand the 
need. We stand ready to work with manufacturers to expedite the 
review of these products so that we make opioid reversal agents 
more broadly available to the American people.

    The Chair. Okay, thank you. And my time is expired. I do 
you have additional questions, but I will turn to Senator Burr.

    Senator Burr. Thank you, Madam Chair. Dr. Cavazzoni, in the 
last PDUFA agreement, FDA committed to 230 new hires by Fiscal 
Year 2022. According to the FDA's Performance Report for Fiscal 
Year 2021, it has hired 212 of those new hires.

    Yet there are currently a total of 260 PDUFA funded 
vacancies across the Drugs and Biologics Center. Here is my 
question, how can the FDA say that it has met its hiring 
commitments with so many underlying vacancies in the PDUFA 
program? And why does FDA not account for net employment?

    Dr. Cavazzoni. Thank you, Senator, for that question. When 
we look at the vacancies that we have in place, it is important 
that we put them within context of our total number of staff in 
the user fee program. And so our current vacancies represent 
approximately 7 to 8 percent of our total staff. And this is 
not an unexpected rate of vacancy or attrition in large 
organizations. It is also important to keep in mind that when 
an employee leaves, we immediately start the process to 
backfill that position.

    If you look behind those vacancies, they have activities 
behind them to bring them on board. We are overall on track to 
meet our hiring commitments by the end of the cycle. And yes, 
we are asking for additional personnel as part of the next 
authorization cycle. And it is important to keep in mind that 
the additional personnel are really meant to support the 
incremental activities and commitments that we have negotiated 
with industry, and that the current personnel, including those 
backfilled vacancies, have--are really there to meet our 
current commitments.

    We work very, very fast to try to backfill those open 
vacancies, utilizing the tools that Congress has given us, for 
example, 21st Century Cure hiring authority, which has been 
very, very helpful to us.

    Senator Burr. I think it has been helpful. And Dr. 
Cavazzoni, I have been here for 28 years, but I still don't buy 
into the belief that if you have hired 212 people under the 
commitment, but you have 260 vacancy, I as an applicant should 
feel good about that. That tells me that there are less people 
working on application, work in the entire division. So maybe 
we will have a disagreement there. But I certainly understand 
why the industry looks at this and says, well, technically you 
may have reached your goal, but if you actually have less 
people working in the PDUFA than you did when we started, so it 
is a net loss.

    Dr. Shuren, the pandemic highlighted the fragmented 
approach for our Country to take to--takes to diagnostic test 
regulations. I have been working for more than 3 years together 
with a new proposal, the VALID Act, to reform the way we 
regulate test and encourage innovation in the field. Do you 
agree that our approach to clinical tests needs to be reformed?

    Dr. Shuren. I do. We are supporters--and first of all, I 
just want to thank you and Chair Murray for your leadership on 
trying to drive diagnostic reform. And we are very supportive 
of having reform, working with you on the final product. What 
that has to be, though, is to make sure that it covers all 
tests. Doctors and patients don't care who makes your test, 
they just care that your test works.

    Senator Burr. Jeff, you said a minute ago, we are trying to 
be transparent, so let me just be candid. By law, meeting 
minutes for MDUFA negotiations are required to be posted 
publicly before the agreement is transmitted to Congress.

    Today, there are no meeting minutes from any meeting since 
February of this year. You posted minutes for nine meetings 
between September and February over the weekend. We are still 
missing the minutes from seven meetings. Congress--well, will 
you commit to publish 100 percent of the meeting minutes before 
finalizing the commitment letter?

    Dr. Shuren. Yes. We are hoping to have all the meeting 
minutes through March 7th posted today.

    Senator Burr. Why has that been so difficult? Just out of 
curiosity.

    Dr. Shuren. Out of curiosity--you know what, it is a 
negotiation in and of itself with the industry parties. And you 
have seen how those negotiations go, a lot of diverse opinions. 
And the big focus was trying to get the deal done, get the 
meetings afterwards. We agree with you. It is hard for you to 
make informed decisions without those meeting minutes present.

    I think we and industry both struggled with the resources 
available with COVID as well. So we see this as an unusual 
circumstance, and we know this is not the way going forward. We 
will have the rest of the meeting minutes out by the end of 
this week. And we are targeting to have the final package to 
you all by the end of next week.

    Senator Burr. Thank you, Madam Chair.

    The Chair. Thank you.

    Senator Hassan.

    Senator Hassan. Well, I want to thank you, Madam Chair and 
Ranking Member Burr, for having this hearing. And thank you for 
the witnesses for being here today. Dr. Cavazzoni, last summer, 
I led a bipartisan letter to the FDA, raising concerns about 
the apparent conflicts of interests surrounding the consulting 
firm McKinsey. The firm worked for the agency on opioid related 
projects while also simultaneously working for opioid 
manufacturers like Purdue Pharma.

    The FDA's response to the letter indicated that McKinsey 
failed to disclose any potential conflicts of interest when 
applying for FDA contracts. And earlier this month, Chair 
Murray and I led a letter asking the HHS Inspector General to 
investigate further. What actions is the FDA now taking against 
McKinsey based on the firm's failures to disclose apparent 
conflicts of interest?

    For example, is the FDA's suspending current and future 
contracts with McKinsey and referring this case to the 
Department of Justice for potential violations of the False 
Claims Act?

    Dr. Cavazzoni. Thank you, Senator, for that question. It is 
very important to establish that while McKinsey have I work 
with FDA under contract for over several years, their work did 
not entail specific regulatory work or a scientific review work 
pertaining to products or product classes.

    Senator Hassan. But my question is, what are you doing to 
make sure that we don't come to a place like this again, and to 
hold McKinsey accountable for failure to disclose what is an 
apparent conflict of interest?

    Dr. Cavazzoni. So FDA follows the U.S. Government 
contracting rules, and those rules require contractors to 
disclose any conflict of interest. And we expect contractors to 
do so. So this is the framework under which we operate, and we 
will continue to set those expectations.

    Senator Hassan. So I am going to follow-up with you 
additionally, because I am still interested in wanting an 
answer to whether you are going to suspend contracts, current 
or future contracts with McKinsey. Whether there is a case for 
referring this to DOJ. And I will continue to follow-up on the 
issue, including with the HHS Inspector.

    Dr. Cavazzoni. To orient you to that--the Center for Drugs 
currently does not have a contract with McKinsey. And across 
FDA, the--we anticipate that certain contracts will not be 
issued pending the outcome of the investigations. And I can 
defer to my colleagues, Dr. Marks, to speak to CBER.

    Senator Hassan. Well, I am going to hold off on that 
because I have a few other questions and limited time. But I 
will follow-up with you, Dr. Marks. I have another question. 
Dr. Cavazzoni. In the FDA's response to my original letter, the 
agency claimed that it first became aware that McKinsey had 
taken on opioid manufacturers as clients in early 2021.

    However, the New York Times reported on McKinsey's 
representation of Purdue Pharma in February 2019. Contracting 
data bases show that from February 2019 to January 2021, 
McKinsey received more than $20 million in new contracts from 
the FDA. How did the FDA fail to notice McKinsey's apparent 
conflicts of interest until almost 2 years after they were 
public knowledge printed in the New York Times?

    Dr. Cavazzoni. As I mentioned earlier, we rely on 
Government contracting rules which set the expectations for 
contractors to disclose conflicts of interest. And it is also 
very important to highlight that the work that McKinsey did at 
FDA was about general process, concept of operations, 
organizational design, and did not entail involvement, direct 
involvement in product regulation or scientific review.

    Senator Hassan. That may or may not be true, but the 
reality is that when somebody who is bragging to drug 
manufacturers that they know what questions to ask and have 
influence at the FDA, that should be of concern. And it strains 
credulity to think that nobody at the FDA involved with 
McKinsey between 2019 and 2021 had any idea that the company 
had major potential conflicts of interest based on news reports 
in major publications.

    How is the FDA adjusting its contracting processes going 
forward to ensure that it is aware of publicly reported 
information about apparent conflicts of interest with major 
companies to which it is awarding tens of millions of dollars 
in contracts?

    Dr. Cavazzoni. As I indicated earlier, we follow 
contracting regulations that apply across the entire U.S. 
Government, including other agencies. And we rely on 
contractors to follow those rules and to inform us of any 
conflicts of interest.

    Senator Hassan. I appreciate that answer. I think it is not 
sufficient for us to rely on self-reporting anymore. And I look 
forward to working with Members of committees on whether we 
should exclusively rely on self-reporting from contractors, 
given what we have seen from McKinsey. Thank you, Madam Chair.

    The Chair. Thank you.

    Senator Cassidy.

    Senator Cassidy. Dr. Cavazzoni, I introduced legislation 
with Dr. Smith that would consolidate the process for FDA to 
make therapeutic equivalence determinations for 505(b)(2) new 
drug applications. What data does FDA need to make a 
therapeutic equivalent determination, which is not otherwise 
included in the 505(b)(2) application?

    Dr. Cavazzoni. Thank you, Senator. And we are aware of that 
legislation, and we understand and agree with the importance of 
the therapeutic equivalence evaluations as a means to allow a 
substitution of drugs at the pharmacy. The pathway that we have 
to generate data that supports a therapeutic equivalence 
application is the generic drug review pathway. It is really 
fit for purpose to provide that answer by the time--at the time 
an application is approved.

    When--conversely, the 505(b)(2) pathway is really not set 
up to generate the data that by the end of the review of the 
application or even after the application has been reviewed, 
would allow us to make a determination of therapeutic 
equivalence. Why? Because the review tools and the actual 
regulations are really not set up to yield those data by the 
time the 505(b)(2) application is reviewed.

    We are concerned that requiring a proposal to require that 
therapeutic equivalence evaluation be done within the context 
of 505(b)(2) applications would be very difficult to implement 
under the current framework.

    We are interested in better exploring any barriers in the 
generic drug review program that may make it more difficult for 
some of these applications to come through the generic program 
where we can make those determinations very efficiently.

    Senator Cassidy. Thank you. Doctor--either Dr. Cavazzoni or 
Dr. Marks, there has been a recent court ruling that has called 
into question some aspects of the Orphan Drug Act. 
Specifically, courts have determined FDA can only award orphan 
drug exclusivity for an entire condition as opposed to 
indications within a condition.

    Can you elaborate on how this change in the scope of orphan 
drug exclusivity would impact current and future patient access 
to generics and biosimilars?

    Dr. Marks. Thanks, Senator, for that question. So that 
particular decision has particular implications on the 
development of drugs, particularly in the pediatric realm for 
pediatric rare diseases. With orphan drug exclusivity, one does 
not necessarily have to develop a drug for a pediatric 
population with this decision now. In the past, there would be 
a separate population that could have been granted for the 
pediatric population, allowing development to occur both in the 
adult orphan population and in the pediatric orphan population.

    With this, that pediatric place is blocked. We view that as 
a potential problem for the development of drugs for rare 
diseases. And we would very much look forward to working with 
Congress to try to find a solution to this issue.

    Senator Cassidy. To the point on it, working with Baldwin 
and Cassidy, because we are the ones who have the bills, just 
to say that, Madam Chair, Mr. Ranking Member. Dr. Shuren, 
Congress has previously directed that the FDA issue 
certificates to foreign governments for FDA approved medical 
devices that are exported from an FDA registered establishment 
outside of the U.S..

    However, instead of doing that, I am told, in 2020, FDA 
established a new form of certificate known as the certificate 
for device not exported from the United States. And this is, as 
I understand it, explicitly says that the FDA has not--does not 
convey that it would be lawful to import the market--or market 
the device in the United States.

    The FDA is the gold standard, this is unnecessarily 
burdensome language, so it seems, and has caused confusion 
among manufacturers and foreign regulators. Congress asked you 
to do this and you have not done it. Can you comment on all 
this?

    Dr. Shuren. Well certainly. There are two different 
situations. The certificate for foreign government is where we 
have a device that is made in the U.S. that has been exported 
to another country. It is subject to requirements in the U.S. 
like oversight on the manufacturing.

    The FDA is in a different position to provide assurances 
regarding that device. Under the new provision, these are 
devices that are made in another country, and they are sent to 
a different country. They are not in the U.S..

    They are not subject to the U.S. requirements. The FDA 
hasn't overseen them. We can't make the same assurances, and we 
do not want to convey to a foreign government something that 
would be incorrect. That said, there may be ways to fix this. 
There are some Members in the House who are interested in doing 
so.

    If there is interest in the Senate, we would be interested 
in working with you or other Members to go ahead and do that.

    Senator Cassidy. May I have a follow-up question? I am 
told, though, that these are devices manufactured in 
facilities, and these facilities export these devices into the 
United States. Presumably that means the facility would then 
have been inspected by FDA.

    FDA does not allow devices to be imported unless they have 
inspected the facility. So I have I been told incorrectly that 
FDA has not inspected these facilities and has not approved 
these devices for sale within the U.S.?

    Dr. Shuren. Well, for devices that are made overseas, and 
they are not for the U.S. marketplace, we would not have 
reviewed----

    Senator Cassidy. That is not what I am asking you.

    Dr. Shuren. Yes----

    Senator Cassidy. If there is a device from a facility, and 
that facility is approved to send the device into the U.S., 
that same facility is sending the same device to another 
country. That is my understanding of the current circumstance 
and that for which a certificate for foreign government was 
directed by Congress to be issued. Now, is my understanding of 
this situation incorrect?

    Dr. Shuren. If that device, sometimes when you deal with a 
device that is made on a different manufacturing line for 
another country, that goes----

    Senator Cassidy. Again, I am not saying that. It is the 
same device brought to the U.S. that is then being sent to 
another country. And so same manufacturing lines, same device, 
it is just going in two different directions. And I think that 
was Congress's intent.

    Dr. Shuren. And that is a point where we think we could 
deal with clarification and then allow for those circumstances.

    Senator Cassidy. And so your point is, it is not clear in 
what Congress previously passed that has that specificity?

    Dr. Shuren. That has been my understanding. But I would be 
happy to get back to you on that.

    Senator Cassidy. Thank you. I yield. Thank you.

    The Chair. Thank you. Senator Baldwin

    I am sorry, Senator Rosen.

    Senator Rosen. Well, thank you, Chair Murray, Ranking 
Member Burr, for holding this important hearing, for our 
witnesses, for your service and participating today. And 
speaking with bills with partners, Senator Cassidy and I have 
quite a few bills too. I am going to talk about one of them 
right here, because as we have discussed previously, 
cyberattacks, of course, are a growing threat to our health 
care sector.

    Senator Cassidy and I have just introduced legislation that 
improves collaboration among agencies to bolster protections 
for the medical field. So as we work to strengthen protection 
for our health system, we must also provide protections for all 
the way down to these medical devices.

    To address this, I am working on additional legislation to 
ensure cybersecurity guidance for medical device manufacturers. 
We want that guidance to be up to date and nimble so that 
Federal resources through CISA, they are easy to understand and 
easy to access for health care providers. So Dr. Shuren, the 
current FDA guidance for medical device cybersecurity is from 
2018 and is in the process of being updated.

    With technology rapidly evolving, has the FDA consider 
updating guidance more frequently, and do you have the 
authority, the tools to update specific sections of the 
guidance that have to--maybe have to change more often to 
protect medical devices from cyber-attacks? Would it be helpful 
for you to coordinate with CISA?

    Dr. Shuren. Well, I completely agree. This is an important 
topic. And it is not just about the security of medical 
devices. This really is about our National Security. We have 
seen a rise in cybersecurity risks and incidents over the past 
few years. We have had to put out 11 communications on this.

    We have folks who are intending to either, they may not be 
intending to go for the medical device, they are in fact 
intending to get to the network system to which the medical 
device connects. We recently updated the guidance that you 
talked about. It was based upon feedback we got on the 2018 
guidance, as well as additional lessons learned. So that is 
currently out for public comment.

    We agree with you, we would like to continue to keep that 
fresh because it is constantly changing. Two things would be 
very helpful. One is, and we have this in the budget proposal 
for this year of 2023, funding for us because we only have 
gotten, and we are thankful for this $500,000 in our base to 
support medical device cybersecurity and that is it.

    We have asked for $5 million. The other is authorities, 
because this is a place where we do not have the full authority 
to assure that these devices are cyber safe. And if we don't, 
we are going to continue to have threats. We have already seen 
the cost of ransomware, medical devices directly impacted and 
patient care directly impacted.

    Senator Rosen. Well, I might suggest that you speak with 
CISA. They have some shields up, a shields up program, other 
programs about good cyber hygiene for companies and might be a 
place that you can direct folks and as we work on getting----

    Dr. Shuren. But we actually are strong partners with CISA. 
We also work with the National Security Council, the National 
Cyber Chief. The little money I got, I was able to hire 
someone. She is working there part time, they took her----

    Senator Rosen. Wonderful.

    Dr. Shuren. We work with the FBI. We work with all those. 
In fact, they depend upon us for the information on medical 
devices, which is why it is so important we have the expertise 
and the authorities to be able to do our part of the job so 
they can do their part of the job.

    Senator Rosen. Wonderful. Thank you. I would like to move 
on and talk about UNLV, University of Nevada, Las Vegas, 
University of Nevada Reno. They both participate in network 
funded in the NIH to enhance translational research.

    UNLV serves as a host institution to advance research in 
Alzheimer's, Parkinson's, and reducing health disparities. And 
UNR has done great work in a wide range of research areas, 
including cancer and diabetes. And we know the translational 
research, bridging the lab concept to impacting patients' 
lives, is an area that, of course, we must continue to 
strengthen. And so the research is happening at lots of 
universities, not just UNLV and UNR. It is critical to the 
pipeline of new treatments and cures.

    Dr. Cavazzoni, does FDA currently provide outreach or 
learning opportunities for early career researchers to better 
understand the regulatory process, what could help advance 
their work to the next level, such as a spinoff company? And 
how can the FDA provide greater support to university research 
collaborations like these?

    Dr. Cavazzoni. Thank you for the question. We have--we do a 
lot of outreach and have partnerships with the academic 
community, and we view it as really an essential part of our 
job, particularly when it comes to translational research, 
because that is research that will allow us--will accelerate 
drug development in areas of unmet medical need by identifying 
new biological targets.

    Also to help us understand potential surrogate markers of 
diseases that might allow us to use the great tools that 
Congress has given us, such as accelerated approval, expedited 
pathways to accelerate the delivery of drugs for--in areas such 
as neuroscience, Alzheimer's, Parkinson's, and so on. So we 
view it as a very important part of our job.

    Senator Rosen. Thank you.

    I yield back, Madam Chair.

    The Chair. Thank you.

    Senator Baldwin.

    Senator Baldwin. Thank you, Madam Chair. I want to 
associate myself with Senator Cassidy's earlier comments 
relating to the Catalyst decision. And I know that I share a 
concern with many Members of the Committee about the ways in 
which drug companies can exploit loopholes in our existing 
laws, and I think Catalyst opens up another opportunity.

    We are obviously looking at reauthorization and would love 
to see our legislation, that I am developing with Dr. Cassidy 
as an amendment in that forthcoming package. I wonder if, Dr. 
Cavazzoni, if you could expand upon the potential impacts of 
this decision in the Catalyst case on patients and what the 
general concerns are at FDA about addressing drug development 
for rare diseases.

    Dr. Cavazzoni. Thank you, Senator. We share the concern and 
want to work with Congress to find a solution. The Catalyst 
decision will send a chill through the development of rare 
diseases, and it will disproportionately affect children with 
rare diseases. It is essential that we continue to generate and 
spur the study of drugs in children. And so this decision will 
really go counter to that.

    I said, the situation right now is that, and as you heard 
from Dr. Marks, the situation following that decision is that a 
sponsor could study a disease in a very narrow segment of the 
population and then be able to block further approvals and 
throughout the entire, the entire condition that drug could 
address. So it is very concerning, and we appreciate Congress's 
interest and look forward to working with you.

    Senator Baldwin. Thank you. Dr. Shuren, I have long been 
concerned about our failure to protect consumers from harmful 
personal care products. As I noted during our last hearing, the 
FDA has extremely limited staff working to make sure that these 
products are safe despite the massive size of this industry. 
So, Dr. Shuren, yes or no, does the FDA have mandatory recall 
authority for personal care products?

    Dr. Shuren. That--although that isn't my particular area, I 
would be happy to take that back to the agency and get you an 
answer on that.

    Senator Baldwin. All right. Is anyone able to answer that 
question at this point, other witnesses?

    Dr. Shuren. My understanding is they don't, but I would 
like to confirm that for you.

    Senator Baldwin. Okay.

    Dr. Cavazzoni. I could try to chime in. So some of the 
over-the-counter products, such as, for instance, hand 
sanitizers are regulated as drugs. And the answer is no, we 
unfortunately do not have a mandatory recall authority for 
drugs, with the exception of biologics, where that authority 
has existed for decades. And that includes over-the-counter 
products that are regulated like drugs.

    What happened with the adulterated or contaminated hand 
sanitizer last year exemplifies the challenges of not having 
that mandatory recall authority for drugs. We had a situation 
where hand sanitizers imported from one particular country were 
contaminated with methanol, which is a poison.

    We had several deaths. We were able to intervene, but we 
could have intervened much faster and much more effectively had 
FDA had a mandatory recall authority for drugs, including over-
the-counter drugs.

    Senator Baldwin. And if you are able, can you describe some 
of the instances in which the agency has requested companies 
voluntarily recall their products?

    Dr. Cavazzoni. We--that is a current process when it comes 
to drugs. We engage with the companies, and we ask them to 
withdraw voluntarily. Some companies, good actors, will do it 
very quickly.

    However, some companies will take some time, and we have to 
engage in lengthy negotiations, often with--dealing with law 
firms who have been engaged on the company's behalf. And that 
takes time. And the clock is ticking when a poison is out there 
and it is either killing or making people blind, like the 
example that I gave you earlier.

    Senator Baldwin. Thank you.

    The Chair. Senator Collins.

    Senator Collins. Thank you, Madam Chair. It only seems 
appropriate, given Senator Baldwin's questions, that I thank 
you, Madam Chair, and Senator Burr, the Ranking Member, for 
working so closely with me and Senator Feinstein on our 
personal products bill, which we have had for two Congresses 
now. And this is an area where there is a gap in regulation, 
and I hope that we will be able to fill it. But I do want to 
thank both of you for--and your staffs for working so closely 
with us.

    Dr. Cavazzoni, the Centers for Medicare and Medicaid 
Services recently finalized the national coverage determination 
for monoclonal antibodies directed at the amyloid plaque for 
the treatment of Alzheimer's disease. Under the NCD, if these 
monoclonal antibodies received accelerated approval, Medicare 
will cover them only in the FDA or NIH approved trials. Now, 
Congress charged the FDA, not CMS, to be the agency responsible 
for evaluating the safety and efficacy of biomedical products.

    But CMS often makes coverage decisions on the basis of 
cost, an area where Congress has not empowered the FDA to weigh 
in. In this case, however, CMS routinely cites concerns about 
patient safety to justify their coverage determination, calling 
into question FDA's ability to evaluate this product class.

    CMS is saying that in order to cover a drug that FDA has 
determined is safe for marketing, more safety data need to be 
generated. In light of the decision by CMS, do you question the 
FDA's decisionmaking regarding Aduhelm's accelerated approval?

    Dr. Cavazzoni. Thank you, Senator. First, I would like to 
emphasize how committed we are to continue to utilize expedited 
pathways, including accelerated approval, to bring medicines to 
underserved populations, such as people suffering from 
Alzheimer's. And our decision on aducanumab exemplifies our 
commitment, and we stand by that by decision. We believe that 
the data are solid, and that the drug is appropriately made 
available to patients based on FDA's decision.

    It is important to distinguish FDA's role and CMS's role. 
So FDA is squarely and solely responsible for determining 
whether a drug is safe and effective. And we made that 
determination when we approved aducanumab. And that 
determination entailed our belief that--represented our belief 
that the drug can be made available to patients. Now, FDA does 
not have a role in making decisions about coverage.

    CMS works in tandem with FDA and have a different standard 
than the safe and effective standard, which is reasonable and 
necessary. And based on that standard, CMS have made decisions 
about coverage and reimbursement, which translate into the 
setting in which they will be covering the drug for their 
beneficiaries.

    Senator Collins. What concerns me in this case is not FDA's 
approach. I think you stayed within your lanes. Whether one 
agrees with the decision or not, you clearly state within your 
lane. But CMS did not because CMS commented not just on the 
reasonableness and the cost, but on the safety.

    My next question for you is, do you think that CMS getting 
outside of its lane and imposing additional restrictions will 
affect the number of pipeline products that may be reviewed 
through this pathway and may be of benefit to those suffering 
from Alzheimer's?

    Dr. Cavazzoni. I cannot--I mean, I am not in a position to 
explain CMS's thinking. Having said so, when it comes to the 
pipeline, it is actually very robust. We have a lot of drugs in 
the pipeline for Alzheimer's disease, including drugs in the 
same class as aducanumab. It would be speculation to try to 
guess whether the decision might or might not impact future 
development.

    Having said so, what I can tell you is that the pipeline is 
very healthy. And we are very encouraged by the advances that 
are taking place in the fields of Alzheimer's and neuroscience 
in general.

    Senator Collins. I guess what I would respond to that is 
CMS is so broad in its coverage decision on this that I fear it 
will discourage research and have an impact on the pipeline of 
drugs. I hope I am wrong about that. My time has expired. Dr. 
Marks, I am just going to just submit for the record a question 
to you. I am receiving complaints that CBER is responding to 
meeting requests with a written response only, which is not 
nearly as valuable as sitting down and talking with drug 
sponsors. So I will submit that for the record, but I do think 
it is an issue.

    The Chair. Thank you.

    Senator Braun.

    Senator Braun. Thank you, Madam Chair. Since I have been 
here in the Senate, I have been a disciple for fixing the whole 
health care system, along with the regulatory agencies that 
feed into it. It is a classic example of huge corporations, I 
think, involved with a very, very large and clumsy Government 
and a lot of it is needed. And Madam Chair refers to the gold 
standard of the FDA. Try explaining that to all of the rare 
disease victims out there and the families that have to contend 
with it.

    I have a bill out there called the Promising Pathways Act, 
that simply says, acknowledge that it is a different dynamic 
when you have got maladies that have a prognosis of 2 to 4 
years, 3 to 5 years, if you are lucky. You know, when we had 
the last hearing I felt that there is not enough attention 
being paid to that.

    Do you think we have got the dynamism within the system 
that can differentiate between two different issues, those that 
have been around for a long while, where there is maybe plenty 
of options, even though the industry does things like patent 
tweaking and so forth--and I am doing this from the point of 
view of patients, employees, and business owners that don't own 
a health care company?

    Let's, Dr. Marks, tell me what you think about, do you feel 
comfortable with the agility and the framework that is 
currently in place to address the issues that I am talking 
about?

    Dr. Marks. So thank you for that question. So we have 
tremendous flexibility that Congress has granted us with use of 
our accelerated approval program. That allows us to use a 
variety of surrogate and intermediate endpoints. It allows us 
to look at products that have been studied in as few as two 
handfuls of patients and potentially approve a product if they 
meet the standard for safety and effectiveness.

    I think we have a tremendous essentially canvas to work 
with. Sometimes I think we have to be more creative with how we 
go about that. Toward that end, we are working in our Center 
toward trying to find ways to allow cell and gene therapies, 
particularly for very small populations. That is perhaps 10, 
20, 30 people in the United States who might be treated with 
these to find their way into the marketplace more rapidly.

    There are some work that has to be done there, and some of 
those actually may interface with some potential legislation 
that is pending that has to do with essentially using platform 
technologies. But we do have a tremendous amount of flexibility 
here. We have approved products on the basis of even eight 
patients worth of data when those data are very sound.

    Senator Braun. Do you think we are using research and 
development from other countries that might be ahead of us--and 
again, I hear, well, that is done somewhere else? You know, we 
need to still run it through the gold standard of our own FDA.

    We don't have the market cornered on all the best ideas. 
And if it is increasingly bureaucratic, and even though you say 
you have the ability to do this, should we be partnering up 
with other analogous agencies and efforts across the world?

    Dr. Marks. Thank you. We are very open to looking at data 
that come from trials conducted overseas. I do agree with you 
that to the extent, particularly for rare disease patients, we 
need to try to work with colleagues globally to benefit 
patients as much as we can. We will continue to do so. And that 
actually has been an area of focus of the Center working 
actually with WHO and partners in Europe.

    Senator Braun. You know, in building a successful business 
over the years, you do two things well. You size up the market 
and you listen to the customers. And in this case, I was 
disappointed in the last hearing, we weren't getting patient 
input. You learn more there at the grassroots level than you 
many times do in the ivory tower.

    I think it would behoove your entity to pay attention to 
the patients, the people out there talking about it, living 
with it. And many of these innovations, these new cures, aren't 
coming from big pharma because they don't get the return on 
investment.

    You may want to look at doing something that gives extra 
help to the smaller companies and the startups that maybe 
wouldn't measure it in the same way. Do you think that has 
merit?

    Dr. Marks. Certainly it does potentially so. Very happy to 
continue to work with you on that.

    Senator Braun. Thank you so much.

    The Chair. Senator Marshall.

    Senator Marshall. Thank you, Madam Chair. My first question 
for Dr. Cavazzoni. Last week we received a letter from 
Commissioner Califf on the FDA's changes to mifepristone risk 
evaluation mitigation strategies for medical termination of 
intrauterine pregnancies up to 70 days of gestation. I want to 
submit for the record a study from the Health Services Research 
and Managerial Epidemiology. And basically it talks about 
chemical abortion increased E.R. visits by 500 percent from 
2002 through 2015.

    As an OBGYN myself, certainly I was the doctor taking care 
of these complications, though I never would have ever 
considered prescribing this drug. Our big concern is this is 
now going to be done over the phone or through telemedicine. 
And based upon my clinical experiences, a woman's guessing of 
her gestational age is exactly that, it is a guess. And trying 
to make that determination, even physically by putting your 
hands on that woman's uterus, is off easily a month or two.

    Really without an ultrasound, I am very concerned about 
this drug being prescribed through telemedicine or over the 
phone. How can the FDA stand by its current policy knowing 
there is a direct correlation between the E.R. visits and the 
chemical abortions, depending upon some other doctors to take 
care of the complications created by another physician or most 
likely a nurse practitioner PA's doing?

    Do you think it is safe to mail these dangerous drugs, even 
potentially to underage women, without going through proper 
diagnostic protocols, including ultrasounds?

    Dr. Cavazzoni. Thank you, Senator. Just to clarify some of 
the aspects of this. As part of litigation that FDA was 
involved in, we undertook a review of the mifepristone, REMS, 
asking ourselves, is the REMS still necessary and should--and 
are any modifications warranted to the REMS based on the data 
that are available?

    Under this exhaustive review of the data, which entailed 
data from our adverse event reporting system, data submitted 
from stakeholders, the litigants, and the sponsor, we concluded 
that the REMS has to stay in place. And the REMS entails a 
requirement for a confirmation of gestational age.

    It is not prescriptive on how that is done. It leaves it up 
to standard of care for the prescriber, but it does require 
confirmation of--evaluation of gestational age. We also 
determined that as part of the REMS modification, the drug is 
safe and effective.

    The benefit outweighs the risk if the in-person dispensing 
requirement is removed. Having said so, we also introduced a 
new requirement for pharmacies to be certified in order to be 
able to dispense the drug.

    These are the safeguards that are in place right now. And 
we believe that those safeguards will ensure that the drug is--
that the drug's benefit outweighs its risks.

    Senator Marshall. Yes, I can only wish the people 
prescribing these drugs were in the E.R. taking care of these 
patients at midnight, and 2 in the morning, and taking care and 
seeing the complications from the drugs themselves. And my 
guess is this will turn into a huge technology financial gig 
for certain companies.

    They will set this up to be very profitable. And many, many 
women are going to be harmed because of your decision. Dr. 
Marks, Senator Cassidy, Smith, and I championed the Ensuring 
Innovation Act, which prevents so-called evergreening, where 
brand name drug makers make not so innovative modifications to 
active ingredients and get additionally exclusivity.

    I am now hearing their brand name drug makers are using 
slight modification in its inactive ingredients, as well as 
something as simple as changing the gauge, so that the next 
biosimilar isn't interchangeable. Does FDA have authority to 
recognize these loopholes and stop it?

    Dr. Marks. So we do have the ability to take care of some 
of this. I am going to pass this to Dr. Cavazzoni, who is--
handles most of these products.

    Dr. Cavazzoni. So thank you for that question. Advancing 
the development of interchangeable biosimilars is a priority of 
the BsUFA program.

    The BsUFA III commitment letter gives us additional tools 
that will allow us to put even more effort into this, including 
the issuance of a very foundational guidances to guide 
developers on how to develop interchangeable biosimilar, as 
well as a new regulatory science pilot program that is really 
geared toward identifying novel approaches in science to 
accelerate the development of interchangeable biosimilars.

    We are aware that there is some interest in Congress to 
also look at clarifying the parameters or the situation around 
exclusivity for biosimilars, to clarify that two biosimilars 
that are approved, interchangeable biosimilars that are 
approved on the same day would be able to share exclusivity.

    We support any new tools that would allow us to continue to 
advance their development.

    Senator Marshall. Thank you, Madam Chair. I am over my 
time. I will submit for the record a question about using 
bioprinting to replace animal models. Thank you.

    The Chair. Senator Hickenlooper.

    Senator Hickenlooper. I am not sure this--is this on? Good 
enough. Thank you for your time and your service. This 
discussion, obviously, we have been in and out watching you on 
zoom and clearly the issues around how the FDA's approval, 
accelerated approval pathway has had great benefits for 
providing patients with serious life threatening diseases with 
timely access.

    But it has come under increased scrutiny, and I know you 
have discussed Aduhelm a little bit earlier. Which it was 
approved against the recommendations of the Independent 
Advisory Committee, and the mismatch with the scientific 
recommendations could just as easily have gone the other way.

    You could have, let's say the FDA did not approve a drug 
that otherwise got unanimous support from the Advisory 
Committee. So Dr. Cavazzoni, why don't we turn to you and say, 
how can we enhance agency processes to promote--to promote at 
the very least transparency, if FDA's decisions diverge from 
that of the Independent Advisory Committee?

    Dr. Cavazzoni. Thank you, Senator. Before I address your 
question directly, I would like to clarify a couple of points. 
As we reviewed the data for aducanumab, we in fact took the 
input from the Advisory Committee into consideration, and we 
actually heard from the Advisory Committee that the data in the 
application did not support approving the drug use in the 
traditional approval pathway.

    We continued to review the data over the months that 
followed the Advisory Committee, and also became aware of 
additional data from other drugs that are developed in the same 
class, we concluded that the data in the application supported 
approving the drug use in the accelerated approval pathway. And 
we are always very, very grateful for the input from our 
Advisory Committees, and we listen very carefully.

    Now there are some areas, when it comes to accelerated 
approval, where we could use some help from Congress. We 
currently work with sponsors to make sure that they meet their 
commitments to conduct confirmatory trials, and they do so 
within the timeframe that we establish that approval.

    Having said so, we don't have the authority to require that 
confirmatory trials be started or underway by the time the drug 
is approved, or if they are not started, that the sponsor 
provide a very detailed plan to conduct those trials in a way 
that is feasible and that will meet the timelines and the 
milestones that we have established.

    Another area where we could use some help in is in 
expediting the withdrawal of drugs when the confirmatory trials 
do not confirm that the drug is associated with clinical 
benefit. And right now the expedited withdrawal path is 
anything but expedited. It will take up to years. It will 
require lots of resources and lots of administrative burden.

    We could use help in shoring up advisory--the very 
important accelerated approval tool that you have given us to--
in those two areas.

    Senator Hickenlooper. Yes, I can imagine that would be very 
difficult, but I appreciate that. I was asking more about 
transparency. When you do have a different result than what the 
Advisory Committee says, right now it is not clearly stated why 
that--why you diverged. You gave an explanation now, but that 
was not what came out then.

    Dr. Cavazzoni. And thank you for clarifying and my 
apologies for not addressing that point. And we have a lot of 
information in our reviews. And the--if one looks at the review 
of aducanumab, for instance, there are hundreds and hundreds of 
pages that will lay our rationale, our thinking about the data 
and our rationale for approving the drug using accelerated 
approval.

    Certainly we welcome additional ways in which we can have 
more transparency in the space. For instance, we already have a 
website that lists all of the surrogate endpoints that are 
being used for accelerated approval and traditional approval.

    Senator Hickenlooper. Great. Thank you. Dr. Marks, I was 
going to ask you about the--how we can leverage the window of 
opportunity we have from this pandemic before what we know will 
be the next pandemic, to see if we can be better prepared.

    Asking how we can help accelerate and encourage biomedical 
research on pathogens of pandemic level concern, so we are 
prepared for future threats. Maybe you can give a 30 second 
answer now, if that is okay with the Chair, and then I will 
submit this in writing, and we can have a more thorough answer.

    Dr. Marks. So in 30 seconds, I think we have to leverage 
what we did best during this pandemic, which was to have very 
good active dialog with those in the development stages of 
this. And to strengthen our manufacturing-type capabilities, so 
that when we do have a new pathogen and we do develop 
something, we are able to manufacture it very rapidly.

    Senator Hickenlooper. Great. Well, so concise.

    I yield back to the Chair.

    The Chair. Thank you.

    Senator Burr.

    Senator Burr. Thank you, Madam Chair. I have one question 
and a few comments. Peter, I can't--excuse me, Dr. Shuren, I 
can't let you get out, Jeff, without talking about TAP. You and 
I sort of look at the same room from two different windows. As 
you know, I am not too excited about it. But let me ask the 
question in this way, what performance goals do you want us to 
put in the statute?

    Dr. Shuren. I think what is in the commitment letter is the 
right place to start. And we will learn from the pilot what is 
the best way to make this work optimally. And from there, we 
will also be well informed about what additional metrics go in. 
I will tell you, quite frankly, I would like to see us shorten 
the time from when you go from concept--it is really the 
development phase, that valley of death.

    You said before, we get so focused on pre-market review, 
but the most important time is everything that leads up to that 
moment, because if you do that right, pre-market review should 
be a coronation. And TAP is about addressing the development 
side of the house. I would love to shrink that.

    Today, it is hard to get the data to really know what real 
time is involved there and how to compare apples to apples for 
different kinds of technology. But that is what I would love to 
see down the road. We are not ready for today.

    Senator Burr. When you leave, I hope you will think about 
this a little bit because I have given you the opportunity to 
tell us what tools we should use to measure the success of the 
pilot program. I want to stress, of the pilot program. Right 
now, I am not sure that there are metrics or guardrails or 
goals that give us something to measure.

    I don't want you to fall into a situation where 3 years 
from now you are coming back and say, we have got to 
permanently put this in, and you have got Members who are 
going, how do we know, or do we just take your word for it that 
it has been successful? I mean, we have got accelerated 
pathways out there, as you know. I think the authority--the 
opportunities already exist for everything you are trying to 
design in TAP. So I think you can do them today. But think 
about it.

    Tell us what you would like to have in statute versus leave 
it up to me, because there will be something in there that I 
think will allow Members to get you in the future. I would 
rather you be the author of it. Peter, just want to comment on 
one thing you said, global collaboration. I agree with you. It 
is robust. It is getting better. But I want to remind you that 
global collaboration and acceptance of foreign data are two 
different things. And the authorities existed at FDA since 1997 
when I did the predominant bill. But we really didn't accept 
foreign data until COVID.

    My hope is that is one of those reflection points that we 
will look going forward at how we use more foreign data in 
substantiation of the applications versus to roll this back. I 
think you guys deserve a tremendous amount of credit going 
through two and a half years of hell.

    Every Center, and the overall FDA, and how you have handled 
it, how you have taken advantage of the authorities that we 
presented that none of us ever knew whether we would ever need, 
but we needed every one of them that were out there, and the 
Chair and I are trying to comb through to figure out how we can 
envision--how visionary we can be in redesigning this for 
things that might be needed in the future for all of you.

    I just can't thank you enough for the performance of the 
individuals that work in each of your centers, because I know 
they have put in long hours over a protracted period of time, 
and unfortunately I don't see yet an endpoint to this.

    I see light at the tunnel, I just don't know whether it is 
a train or the sun. But just to understand, we are in this with 
you together. And Dr. Cavazzoni, I just want to commend you. 
You have been criticized greatly for using--for making a 
decision to approve using endpoints, surrogate endpoints for 
Aduhelm.

    I think it is the right thing to do. I think the point that 
Senator Collins was trying to make is that when we have 
innovation like that, in an area that everybody is out trying 
to find something that helps Alzheimer's patients and other 
disease categories that are out there, and we do an approval at 
FDA, and CMC then limits the people who it would be applicable 
to--even as severely as what they just did. They have just 
crushed the capital markets that financed the development of 
that drug.

    This is sort of my last opportunity to say to you guys. 
What--the capital markets, how they look at what you do and the 
products that come out, is absolutely crucial to our success in 
this Country. If in fact, they are not shareholders that are 
going to invest in these companies, if there is not private 
capital that is chasing that two person innovation bench, Peter 
trying to get that next technology out, whether it is mRNA or 
something else, if they don't see when you approve those 
technologies that you don't have to go back through approval 
when it is used for a new indication, just the clinical trials 
for the new indication, those are the messages we send out 
there to fuel more of this innovation and growth in the market.

    We have had a great success, I believe, and we have got 
another agency of the Federal Government that just absolutely 
cut our legs out from under us. And I would tell you, it is 
going to be devastating if you look at biotechnology and you 
look at how much investment is going into the field right now, 
it is at one of the lowest points that we have seen since it 
has been tracked.

    It is cut in half from where it was pre-pandemic. Don't 
know the reason. But I can assure you that if we want the 
capital to flow for these innovative new technologies that may 
have the key that unlocks the door to this cancer cure or HIV 
aids or something else, we have got to fuel those research 
ventures. It is not going to be discovered internally within 
Government.

    It is going to be some promising person, just like we got--
oh, that is the advantage to getting old, you forget words. But 
we had a breakthrough with one particular scientists, immune--I 
can't come up with it. But it is a whole new category of cancer 
treatment today. You know what I am talking about.

    Had we not financed that from NIH, we wouldn't have that 
fourth or fifth, I can't remember, treatment pathway that we 
have got. All because of one guy. And we can't look out and 
say, here is the one. So we have got to place bets across the 
board, and they have got to have financing to be able to get, 
Jeff, to where you talked about, the valley of death, and then 
we have got to figure out how to get them through it.

    Madam Chair, thank you. I look forward to going forward on 
the Committee's work. Once again, I thank all of you for the 
job that you do, and more importantly, the people that are 
behind you at the agency. Thanks.

    The Chair. Thank you, Senator Burr. Dr. Cavazzoni, just for 
the record, FDA has confirmed the safety and effectiveness of 
mifepristone, which FDA approved, I believe, over 20 years ago. 
Is that correct?

    Dr. Cavazzoni. That is correct. And--my apologies. After 
our review of the REMS, and taking into consideration the 
modifications that we made, we conclude that the benefits 
outweigh the risk, and the drug is safe and effective.

    The Chair. Thank you very much for clarifying that. Dr. 
Shuren, for years I have called on FDA to improve surveillance 
of medical devices to protect patients from infection and other 
dangers. Actually, 7 years ago, I asked my Committee staff to 
investigate a series of dangerous infections in my home State 
of Washington linked to contaminated medical devices. And we 
found at least 25 different outbreaks of antibiotic resistant 
infections connected to the device that sickened over 250 
patients worldwide.

    FDA has to have the tools and resources it needs to ensure 
the safety of medical devices. How does the user fee agreement 
help enhance FDA monitoring of medical devices that are on the 
market?

    Dr. Shuren. Well, currently the scope in MDUFA does not 
include post market surveillance. It certainly was a topic that 
we had raised and discussed in negotiations. We did feel it was 
important to reach accord with industry, to have a consensus 
agreement. I know there were differences of opinion here that 
maybe it would be better to fund it through appropriations.

    That said, I think the agreement we have is still a strong 
one and ultimately does help for patients in assuring timely 
access to safe and effective devices. I think it supports more 
of our work under the Safer Technologies Program, or at least 
it tackles the side of the equation about having safer devices 
on the market, but it does not currently cover once those 
devices are on the marketplace--continued monitoring and 
surveillance----

    The Chair. So post-Market surveillance is not covered?

    Dr. Shuren. Is not currently covered.

    The Chair. Thank you. Thank you for clarifying that. That 
will end our hearing today. And I want to thank all of our 
colleagues for their participation and our witnesses, Dr. 
Cavazzoni, Marks, and Shuren.

    Thank you for joining us today and answering your 
questions. For any Senators who wish to ask additional 
questions, questions for the record will be due in ten business 
days, May 10th at 5 p.m..

    The Subcommittee on Employment and Workplace Safety will 
meet next week on May 3d at 10 a.m. in Dirksen 430 for a 
hearing on connecting workers and communities, preparing and 
supporting the broadband workforce. With that, the Committee 
stands adjourned.

                          ADDITIONAL MATERIAL


   joint prepared statement of patrizia cavazzoni, peter marks, and 
                             jeffrey shuren


    Chair Murray, Ranking Member Burr, and Members of the 
Committee, thank you for the opportunity to testify today on 
the reauthorizations of the Prescription Drug User Fee Act 
(PDUFA), Generic Drug User Fee Amendments (GDUFA), and the 
Biosimilar User Fee Act (BsUFA), Medical Device User Fee 
Amendments (MDUFA) and the Food and Drug Administration's (FDA, 
the Agency, we or our) efforts to deliver timely access to safe 
and effective medications and medical devices for all 
Americans. We appreciate the efforts of Congress and this 
Committee in particular in successfully reauthorizing these 
programs in previous cycles, and look forward to continuing our 
partnership this year.

                                 PDUFA

    The PDUFA VII reauthorization proposal described below was 
submitted to Congress on January 12, 2022. The Administration 
looks forward to working with Congress on reauthorization of 
PDUFA to continue to speed the development and approval of 
vital drugs and biologics that are safe and effective.

    The timely review of the safety and effectiveness of new 
drug applications (NDAs) and biologics license applications 
(BLAs) is central to FDA's mission to protect and promote the 
public health--and PDUFA is essential to these efforts.

    FDA is committed to scientific quality and integrity during 
its review process for marketing applications to ensure that 
the medications we approve are safe and effective for American 
patients. Before PDUFA's enactment in 1992, the Agency lacked 
sufficient staff to perform timely reviews or develop 
procedures and standards to ensure a consistent and predictable 
premarket review process. As a result, Americans' access to 
innovative, new medicines often lagged behind other countries.

    The enactment of PDUFA I in 1992, and subsequent 
reauthorizations, have addressed these challenges. 
Specifically, PDUFA authorizes FDA to collect industry user 
fees to, among other things, hire additional staff, and manage 
and enhance information technology systems. The user fees 
collected under PDUFA have enabled the Agency to speed the 
application review process for new drugs and biological 
products without compromising FDA's high standards for new drug 
safety, efficacy, and quality.

     Speeding Americans' Access to Safe and Effective New Therapies

    PDUFA revolutionized the United States' drug approval 
process. It reversed the lag in drug approvals that prompted 
its creation, providing Americans with more timely access to 
safe and effective medical products.

    The PDUFA program began with a general focus on shortening 
review times, and its scope has expanded beyond the time for 
review of an application. The 5-year reauthorization cycles for 
PDUFA support continuous program innovation, evaluation, and 
improvement. The enhancements to the process for the review of 
human drug applications originally focused on the FDA pre-
market review of NDAs and BLAs. Through successive PDUFA 
reauthorizations, program enhancements have evolved and 
expanded to include extensive communication and consultation 
between drug sponsors and FDA throughout the drug development 
process. These enhanced interactions give us the opportunity to 
provide more guidance to sponsors, including setting clearer 
expectations of what data are necessary to properly review and 
evaluate a drug, improving the potential for first-cycle 
approval, and getting safe and effective drugs to patients 
sooner--supporting FDA's mission. These interactions also 
enable sponsors to incorporate advances in regulatory science 
into their development programs, expediting drug development 
and facilitating timely regulatory decisions.

    As discussed in more detail below, PDUFA VI included 
additional resources for breakthrough therapy review to 
expedite those products that offer early promise of benefit 
over existing therapies, initiated pilot programs for complex 
innovative trial designs and model-informed drug development, 
and expanded the provisions of the 21st Century Cures Act 
(CURES) in its focus on activities for patient-focused drug 
development and use of real-world evidence (RWE) in regulatory 
decisionmaking. The continued modernization of drug review 
under PDUFA is supported by FDA's enhancements in informatics 
and hiring practices, including the Agency's implementation of 
hiring authorities under CURES to bring top talent to the 
Agency enabling us to consistently meet or exceed PDUFA 
commitments.

    With these enhancements the United States continues to be a 
global leader in drug innovation and Americans are now 
typically the first to benefit from new safe and effective 
medicines. As shown in the figure below, this is a consistent 
pattern for novel drugs and biological products and while it 
may also be influenced by other factors, e.g. economics, it 
would not be possible without a robust approval process that is 
predictable and efficient. As shown in Figure 1, today, almost 
two-thirds of new active substances approved in the world 
market are launched first in the United States.

  Figure 1: U.S. Share of New Active Substance Launched on the World 
                           Market, by region


    *New active substances (NASs): new chemical or biological 
entities where the active ingredient had received no prior 
approval for human use.

    Throughout this program evolution, FDA has continued to 
review large volumes of submissions and to deliver predictably 
high levels of performance against PDUFA goal commitments for 
timely regulatory review, as shown in Figure 2, below. This was 
accomplished even as FDA witnessed an unprecedented increase in 
submissions during the COVID-19 pandemic, and as FDA 
facilitated the development of therapeutics and vaccines, 
resulting in the authorization and approval of numerous COVID-
19 vaccines and treatments.

    *Goal 90 percent

Figure 2: FDA Review Performance--FY 2021: Percent of Submissions Acted 
                          on by Goal Date \1\
---------------------------------------------------------------------------

    \1\  NME = New Molecular Entity; NDA = New Drug Application; BLA--
Biologic Licensing Application


      Increasing the Timeliness and Efficiency of Premarket Review

    A key element of the success of the PDUFA program is the 
ongoing development-phase consultation FDA provides to drug 
sponsors. FDA's capacity to provide sponsors, including small 
first-time innovators, with timely advice enabled by PDUFA 
funding, has contributed to the strong drug development 
pipeline in the United States today. This is reflected in the 
increased numbers of drug development programs underway 
(measured by commercial INDs with activity), and the 
corresponding growth in company requests for development-phase 
meetings, as shown in Figure 3.

Figure 3: fiscal year 2004, 2016, and 2021 Formal Meeting Requests and 
      FDA Commercial Investigational New Drug (INDs) with Activity


    The volume of formal meetings requested by drug sponsors 
has steadily grown over the course of PDUFA. Early and frequent 
communication between sponsors and FDA serves to improve the 
efficiency of drug development. These meetings help sponsors 
navigate key milestones during drug development, increase the 
likelihood of well-designed and executed studies, and enable 
sponsors to clarify requirements for complete application 
submissions and potentially avoid the need for an additional 
review cycle, translating into earlier treatments and cures for 
patients.

    The improvement in the quality of drug development programs 
and the submitted applications, supported by these PDUFA-
enabled consultations, is an important factor that explains the 
87 percent first cycle approvals (52 of 60) of applications for 
new molecular entity (NME) NDAs and BLAs. Figure 4 provides key 
attributes of NME approvals for the calendar year 2021.

  Figure 4: CY 2021 New Molecular Entity (NME) and Original Biologics 
                         Approvals by Category



    Development-phase consultations can be particularly helpful 
in support of the most innovative or challenging drug 
development programs. For instance, of the NME, NDAs, and BLAs 
that FDA approved in calendar year 2021, close to half (47 
percent) were indicated for rare diseases. In addition, over 
half (61 percent) of the drugs and biologics approved were 
first in their class, i.e., drugs and biologics with different 
mechanism of action from existing therapies.

    While the standard review target for NMEs and original 
biologics submissions that are filed is 10 months after the 60-
day filing date, \2\ FDA expedites review for eligible drugs 
through a priority review, with a goal to review drugs within 6 
months after filing. Priority review is generally targeted at 
drugs for serious conditions that, if approved, would provide 
significant improvements in safety or effectiveness in safety 
or effectiveness in safety or effectiveness. \3\ In 2021, 43 of 
60 NMEs and original biologics (72%) were designated for 
priority review.
---------------------------------------------------------------------------
    \2\  There is a 60-day filing review period, which begins on the 
date FDA receives the application, to ensure the application is 
substantially complete and meets filing requirements. For non-NMEs the 
standard review target is 10 months after receipt date not the 60-day 
filing date.
    \3\  Priority review is also available for a drug designated as a 
qualified infectious disease product, certain supplements that propose 
a labeling change pursuant to a report on a pediatric study, or an 
application or supplement submitted with a priority review voucher.

    Many drugs and biological products that receive priority 
review also benefit from other expedited programs intended to 
accelerate development, such as fast track designation and 
breakthrough designation. Both these programs offer greater 
interactions between sponsors and FDA reviewers throughout the 
development process, including FDA providing advice on the 
design and implementation of the clinical trials necessary to 
demonstrate product safety and effectiveness. In addition, 
breakthrough designation typically includes greater involvement 
of FDA leadership. For cell and gene therapies, the 
Regenerative Medicines Advanced Therapy (RMAT) designation 
program is designed to expedite the review of cellular and gene 
therapy, therapeutic tissue engineering product, human cell and 
tissue product, or any combination product using such therapies 
for which preliminary clinical evidence indicates that the 
product has the potential to address unmet medical needs for 
such disease or condition. RMAT designated products receive the 
same benefits as breakthrough therapies and approval of cell 
and gene therapies that have RMAT designation may be able to 
fulfill post-approval requirements by other than traditional 
---------------------------------------------------------------------------
clinical studies.

    Accelerated approval, another expedited program, also 
speeds the development process by shortening premarket clinical 
trials using a surrogate endpoint reasonably likely to predict 
clinical benefit with a requirement to confirm clinical benefit 
in the post market setting. Thirty-nine of the 60 NME approvals 
of 2021 (65 percent) used one or more expedited programs, 
specifically fast track designation, breakthrough designation 
and/or accelerated approval.

                                COVID-19

    As part of the government wide response to the COVID-19 
pandemic, the Agency has been working around the clock over the 
past 2 years to facilitate the development and availability of 
therapeutics and vaccines as expeditiously as possible. FDA 
accelerated the development and publication of guidance and 
other information for industry and researchers on developing 
COVID-19-related treatments and vaccines.

    In March 2020, FDA announced the creation of an emergency 
review and development program for possible therapies for 
COVID-19, the Coronavirus Treatment Acceleration Program, or 
``CTAP.'' The primary goal of CTAP is to help accelerate the 
development of therapeutics for patients and consumers. The 
Agency supported the program by reassigning staff and working 
continuously to review requests from companies and researchers 
who are working to develop therapies. Under CTAP, FDA is using 
every available authority and appropriate regulatory 
flexibility to facilitate the development of safe and effective 
products to treat patients with COVID-19. As of February 28, 
2022, there were more than 690 drug development programs in the 
planning stages and we reviewed more than 470 trials of 
potential therapies for COVID-19. These include antivirals, 
immunomodulators, neutralizing antibodies, cellular and gene 
therapies, and combinations of these products. The diversity of 
therapeutic approaches being investigated is important because 
it rapidly expands our understanding of the effect of different 
categories of potential treatments. In addition, drugs have 
been identified that meet the standard for emergency use 
authorization, and FDA has acted to make these products 
available while continuing to collect information about their 
safety and effectiveness. As of April 18, 2022, the Agency 
authorized 15 drugs and non-vaccine biological products and 
approved one antiviral drug. Notably, these drugs are 
authorized or approved for the continuum of medical needs, from 
pre-and post-exposure prophylaxis, to treatment of outpatients 
with mild-moderate disease, to treatment of hospitalized 
patients with severe or critical COVID-19.

    As of April 18, 2022, FDA has authorized three COVID-19 
vaccines. All three vaccines are authorized for individuals 18 
years of age and above with one of these vaccines authorized 
for individuals as young as 5 years of age. FDA has also 
approved two COVID-19 vaccines, one of these vaccines is 
approved for individuals 16 years of age and above and the 
other is approved for individuals 18 years of age and above.

    In addition to providing access through authorizations and 
approvals, since the start of the pandemic, as of February 3, 
2022 CDER has authorized over 2,100 expanded access requests 
for COVID-19 therapeutics, including emergency requests and 
CBER authorized 6,306 expanded access requests, 6,084 (96 
percent) of which were in support of COVID-19 convalescent 
plasma.

    Over the past 2 years, FDA has continued to work at a pace 
that is unprecedented, and not sustainable outside of an 
emergency, to deliver authorized and approved therapeutics and 
vaccines with unparalleled speed to the meet critical public 
health needs. Notwithstanding the increased workload, the 
average time between the request and meeting with sponsors for 
COVID-19 products was reduced by 50 percent. Although not all 
COVID-19 work is supported by user fees, without the staff, 
expertise and infrastructure provided by PDUFA user fees, our 
COVID-19 efforts would have been impossible to carry out. 
Furthermore, it is a testament to the seriousness with which we 
take our commitments under PDUFA that we continued to succeed 
in meeting key PDUFA commitments in the face of a large 
increase in non-PDUFA COVID-19 work. For instance, in fiscal 
year 2020 FDA received 46 percent more new INDs and 26 percent 
more formal meeting requests compared to fiscal year 2019.

                  PDUFA VI_Fulfilling Our Commitments

    We are currently in the final year of the PDUFA VI program. 
Since the enactment of PDUFA I in 1992, the complexity of 
scientific and clinical issues in the study of new drugs has 
grown, including the use of genetic targeting, biomarkers, 
novel trial designs, and plans and programs to ensure effective 
post-market risk management relying on the Sentinel system, one 
of the largest RWE sources in the United States. In addition, 
PDUFA has enabled FDA to provide increased communication and 
consistent guidance during drug development and application 
review, a top priority for drug sponsors.

    PDUFA VI (FY 2018 to fiscal year 2022) built upon the 
achievements of PDUFA V and committed the Agency to numerous 
initiatives to ensure the continued success of the human drug 
review program including:

         LCapturing the patient voice in drug 
        development;

         LEnsuring sustained success for breakthrough 
        therapies;

         LEnhancing biomarker development;

         LAdvancing the use of complex innovative trial 
        designs and model-informed drug development;

         LStreamlining the review of combination 
        products;

         LEnhancing the use of RWE;

         LHiring and retaining highly qualified staff; 
        and

         LEnhancing the management and transparency of 
        user fee resources.

    The Agency's progress on these priorities is detailed 
below.

            Capturing the Patient Voice in Drug Development

    Elevating patient voices in developing new drugs to treat 
their diseases and conditions was a central part of PDUFA VI. 
The commitments in PDUFA VI complemented the patient focused-
drug development (PFDD) provisions in the CURES Act by 
leveraging essential patient input and insights to fight 
disease.

    Under the PDUFA VI authorization, the Agency focused on a 
series of four methodological PFDD guidance documents to 
address, in a stepwise manner, how stakeholders can collect and 
submit patient experience data and other relevant information 
from patients and caregivers. This series of guidance documents 
is intended to facilitate the advancement and use of systematic 
approaches to collect and use robust and meaningful patient and 
caregiver input that can better inform medical product 
development and regulatory decisionmaking.

    In addition, over the course of PDUFA VI, FDA engaged with 
patient advocacy groups to support their conduct of 54 
externally led PFDD meetings and convened five public workshops 
to allow the patient voice to inform not only the above 
guidances but other disease specific development programs.

         Ensuring Sustained Success for Breakthrough Therapies

    The Breakthrough Therapy designation program is designed to 
expedite the review of therapies for serious conditions that 
show preliminary clinical evidence of a substantial improvement 
on a clinically significant endpoint over available therapy. 
This program has become a critical component of the human drug 
review program with requests and designations far exceeding 
expectations. PDUFA VI sought to ensure the sustained success 
of the breakthrough program by investing additional resources 
into the program. For the first 4 years of PDUFA VI, fiscal 
year 2018--fiscal year 2021, FDA received 586 breakthrough 
requests and granted 248. Drugs approved during PDUFA VI with 
breakthrough therapy designation include many new options for 
both adult and pediatric patients with cancer. Targeted 
oncological therapies with breakthrough designation included 
treatment for metastatic cancers with NTRK fusion proteins and 
a host of new treatments for non-small cell lung cancer 
targeting clinically relevant biomarkers--ALK, EGFR, MET, RET 
and KRAS. In addition, novel treatments with breakthrough 
designation were approved across many other cancers including 
breast cancer, bladder cancer, lymphoma, cholangiocarcinoma and 
rare tumors such as tenosynovial giant cell tumor and plexiform 
neurofibromas. Rare disease approvals during this period 
included the first triple therapy for the most common cystic 
fibrosis mutation, the first therapy to treat heart disease 
(cardiomyopathy) caused by transthyretin mediated amyloidosis, 
treatment for Hutchinson-Gilford progeria syndrome, and the 
first therapy for thyroid eye disease.

                    Enhancing Biomarker Development

    FDA and industry share the goals of the CURES Act and PDUFA 
VI to accelerate development of reliable biomarkers to advance 
important new therapies. Biomarkers are currently used 
throughout the drug development process, including as surrogate 
endpoints to support earlier evidence of effectiveness for 
regulatory decisionmaking when evidence from a clinical 
endpoint could take much longer or require many more patients 
to be studied.

    A surrogate endpoint that is well established to predict 
clinical benefit, such as blood pressure as a predictor of risk 
of stroke, or viral load in certain infectious diseases, is 
considered validated and can be used to support traditional 
approval. Other surrogate endpoints are those for which there 
is evidence that they are reasonably likely to predict an 
improvement in a clinical outcome. Such surrogate endpoints may 
be used to approve a drug under accelerated approval for a 
serious or life-threatening disease for which there are not 
adequate therapies. For accelerated approvals, FDA requires 
post-marketing studies to verify the expected clinical benefit. 
FDA publishes a list of surrogate endpoints that have been used 
to support drug approval or licensure that includes whether the 
surrogate endpoint was used to support traditional or 
accelerated approval whether the surrogate endpoint was used to 
support traditional or accelerated approval whether the 
surrogate endpoint was used to support traditional or 
accelerated approval. \4\
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    \4\  https://www.fda.gov/drugs/development--resources/table--
surrogate--endpoints--were--basis--drug--approval--or--licensure

    Meaningful progress in developing additional biomarkers for 
public qualification requires a sustained effort and 
collaboration among a wide range of stakeholders. The Agency 
continues to have success via the Biomarker Qualification 
Program. In 2018, FDA qualified two additional biomarkers, one 
a safety biomarker panel to aid in the detection of kidney 
injury in early trials and the second a biomarker to monitor 
malaria treatment. Other promising biomarkers have progressed 
to the Qualification Plan stage, including biomarkers for 
important diseases such as inflammatory bowel disease, 
Parkinson's disease, emphysema, non-alcoholic steatohepatitis, 
osteoporosis and others. FDA continues to work with the 
National Institutes of Health, the Biomarkers Consortium, the 
Critical Path Institute and others to advance biomarker 
development under PDUFA VI.

            Streamlining the Review of Combination Products

    More streamlined review of combination products is another 
FDA and industry priority reflected in PDUFA VI. Combination 
products are therapeutic and diagnostic products that contain 
two or more types of medical products as constituent parts: a 
drug and device, a drug and biologic, a biologic and device, or 
all three (drug, biologic, and device).

    Under PDUFA VI, FDA assessed combination product review 
practices. Based on the resulting recommendations, FDA pursued 
improvements in inter-center and intra-center combination 
product review coordination, consistency, and transparency for 
PDUFA products that are combination products regulated by CDER 
and CBER (PDUFA combination products), including through IT 
enhancements and training. FDA published several guidances 
regarding combination products to review more efficiently, 
effectively, and consistently combination products, including 
guidance that describes the ways in which combination product 
sponsors can obtain feedback from FDA on scientific and 
regulatory questions as well as best practices for FDA and 
sponsors when interacting on these topics. \5\
---------------------------------------------------------------------------
    \5\  https://www.fda.gov/combination-products/guidance-regulatory-
information/combination-products-guidance-documents
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    Advancing the Use of Complex Innovative Trial Designs and Model-
                       Informed Drug Development

    FDA routinely works closely with industry to facilitate 
innovative approaches to drug development that maintain our 
high standards for drug safety and efficacy. PDUFA VI 
encouraged these efforts by advancing Model-Informed Drug 
Development (MIDD) and the use of Complex Innovative Trial 
Designs (CID).

    To fulfill the goals and commitments of PDUFA VI, the 
Agency developed the MIDD Pilot Program \6\ and the CID Pilot 
Meeting Program. \7\
---------------------------------------------------------------------------
    \6\  https://www.fda.gov/drugs/development--resources--model--
informed--drug--development--pilot--program
    \7\  https://www.fda.gov/drugs/development--resources--complex--
innovative--trial--design--pilot--meeting--program

---------------------------------------------------------------------------
    The MIDD Pilot Program is designed to:

         LProvide an opportunity for drug developers 
        and FDA to discuss the application of MIDD approaches 
        to the development and regulatory evaluation of medical 
        products in development; and

         LProvide advice about how particular MIDD 
        approaches can be used in a specific drug development 
        program.

    Under the pilot program, FDA accepts two to four paired-
meeting requests for meetings each quarter. For each meeting 
request granted as part of the pilot, FDA conducts an initial 
and follow-up meeting on the same drug development issues to 
occur within a span of approximately 120 days. Under the pilot 
program from fiscal year 2018--fiscal year 2021, FDA received 
46 meeting requests and granted 38 of those requests. The total 
number of sponsor meetings during that time period was 43. The 
meeting requests spanned 14 different therapeutic areas--
cardiology, oncology, non-malignant hematology, neurology, 
infectious disease, immunology/inflammation, dermatology, 
pulmonary, psychiatry, gastroenterology, ophthalmology, 
endocrinology, nephrology, and hepatology.

    The CID Pilot Meeting Program developed under PDUFA VI is 
designed to:

         LFacilitate the use of complex adaptive, 
        Bayesian, and other novel designs in late-stage drug 
        development; and

         LPromote innovation by allowing FDA to 
        publicly discuss the trial designs considered through 
        the pilot meeting program, including trial designs for 
        medical products that have not yet been approved by 
        FDA.

    Under the pilot meeting program, FDA accepts up to two 
meeting requests per quarter yearly. For each meeting request 
granted as part of the pilot, FDA conducts two meetings on the 
proposed CID within a span of approximately 120 days. From 
fiscal year 2018--fiscal year 2021, the CID pilot program 
received 15 meeting requests--13 for CDER and 2 for CBER--and 
granted five of the CDER meeting requests. The total number of 
sponsor CID meetings was 16, as FDA granted additional meetings 
during the 120-day span. The meeting requests spanned seven 
different therapeutic areas--neurology, oncology, malignant 
hematology, non-malignant hematology, pain, rheumatology, and 
gastroenterology.

             Enhancing the Use of Real-World Evidence (RWE)

    Medical care and biomedical research are amid a major 
transformation with data from electronic health records, 
insurance claims data bases, patient registries, digital health 
technologies, and other new sources comprising an immense new 
set of information about health and healthcare. Sponsors and 
the research community are seeking to take advantage of the 
quantity of data generated in routine medical practice to help 
inform regulatory decisions about the safety and effectiveness 
of drugs. Importantly, these real-world data (RWD) sources 
provide data about patients outside of structured clinical 
trial visits and in the social context of their day-to-day 
lives. These sources of data are now becoming increasingly 
available to researchers, clinicians, and patients with the 
potential to improve medical care and public health.

    FDA recognizes the potential value of utilizing RWD to 
generate RWE in evaluating not only the safety of medications 
but also their effectiveness. Under PDUFA VI, the Agency 
continues to fulfill our commitment to enhance the use of RWE. 
The Agency has conducted multiple demonstration projects, 
engaged with external stakeholders, and to date published four 
guidances on the use of RWE in regulatory decisionmaking. For 
example, FDA published draft guidance with recommendations on 
using data from electronic health records, medical claims, 
registries, and data standards for applicable submissions 
containing study data derived from RWD sources. In addition, 
another draft guidance describes regulatory considerations for 
the design and conduct of non-interventional (or observational) 
studies.

             Hiring and Retaining Highly Qualified Experts

    To efficiently conduct reviews of human drug applications 
and meet PDUFA commitments, FDA must be able to hire and retain 
sufficient numbers and types of technical and scientific 
experts. To strengthen this core capability during PDUFA VI, 
FDA established a modernized position management system, more 
efficient recruiting practices, a dedicated scientific 
recruiting function and metric goals for human drug review 
staff hiring. We also conducted a comprehensive independent 
assessment of hiring and retention system performance. The 
Agency thanks the Committee for providing vital hiring 
authorities in the CURES Act, greatly improving FDA's ability 
to hire and retain scientific experts in more complex and 
specialized areas and meet our growing responsibilities.

    The Agency continues to put every effort into meeting our 
hiring goals under PDUFA VI. FDA is committed to hiring 230 
Full-Time Equivalents (FTEs) from fiscal year 2018 to fiscal 
year 2022 as agreed upon in the PDUFA VI commitment letter. FDA 
has successfully hired 212 FTEs of the 230 FTEs (92 percent) as 
of September 30, 2021.

             Enhancing the Management of User Fee Resources

    FDA is committed to enhancing management of PDUFA resources 
and ensuring PDUFA user fee resources are administered, 
allocated, and reported in an efficient and transparent manner. 
Under PDUFA VI, the Agency established a resource capacity 
planning function to improve its ability to analyze current 
resource needs and project future resource needs, modernized 
its time reporting approach (e.g., ?99 percent of CDER and CBER 
employees time report), conducted an evaluation of PDUFA 
program resource management, and published a 5-year PDUFA 
financial plan with annual updates. \8\
---------------------------------------------------------------------------
    \8\  https://www.fda.gov/about-fda/user-fee-reports/user-fee-five-
year-financial-plans

    In 2020, FDA embarked on its own initiative--not a PDUFA 
commitment--to modernize the New Drugs Regulatory Program. \9\ 
These changes are intended to improve efficiency and 
consistency of our work to free up resources so that our 
scientists have more time to focus on the increasing challenges 
of drug development, particularly for unmet medical needs, and 
on the multiple collaborations needed to make sure candidate 
drugs are developed and assessed properly, with appropriate 
input from external scientists, expert physicians, and patient 
communities. The initiative includes regulatory and review 
process changes, as well as organizational restructuring and 
strengthening the institutional support structures, including 
personnel and information technology (IT), that underpin the 
regulatory process.
---------------------------------------------------------------------------
    \9\  https://www.fda.gov/drugs/regulatory--science--research--and--
education--reorganization--office--new--drugs--corresponding--changes--
office--translational--sciences--and--office
---------------------------------------------------------------------------

                       PDUFA VII Reauthorization

    As part of PDUFA VI, Congress directed the Agency to reach 
out to all stakeholders to solicit thoughts and insights on 
PDUFA reauthorization and changes to PDUFA performance goals. 
FDA followed the process, as described in statute, in 
developing the recommendations for reauthorization. This 
included holding two public meetings, conducting negotiations 
with the regulated industry, and having regular consultations 
with stakeholders, including patient and consumer advocates. To 
ensure transparency in this work, the Agency posted the meeting 
minutes for the various engagements, including: the two public 
meetings; over 100 negotiation sessions with industry, and six 
stakeholder discussions. \10\
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    \10\  https://www.fda.gov--industry--prescription--drug--user--
fee--amendments--pdufa--vii--fiscal--years--2023--2027
---------------------------------------------------------------------------

                           PDUFA VII Overview

    Based on the maturity and success of the PDUFA program, the 
recommendations for PDUFA VII focus on ensuring FDA has 
capacity to review new and innovative products, including cell 
and gene therapy products. To provide the capacity needed to 
successfully implement the commitments outlined below, while 
maintaining current performance, PDUFA VII recommends 
increasing fees to fund 352 new staff and to support critical 
investments in program infrastructure, such as data IT 
modernization. The new staff and investments are scheduled to 
phase in over the 5-years of PDUFA VII.

    The commitments thematically fall into the following 
categories:

         LEnhancing CBER's capacity to support 
        development, review, and approval of cell and gene 
        therapy products and new allergenic extract products;

         LImproving pre-market review processes and 
        procedures;

         LEnhancing regulatory science to expedite drug 
        development;

         LEnhancing regulatory decision tools to 
        support drug development and review;

         LContinuing enhancement and modernization of 
        the drug safety system;

         LEnhancing product quality reviews, chemistry, 
        manufacturing, and controls (CMC) approaches, and 
        advancing the utilization of innovative manufacturing 
        technologies;

         LContinuing enhancements for management of 
        user fee resources;

         LImproving FDA's hiring and retention of key 
        scientific and technical talent; and

         LEnhancing IT and bioinformatics goals.

Enhancing CBER's capacity to support development, review, and approval 
 of cell and gene therapy products and new allergenic extract products

    FDA has experienced exponential growth in cellular and gene 
therapy submissions over the past 7 years with over 1,993 
active, development programs. We have seen a sustained increase 
in development program activities, including an 85 percent 
increase in original IND receipts, a 139 percent increase in 
IND amendment receipts, and a 158 percent increase in formal 
meeting requests. In addition, the RMAT program has advanced 
the development of a wide variety of cellular and gene 
therapies with many including orphan designations and for 
pediatric populations. From program initiation in December 2016 
through 2021, 68 of 180 requests have received RMAT designation 
with three RMAT designated products receiving approval in 
2021--two allogenic cellular products, one for immune 
reconstitution in pediatric patients with congenital athymia, 
one for wound healing, and a CAR-T gene therapy for B-cell 
lymphoma.

    Therefore, PDUFA VII proposes new enhancements to CBER's 
capacity to support development, review, and approval of cell 
and gene therapy products to accommodate the current and 
expected influx of work in the coming years. The proposal will 
support development of multiple guidances, numerous public 
meetings to examine new technologies and approaches, a patient-
focused drug development meeting to better understand patient 
perspectives on gene therapy products, and public outreach to 
facilitate product development and approval. In addition, if 
the negotiated commitments are adopted, new allergenic extract 
products will be included in PDUFA VII, and the program will 
provide needed resources to facilitate the development and 
approval of new therapies, including those for food allergens, 
which constitute most new allergenic extract products under 
development.

          Improving pre-market review processes and procedures

    Communication during drug development continues to be 
critical to successful drug development. PDUFA VII proposes 
several enhancements to the current robust communication 
framework. PDUFA VII proposes exploring a new pilot program for 
certain efficacy supplements, i.e., when a sponsor is seeking a 
new indication for an already approved product that would 
support review earlier than would otherwise occur with the goal 
of expediting patient access to novel uses for existing 
therapies. The proposal also seeks to expand communication and 
feedback during the drug development process by creating two 
new formal meeting types and allowing for follow-up 
opportunities after meetings.

    Finally, the commitment letter also includes new 
performance goals for pre-approval review of postmarketing 
requirements (PMRs), studies done after a drug is on the market 
to further explore efficacy and or safety to ensure timely 
availability of information on the safety and efficacy of 
therapies. In addition, it includes a new process for reviewing 
sponsor-initiated requests to release the applicant from the 
requirement to perform a PMR study.

Enhancing regulatory science and decision tools to expedite development

 Model-Informed Drug Development (MIDD) and Complex Innovative Design 
                                 (CID)

    PDUFA VII proposes to further enhance regulatory science 
and to expedite drug development by continuing FDA's successful 
CID and MIDD programs. Specifically, the proposed CID program 
will continue to facilitate the advancement and use of complex 
adaptive, Bayesian, and other novel clinical trial designs. The 
MIDD program will also continue to further advance and 
integrate the development and application of exposure-based, 
biological, and statistical models in drug development and 
regulatory review.

            Advancing Development of Drugs for Rare Diseases

    In addition, building on the success of the rare disease 
programs in CDER and CBER, a new pilot program will be launched 
to advance rare disease drug development by providing a 
mechanism for sponsor discussion with FDA to facilitate the 
endpoint development process--often a critical challenge in 
efficient trial design.

          Advancing RWE for Use in Regulatory Decision-Making

    FDA will also build on its current RWE program with a new 
pilot program that seeks to improve the quality and 
acceptability of RWE-based approaches in support of new 
labeling claims, including approval of new indications of 
approved medical products, or to satisfy post-approval study 
requirements.

     Enhancing Use of Digital Health Technologies to Support Drug 
                              Development

    Recognizing the growth of digital health technology (DHT) 
and that remote data acquisition from patients and clinical 
trial participants has the potential to measure a wide range of 
activities, behaviors, and functioning in real-life settings 
that can inform important clinical endpoints, PDUFA VII 
proposes to establish a framework to guide the use of DHT-
derived data in regulatory decisionmaking. FDA will undertake 
workshops and demonstration projects to inform this work and 
will address standardized processes for data management and 
analysis of large data bases from digital health tools.

            Furthering the Patient Voice in Drug Development

    PDUFA VII proposes to continue to enhance decisions to 
support drug development and regulatory review by advancing the 
patient's voice in drug development and decisionmaking through 
PFDD, including training and public workshops, and issuing 
guidance on the use and submission of patient preference 
information.

             Furthering the Review of Combination Products

    As noted, under PDUFA VI, the Agency took steps to 
facilitate the review and approval of combination products. 
PDUFA VII would add to these activities by introducing new 
procedures and timelines for use-related risk analysis and 
human factor validation study protocols as part of the 
combination products review process.

   Continuing enhancement and modernization of the drug safety system

    PDUFA VII proposes to continue enhancement and 
modernization of FDA's robust drug safety system by modernizing 
and improving Risk Evaluation and Mitigation Strategy 
assessments, including updates to guidances, policies and 
procedures, and new review performance goals. The proposal will 
optimize the Sentinel Initiative capabilities by enhancing 
analytic functions to help inform labeling on the safety of 
product use in pregnancy, to detect safety signals in a timely 
manner, and to advance the understanding of how RWE can be used 
to study effectiveness.

   Enhancing product quality reviews, chemistry, manufacturing, and 
controls (CMC) approaches, and advancing the utilization of innovative 
                       manufacturing technologies

    PDUFA VII proposes new enhancements related to product 
quality reviews, chemistry, manufacturing, and controls (CMC) 
approaches, and advancing the utilization of innovative 
manufacturing technologies by enhancing communication to 
promote more efficient and effective review through more 
structured CMC information requests. Also included is a 
commitment to notify sponsors in advance of facility 
inspections where FDA needs to see the product being 
manufactured. Under the proposal, the Agency will issue 
guidance on FDA's thinking on the use of alternative tools to 
assess manufacturing facilities included in pending 
applications (such as alternative tools utilized during the 
COVID-19 pandemic). The proposal will also initiate a new pilot 
program to facilitate and expedite CMC development for products 
with accelerated clinical development timelines. Last, PDUFA 
VII proposes to advance the utilization and implementation of 
innovative manufacturing technologies through a public workshop 
and a published strategy document.

      Continuing enhancements for management of user fee resources

    PDUFA VII proposes to continue to enhance management of 
user fee resources by advancing FDA's resource capacity 
planning function and adjustment methodology, including a 
third-party evaluation of the methodology by 2025. The proposal 
will continue financial transparency by FDA issuing a 5-year 
financial plan and annual updates and holding annual public 
meetings to discuss PDUFA finances.

 Improving FDA's hiring and retention of key scientific and technical 
                                 talent

    PDUFA VII proposes to further improve FDA's hiring and 
retention of key scientific and technical talent. FDA commits 
to report on FDA's website progress on annual PDUFA VII hiring 
goals. FDA also commits to utilizing an independent contractor 
to conduct a targeted assessment of the hiring and retention of 
staff for the human drug review program and will post this 
assessment on FDA's website.

                 Enhancing IT and bioinformatics goals

    PDUFA VII proposes to enhance IT and bioinformatics by 
enhancing transparency of IT activities and modernization plans 
through regular meetings, publishing a data and technology 
modernization strategy, and engaging with external stakeholders 
on initiatives around data convergence. The proposal will 
modernize the Electronic Submission Gateway, explore cloud and 
cloud-based technologies, and leverage modern technology to 
accelerate CBER's data and technology modernization. Additional 
staff and resources are added in PDUFA VII to support review 
and analysis of the increasing amounts of bioinformatics and 
computational data submitted during product development and 
review, including the management of submissions with extensive 
and continuous data from digital health technologies.

                                 GDUFA

    GDUFA has helped to significantly expand the timely 
availability of and patient access to affordable, high quality 
generic medicines since its inception. Patient confidence that 
generic drugs will work the same as brand products, and can be 
freely substituted, is the foundation for trillions of dollars 
in savings that generics have produced for the healthcare 
system.

    The generic drug industry has grown from modest beginnings 
in 1984 into a major force in health care to reduce health care 
costs. In the past 10 years (2011-2021) close to 1,000 first 
generic medicines have been approved, offering patients access 
to drugs for which there was no previous generic competition. 
FDA has also approved thousands of additional versions of 
generic medicines over this time, contributing to significant 
price reductions for consumers. According to the Association of 
Accessible Medicines, based on an analysis by IQVIA, generic 
drugs saved the U.S. health care system $2.4 trillion from 2011 
to 2020. \11\
---------------------------------------------------------------------------
    \11\  Analysis done by IQVIA for 1255 generic molecules based on 
sales data and pre-patent expiry prices of brand name drugs https://
accessiblemeds.org--sites--default--files--2021--10--AAM--2021--US--
Generic--Biosimilar--Medicines--Savings--Report--web.pdf

    This success was enabled by the enactment of GDUFA I as 
part of the Food and Drug Administration Safety and Innovation 
Act of 2012 and reauthorization of the program (GDUFA II) as 
part of the FDA Reauthorization Act of 2017. While substantial 
progress has been made, there is still more to be done. With 
more generic drugs on the market there is a corresponding 
increase in the need for FDA regulatory activity over the 
lifecycle of these products. Indeed, we see a steady increase 
in approved abbreviated new drug applications (ANDA) with post-
approvalactions, including Prior Approval Supplements and 
Changes Being Effected (CBE) submissions (Figure 5). Most of 
these submissions involve manufacturing facility and labeling 
updates. In addition, with the steady approval of new molecular 
entities and innovative new uses for previously approved drugs, 
including many new complex products, the GDUFA program faces 
increased industry requests for regulatory feedback to bring 
---------------------------------------------------------------------------
the next generation of generic drugs to the market.

  Figure 5: Receipts of Prior-Approval Supplements and Changes Being 
                  Effected Submissions by Fiscal Year


                  GDUFA II_Fulfilling Our Commitments

    Under GDUFA II, FDA eliminated the backlog of hundreds of 
ANDAs and made significant progress in timely review of generic 
drug submissions. In the first 4 years of GDUFA II we approved 
over 3000 ANDAs and, to facilitate generic drug development, 
issued over 50,000 communications to industry. Under GDUFA II, 
the Agency committed to assess 90 percent of priority ANDAs 
within 8 months of submission and to assess 90 percent of 
standard ANDAs in 10 months. The program has surpassed its 90 
percent goal for assessment of all original standard and 
priority ANDAs (Figure 6) and continued to meet or exceed the 
majority of its goals even during the COVID-19 pandemic, with 
over 1300 approvals for drug products used to treat patients 
suffering from COVID-19. For many of these COVID-19 approvals, 
the decision was made in less than half the applicable goal 
period. In addition, throughout GDUFA II, approximately 13 
percent of annual ANDA approvals were for complex generics 
including the first generic inhaler for asthma and chronic 
obstructive pulmonary disease.

   Figure 6: Achievement of GDUFA II Review Goals by Submission Type


    PFC--those applicants who met the requirements of the Pre-
Facility Correspondence process (21 U.S. C. 355(j)(11)).

    90 percent goal for all submission types

                  Faster assessment of priority ANDAs

    Under amendments made by the FDA Reauthorization Act of 
2017 (which authorized GDUFA II), priority review is available 
for applications for generic drugs with limited competition, as 
well as for generic drugs in shortage, that meet certain 
conditions. This includes the shorter review timeframe under 
the Pre-Facility Correspondence (PFC) framework, under which 
sponsors submit information about manufacturing facilities and 
testing of the drug not later than 60 days prior to the 
submission of the application. In addition, a core element of 
prioritization efforts under the GDUFA II commitment letter is 
to expedite the assessment of potential ``first generic'' ANDAs 
because they can open the market to generic competition for the 
first time. Many ``first generic'' ANDAs cannot lawfully be 
submitted until a specific date after the innovator drug was 
approved. Figure 7 shows the number of first generic drug 
approvals by fiscal year (FY) during GDUFA II.

         Figure 7: First Generic Drug Approvals by Fiscal Year



    To provide some clinical context for these numbers, Table 1 
provides a summary of some significant first generic approvals 
for CY 2021. \12\
---------------------------------------------------------------------------
    \12\  Information on approval of first generics is posted on FDA's 
first generic drug approvals website https://www.fda.gov/drugs/drug-
and-biologic-approval-and-ind-activity-reports/first-generic-drug-
approvals


      Table 1: Significant First Generic Drug Approvals in CY 2021
------------------------------------------------------------------------
 Generic Name     brand Name           Indication          Approval Date
------------------------------------------------------------------------
          LinaclotiLinzess      Irritable bowel syndrome  Feb. 9, 2021
  Capsules                Capsulwith constipation and
                                  chronic idiopathic
                                        constipation
------------------------------------------------------------------------
Apremilast          Otezla        Moderate to severe      Feb. 18, 2021
   Tablets         Tablets          plaque psoriasis
------------------------------------------------------------------------
 Ibrutinib       Imbruvica      Mantle cell lymphoma      Mar. 31, 2021
  Capsules                Capsules                (MCL)
------------------------------------------------------------------------
Enzalutamide        Xtandi           Prostate cancer      May 14, 2021
  Capsules                Capsules
------------------------------------------------------------------------
          LenalidoRevlimid         Multiple myeloma,      May 21, 2021
  Capsules                Capsuleanemia, and certain
                                           lymphomas
------------------------------------------------------------------------
Tofacitinib        Xeljanz                          CertaiJun. 1, 2021
   Tablets         Tablets      arthritis and ulcerative
                                             colitis
------------------------------------------------------------------------
Difluprednate      Durezol         Inflammation/pain      Aug. 9, 2021
 Opthalmic                      associated with ocular
  Emulsion                      surgery and treatment
                                of endogenous anterior
                                             uveitis
------------------------------------------------------------------------
Varenicline               Chantix  Smoking cessation      Aug. 11, 2021
   Tablets         Tablets
------------------------------------------------------------------------
          LinagliTradjenta      Type 2 Diabetes Mellitus  Aug. 31, 2021
   Tablets         Tablets
------------------------------------------------------------------------
          LenalidoRevlimid          Multiple myeloma      Oct. 14, 2021
  Capsules                Capsules
------------------------------------------------------------------------
 Dasatinib         Sprycel                          ChroniNov. 23, 2021kemia
   Tablets         Tablets
------------------------------------------------------------------------

                     Pre-ANDA Program Enhancements

    To reduce the number of cycles to approval, particularly 
for complex generic products, the GDUFA II commitment letter 
established a pre-ANDA program. This program helps clarify 
regulatory expectations for prospective applicants early in 
product development, assists applicants in the development of 
more complete submissions, and provides mechanisms for 
consultation regarding these products after the ANDA is 
submitted, thus promoting a more efficient and effective 
development and assessment process.

    As detailed in the commitment letter, the GDUFA II pre-ANDA 
program established three types of meetings for complex 
products:

         LProduct development meetings in which FDA 
        provides targeted advice concerning an ongoing ANDA 
        development program.

         LPre-submission meetings, which give 
        applicants an opportunity to discuss and explain the 
        content and format of an ANDA before it is submitted.

         LMid-review-cycle meetings, which occur, as 
        the name implies, around mid-cycle after the applicant 
        has received FDA's assessment of any deficiencies in 
        the application and provides the applicant an 
        opportunity to discuss those concerns and plan for next 
        steps.

    During GDUFA II, the Agency has continued to grant these 
meetings and provided industry further information via the 
final guidance titled ``Formal Meetings Between FDA and ANDA 
Applicants of Complex Products Under GDUFA Guidance for 
Industry,'' released in November 2020. \13\
---------------------------------------------------------------------------
    \13\  https://www.fda.gov/media/107626/download

    To facilitate development of new generic products, FDA 
issued Product Specific Guidances (PSGs) to assist the generic 
pharmaceutical industry with identifying the most appropriate 
methodology for generating the evidence needed to support ANDA 
approval, for both complex and non-complex drugs. Under the 
GDUFA II commitment letter, FDA established goals for issuing 
PSGs for non-complex new molecular entities. FDA has 
consistently met this goal and as of April 18, 2022, there were 
currently 1,978 PSGs available to industry. \14\
---------------------------------------------------------------------------
    \14\  https://www.accessdata.fda.gov/scripts/cder/psg/index.cfm

    While the GDUFA II commitment letter did not include a goal 
around PSGs for complex generics, GDUFA supports a robust 
regulatory science program that supports the development of 
additional innovative methodologies and more efficient tools to 
help establish drug equivalence standards and support the 
development of, and access to, new generic drug products. FDA 
consults with and solicits input from the public, industry, and 
academic researchers to develop an annual list of the GDUFA 
regulatory science initiatives specific to research on generic 
drugs. In addition, we engage stakeholders through numerous 
scientific workshops and publish an annual report on 
accomplishments. \15\
---------------------------------------------------------------------------
    \15\  https://www.fda.gov/drugs/generic--drugs--science--research

    Another tool in the pre-ANDA program is controlled 
correspondence, which allows potential applicants to submit 
targeted questions regarding their drug development program and 
receive a response within a specific timeframe. Under the GDUFA 
II commitment letter, FDA made enhancements to its Inactive 
Ingredient Data base, which is an important tool for generic 
drug developers, to enable users to perform electronic queries 
to obtain Maximum Daily Intake and Maximum Daily Exposure 
information for each route of administration for which data are 
available.

                  ANDA Assessment Program Enhancements

    Consistent with the statute, the GDUFA II commitment letter 
refined programmatic timeframes, including for sponsor 
communications, used in the ANDA assessment process. The ANDA 
assessment program starts with submission of an ANDA. When an 
ANDA is submitted, FDA first determines whether an ANDA is 
sufficiently complete to permit a substantive assessment. These 
``receipt'' determinations are made within consistent 
timeframes. The Agency also increased receipt-related 
communications to facilitate the receipt decision and resolve 
certain receipt disputes within consistent timelines.

    When a new ANDA is received and is under assessment, FDA 
communicates assessment deficiencies beginning at approximately 
the mid-point of the review. Communications continue on a 
rolling basis during the assessment. When deficiencies in an 
ANDA prevent FDA from approving it, FDA issues a Complete 
Response Letter (CRL) itemizing the deficiencies that must be 
corrected for the ANDA to be approved. The GDUFA II commitment 
letter established post-CRL teleconferences to allow applicants 
to seek clarification concerning deficiencies identified in 
CRLs. This helps applicants meet FDA's expectations when an 
ANDA is re-submitted for additional review. In 2021, FDA 
conducted 73 such teleconferences, 98 percent within 30 days of 
receipt of the written request.

         Drug Master File (DMF) Assessment Program Enhancements

    Type II DMFs are submissions from a third party other than 
the ANDA applicant that contain confidential information on a 
drug substance (or active pharmaceutical ingredient (API)) or 
drug substance intermediate (or materials used in their 
preparation) that the Agency evaluates independently. These 
submissions can be cross referenced by multiple applicants to 
support approval of their respective ANDAs. Effective 
communication between ANDA applicants, DMF holders, and FDA is 
essential to reduce the likelihood of potential problems that 
could delay approvals. The GDUFA II commitment letter featured 
new and enhanced mechanisms to facilitate this communication, 
including first adequate letters to indicate a DMF has no open 
issues related to the assessment of a referencing ANDA, no 
further comment letters, and expanded opportunities for DMF 
holders to request teleconferences with FDA regarding first 
cycle DMF deficiency letters.

    Pursuant to the GDUFA II commitment letter, FDA issued a 
draft guidance \16\ on post-approval changes to a Type II API 
DMF and submission mechanisms for ANDA applications which 
reference a Type II API DMF. FDA also issued a revised draft 
guidance titled ``Completeness Assessments for Type II API DMFs 
under GDUFA.'' \17\
---------------------------------------------------------------------------
    \16\  https://www.fda.gov/media/84217/download
    \17\  https://www.fda.gov/regulatory--information--search--fda--
guidance--documents--completeness--assessments--type--ii-api--dmfs--
under--gdufa--guidance--industry
---------------------------------------------------------------------------

                    Facility Assessment Enhancements

    To mitigate export-related challenges identified by U.S.-
based API manufacturers, the GDUFA II commitment letter called 
for FDA to issue guidance and conduct outreach to foreign 
regulators on its risk-based manufacturing site selection 
model. To fulfill this commitment, we issued a manual of policy 
and procedures (MAPP) titled, ``Understanding CDER's Risk-Based 
Site Selection Model'' \18\ in 2018, to explain how FDA 
determines which manufacturing facilities to prioritize for 
routine surveillance inspections. To mitigate ANDA sponsor 
concerns, FDA enhanced the speed and transparency of 
communications concerning facility inspection outcomes. 
Specifically, we implemented a process to notify facilities of 
final facility inspection classifications (i.e., No Action 
Indicated, Voluntary Action Indicated, or Official Action 
Indicated) within 90 days from the close of the inspection. In 
addition to enhanced transparency concerning the compliance 
status of GDUFA facilities and sites, FDA updates its publicly 
available facility inspection classification data base every 30 
days to reflect the most recent surveillance inspection 
outcomes. \19\
---------------------------------------------------------------------------
    \18\  https://www.fda.gov--media--116004--download
    \19\  https://3www.fda.gov--inspections--compliance--enforcement--
and--criminal--investigations--inspection--classification--data base
---------------------------------------------------------------------------

               Accountability and Reporting Enhancements

    Under GDUFA II, enhanced information infrastructure and 
analytics increased transparency and accountability for meeting 
performance goals and strengthened program management and 
resource use. FDA developed internal processes to enable 
improved productivity and performance through regular 
assessment of progress toward GDUFA II goals. The Agency also 
enhanced the transparent and efficient administration, 
allocation, and reporting of user fee resources. We expanded 
GDUFA program reporting and provide the information on our 
website ``Enhanced Accountability & Reporting.'' \20\20 Robust 
performance reporting enables Congress, industry, and other 
stakeholders to gauge the generic drug program's performance on 
an ongoing basis. FDA also issued a Five-Year Financial Plan in 
fiscal year 2018 with annual updates \21\ and held an annual 
meeting \22\ on financial transparency and efficiency of the 
user fee programs. In addition, an independent third party 
evaluated FDA's Capacity Planning Adjustment (CPA) methodology 
that in PDUFA and BsUFA adjusts target revenue annually as 
needed within a user fee cycle to account for forecasted, 
sustained increases in workload. This report specifically 
evaluated whether a proposed CPA methodology could be applied 
to the GDUFA program and whether corresponding outputs could be 
applied to the GDUFA program to meet the monitoring and 
reporting of resource needs of the program. \23\ As discussed 
below, industry and FDA agreed to implement a CPA in GDUFA III.
---------------------------------------------------------------------------
    \20\  https://www.fda.gov--industry--generic--drug--user--fee--
amendments--enhanced--accountability--reporting
    \21\  https://www.fda.gov/about--fda--user--fee--reports--user--
fee--five--year--financial--plans
    \22\  https://www.fda.gov/drugs--news--events--human--drugs--
financial--transparency--and--efficiency--prescription--drug--user--
fee--act--biosimilar--user--fee--act--and
    \23\  https://fda.report--media--140656--Independent--Evaluation--
of--the--GDUFA--Resource--Capacity--Planning--Adjustment--Methodology--
0.pdf
---------------------------------------------------------------------------

                       GDUFA III Reauthorization

    The accomplishments under GDUFA II continued to foster a 
strong generic drug market for the American public. For 
example, there are generic versions of the ten most prescribed 
medications by total prescriptions in 2020. Despite this 
success, the average first-cycle approval rate remains around 
15 percent. While progress is improving in the approvals of 
complex generics, about 30 percent of active reference 
products, that do not have generic competition, are complex 
products. Therefore, the GDUFA III negotiations focused on 
building on the successes of GDUFA II by proposing new 
processes and procedures to achieve earlier cycle approvals and 
enhancing the pre-ANDA program.

                           GDUFA III Overview

                            ANDA Assessments

    The GDUFA III commitment letter proposes minimizing 
issuance of complete response letters (CRL) which, as described 
above, are letters from FDA to an applicant detailing the 
deficiencies in an application that must be resolved prior to 
approval, by:

         LUtilizing ``Imminent Actions'' whenever 
        possible to approve an application within 60 days after 
        the goal date if there is a small issue to resolve or a 
        pending expiration of a reference listed drug patent or 
        exclusivity within that time period;

         LExtending goal dates when there is a minor 
        issue that can be resolved within 3 months of the 
        original goal dates, e.g., addressing a labeling issue; 
        this includes changes in labeling review processes to 
        provide more resources to address late-cycle labeling 
        changes;

         LProviding the opportunity to extend the goal 
        date by 6-10 months, depending upon the type of ANDA 
        and need for a pre-approval inspection, if an applicant 
        can respond to a major deficiency before the original 
        goal date; such extensions could shorten the overall 
        time to approval.

    The commitment letter also seeks to refine the Pre-Facility 
Correspondence process for priority ANDAs to focus on the 
information that is available from applicants' pre-ANDA 
submissions to inform FDA's decision regarding the need for a 
preapproval inspection, to expand opportunities for applicants 
to use this process.

    Another commitment is to increase opportunities for timely 
regulatory feedback through the expanded use of controlled 
correspondence to include, for example, questions related to 
generic drug development after receipt of a CRL, in addition to 
the opportunity for a post-CRL teleconference.

             Drug Master Files and Manufacturing Facilities

    For drug master files the commitment letter proposes 
expanding opportunities for early assessment of DMFs before 
certain priority ANDAs are submitted and between review cycles 
to increase the likelihood that the DMF will be adequate at the 
same time as the associated ANDA and thereby promote earlier 
cycle approvals. In addition, there will be new goal dates for 
FDA's response time for manufacturing questions submitted by a 
sponsor using controlled correspondence after their ANDA is 
approved.

    While most facilities are compliant with Current Good 
Manufacturing Practice requirements, a small number of ANDA 
manufacturing facilities are not able to gain approval to 
produce ANDAs for the U.S. market due to significant violations 
identified during an inspection. To assist manufacturers in 
resolving such violations more expeditiously, under the GDUFA 
III commitment letter, eligible generic drug facilities could 
request a Post-Warning Letter Meeting to obtain preliminary 
feedback from FDA on the adequacy and completeness of their 
corrective action plans. Once a facility has completed 
appropriate remediation action and FDA agrees that the next 
step is a facility reinspection, there would be a goal around 
the timing for such reinspection.

                Pre-ANDA Program and Regulatory Science

    The GDUFA III commitment letter proposes to continue to 
enhance regulatory science and expedite complex generic drug 
development by providing additional enhancements to the 
programs. In addition to the GDUFA II goals around PSGs for new 
molecular entities, the GDUFA III commitment letter would 
establish goals around PSGs for NDAs for complex drug products 
approved during GDUFA III. FDA would also commit to improving 
transparency regarding the timing for upcoming new and revised 
PSGs, including the prioritization of PSG development. The 
commitment proposes allowing qualified ANDA applicants or 
potential applicants to request a PSG teleconference or meeting 
to obtain Agency feedback on the potential impact of a revised 
PSG recommendation(s) on ongoing in-vivo bioequivalence 
studies.

    The meeting types provided under GDUFA II are being 
enhanced and expanded. The GDUFA III commitment letter proposes 
providing qualified ANDA applicants with the new option for an 
Enhanced Mid-Cycle Review Meeting to receive scientific advice 
with the goal of resolving a more significant scientific 
deficiency in a single review cycle, with appropriate goal date 
extensions. The proposal also includes providing qualified ANDA 
applicants a post-CRL Scientific Meeting in which the Agency 
may provide scientific advice on possible alternative 
approaches to address deficiencies related to establishing 
equivalence identified in a CRL.

    Finally, the commitment letter proposes setting goal dates 
for suitability petitions, under which generic drug applicants 
can submit ANDAs for drug products that differ from an approved 
brand drug in new dosage form, strength, route of 
administration, or active ingredient for products with a 
combination of more than one active ingredient. These petitions 
usually are submitted in response to market demand that is not 
met by an approved brand product. These goal dates would be 
established starting in fiscal year 2024.

                                 Hiring

    To provide the capacity needed to successfully implement 
the new commitments, while maintaining current performance, the 
GDUFA III proposal recommends increasing fees to fund 128 new 
FTEs (to be hired in fiscal year 2023). Under GDUFA III, the 
Agency will provide transparency with respect to hiring in its 
5-year financial plan reports.

            Enhancement of Management of User Fee Resources

    GDUFA III proposes to enhance the operational agility of 
the GDUFA program and management of user fee resources through 
further maturation of the Resource Capacity Planning (RCP) 
capability and a legislative proposal to establish and 
implement a Capacity Planning Adjustment (CPA) to be used in 
annual fee-setting annually starting in fiscal year 2024. The 
CPA would generally allow for up to a 3-percent increase in 
inflation-adjusted target revenue for the fiscal year if there 
are forecasted, sustained increases in workload. This 
legislative proposal would also eliminate the statutory final 
year adjustment and replace it with authority for an operating 
reserve adjustment, to provide the Agency with the option of 
increasing revenues to help ensure adequate resources in the 
case of significant under collection of fees or other 
disruptions in funding. This operating reserve adjustment would 
allow the Agency the option to increase fees to maintain an 
operating reserve of 8-10 weeks' worth of carryover user fees. 
If projected operating reserves exceed 12 weeks of operating 
costs, FDA would be required to reduce fees for that fiscal 
year to reduce the operating reserve to no more than 12 weeks 
of carryover fees. FDA would provide the rationale for the CPA 
and operating reserve adjustments in the annual Federal 
Register notice publishing fee rates for that fiscal year. 
GDUFA III would continue financial transparency by publishing a 
5-year financial plan and holding a public meeting to discuss 
the plan and other financial commitments every fiscal year.

                                 BsUFA

    Over the past decade, new biological products have led to 
significant clinical improvements for patients who have serious 
and life-threatening medical conditions including cancer, 
rheumatoid arthritis, and diabetes. It is important for the 
public health of the U.S. population to have access to safe, 
effective, and affordable biological products. Biosimilars 
provide more options for patients, and competition has the 
potential to lower treatment costs, enabling greater access for 
more patients. FDA is fully engaged with the development and 
approval of biosimilar and interchangeable biosimilar products 
and is applying a scientifically rigorous review process to 
ensure these products meet approval standards, in conjunction 
with outreach to prescribers and patients. Healthcare providers 
and patients consistently emphasize that FDA's approval of 
biosimilars should provide assurance that they provide the same 
treatment benefits as the originator, or reference product. FDA 
is committed to providing this assurance and recognizes its 
importance to the future success of the biosimilars program.

   Biologics Price Competition and Innovation Act of 2009 (BPCI Act)

    Biological products are generally made from living 
organisms and usually consist of large, complex molecules that 
cannot be easily copied, in contrast to ``small molecule'' 
drugs that are produced through chemical processes and are 
easier to copy as ``generic'' drugs. The BPCI Act established 
an abbreviated approval pathway for biological products shown 
to be ``biosimilar to'' or ``interchangeable with'' an FDA-
licensed biological reference product. A biosimilar product is 
one that is highly similar to the reference product 
notwithstanding minor differences in clinically inactive 
components, with no clinically meaningful differences in terms 
of safety, purity, and potency. An interchangeable product is a 
biosimilar product that meets the additional requirement of 
demonstrating that the product is expected to produce the same 
clinical result as the reference product in any given patient 
and, for a biological product that is administered more than 
once to a patient, the risk in terms of safety or diminished 
efficacy of alternating or switching between the biosimilar and 
reference product is not greater than the risk of using the 
reference product without such alternation or switch.

    The abbreviated approval pathway permits a biosimilar 
application to rely, in part, on FDA's previous determination 
that the reference product is safe and effective, saving the 
applicant time and resources and thereby encouraging 
competition and potentially lowering healthcare costs.

              FDA Biosimilar Approvals--Progress Continues

    FDA approved the United States' first biosimilar product, 
Zarxio, on March 6, 2015, 2 years prior to the most recent 
reauthorization of the Biosimilar User Fee Act (BsUFA II) under 
the FDA Reauthorization Act of 2017 (FDARA). When BsUFA II was 
enacted, there were only five biosimilar products approved for 
four reference products. During BsUFA II the number has grown 
to 33 biosimilars for 11 reference products, including two 
interchangeable biosimilars as of April 18, 2022. \24\ A recent 
analysis by IQVIA provides data on potential savings with 
biosimilars. \25\
---------------------------------------------------------------------------
    \24\  https://www.fda.gov--drugs--biosimilars--biosimilar--
product--information
    \25\  https://www.iqvia.com--media--iqvia--pdfs--institute--
reports--iqvia--institute--biosimilars--in--the--united--states.pdf



    For example, the cost of insulin products is a barrier to 
patients obtaining sufficient supply of this essential drug. 
Interchangeable biosimilars, like generic drugs, may be 
substituted for the reference product without the involvement 
of the prescriber, depending on state pharmacy laws. Pharmacy 
level substitution may further reduce costs, helping to 
increase patient access. On July 28, 2021, FDA approved the 
first interchangeable biosimilar insulin product, indicated to 
improve glycemic control in adults and pediatric patients with 
type 1 diabetes mellitus and in adults with type 2 diabetes 
mellitus. Semglee (insulin glargine-yfgn) is both biosimilar 
to, and interchangeable with (may be substituted for), its 
reference product Lantus (insulin glargine), a long-acting 
insulin analog. On December 17, 2021, FDA approved a second 
biosimilar to Lantus: Rezvoglar (insulin glargine-aglr). These 
two biosimilar products move the needle forward in our common 
goal to help ensure increased access to a critical therapy in 
---------------------------------------------------------------------------
the treatment of diabetes for Americans who depend on insulin.

    Biological products for the treatment of inflammatory 
conditions greatly improve patients' lives. However, treatment 
can be costly--for example, in 2021, the cost of a year's 
supply of Humira was approximately $77,000; equating to about 
$3,000 per syringe. \26\ Currently, the seven approved 
biosimilar products to Humira are not on the market, but some 
could enter the market in 2023. \27\ One of these biosimilars 
was approved as an interchangeable biosimilar product. On 
October 15, 2021, Cyltezo (adalimumab-adbm), originally 
approved as a biosimilar in August 2017, was approved as 
interchangeable with its reference product Humira (adalimumab) 
for Cyltezo's approved uses. Cyltezo is the first 
interchangeable monoclonal antibody.
---------------------------------------------------------------------------
    \26\  House Committee on Oversight and Reform--AbbVie report: 
https://oversight.house.gov--sites--democrats--oversight--house--gov--
files--Committee percent--on percent--Oversight percent--and percent--
Reform percent--percent--AbbVie percent--Staff percent--Report.pdf
    \27\  AbbVie & Allergan, 2020 Annual Report on Form 10-K: https://
investors.abbvie.com/static--files/47512e94--a9a4-4035-8dbc-
6eb59116bb05
---------------------------------------------------------------------------

                  BsUFA II_Fulfilling Our Commitments

    We are currently in the final year of the BsUFA II program. 
BsUFA has enabled FDA to implement a new review model and 
expand staff capacity to provide increased communication with 
companies facilitating biosimilar product development. BsUFA II 
built upon the successes of BsUFA I and established an 
application review model like ``the Program'' established under 
PDUFA V for new molecular entity new drug applications and 
original biologics license applications. This new model is 
intended to promote the efficiency and effectiveness of the 
first cycle review process and minimize the number of review 
cycles necessary for approval. The main parameters of the 
Program include the following: 1) pre-submission meetings, 2) 
original application submissions, 3) Day 74 Letter, 4) review 
performance goals (10-month user fee clock starts at 60-day 
filing date), 5) mid-cycle communications, 6) late-cycle and 
advisory committee meetings, and 7) assessment of the Program. 
These changes contributed to the increase in approvals during 
the first cycle, reaching almost 70 percent during BsUFA II 
compared to 39 percent during BsUFA I.

                       Meetings and Collaboration

    FDA made modifications to meeting processes and procedures 
as part of BsUFA II. We published a draft guidance ``Formal 
Meetings Between the FDA and Sponsors or Applicants of BsUFA 
Products'' \28\ and issued a final guidance on ``Best Practices 
for Communication Between IND Sponsors and FDA During Drug 
Development''. \29\ As of January 3, 2022, there are close to 
100 active biosimilar development programs and we received 
meeting requests to discuss the development of biosimilars for 
47 different reference products. Because these communications 
are often opportunities to share information and provide 
critical advice (e.g., trial design, analytical similarity 
assessment, nonclinical studies, manufacturing, and facility 
issues), it is important that interactions be conducted 
efficiently and consistently, with clear, concise, and timely 
communication. Issuance of guidance on these topics is intended 
to further those goals and help to foster an environment where 
sponsors and FDA can work collaboratively during the biosimilar 
drug development process.
---------------------------------------------------------------------------
    \28\  https://www.fda.gov--regulatory--information/search--fda--
guidance--documents--formal--meetings--between--fda--and--sponsors--
or--applicants--bsufa--products--guidance--industry
    \29\  https://www.fda.gov/regulatory--information--search--fda--
guidance--documents--best--practices--communication--between--ind--
sponsors--and--fda--during--drug--development
---------------------------------------------------------------------------

                      Strengthening Staff Capacity

    The ability to hire and retain qualified staff is critical 
to facilitating the availability of new safe and effective 
biosimilars. The BsUFA II commitments supported this priority 
by strengthening FDA's staff capacity; modernizing the hiring 
system infrastructure; improving human resources capacity 
through use of a dedicated expert contractor; establishing a 
dedicated function for the recruitment and retention of 
scientific staff; and setting clear goals for hiring. In 
addition, FDA committed to conducting a comprehensive and 
continuous assessment of hiring and retention practices. This 
increase in staff capacity during BsUFA II facilitated the 
development of new regulations and guidance to clarify the 
biosimilar pathway and to support reviewer training and timely 
communication with sponsors. This included issuing guidances 
that are foundational to the biosimilar pathway. FDA has issued 
draft or final guidance for all guidances listed in the BsUFA 
II commitment letter.

    Last, BsUFA II included goals related to the publication of 
information about biological products. Addressing these goals 
and commitments, in 2020, FDA released ``The Purple Book: Data 
base of Licensed Biological Products,'' \30\ which is a 
searchable, online data base that contains information about 
FDA-licensed (approved) biological products, including 
biosimilar and interchangeable products and their reference 
products. The data base provides users with a public-facing 
data base that includes important information about biological 
products, including information about product presentations, 
strength, and dosage forms, in addition to other searchable and 
sortable data fields.
---------------------------------------------------------------------------
    \30\  https://purplebooksearch.fda.gov/
---------------------------------------------------------------------------

                     Independent User Fee Structure

    Under BSUFA II, FDA successfully implemented an independent 
user fee structure based on BsUFA I program costs, along with 
other financial enhancements to improve FDA's ability to manage 
program resources and engage in effective long-term planning. 
FDA also implemented commitments to improve financial 
transparency and efficiency, including conducting an 
independent evaluation of BsUFA program resource management 
\31\ and issuing a BsUFA 5-year financial plan with annual 
updates \32\, in addition to the annual financial reports, \33\ 
and annual public meetings to discuss program finances. \34\
---------------------------------------------------------------------------
    \31\  https://www.fda.gov/drugs/development--resources--fiscal--
year--2018--financial--management--evaluation--human--drug--user--
fees--assessment--report
    \32\  https://www.fda.gov/about--fda--user--fee--reports--user--
fee--five--year--financial-plans
    \33\  https://www.fda.gov--about--fda--user--fee--financial--
reports/bsufa--financial--reports
    \34\  https://www.fda.gov/drugs/news--events--human--drugs--
financial--transparency--and--efficiency--prescription--drug--user--
fee--act--biosimilar--user--fee--act--and
---------------------------------------------------------------------------

                         BSUFA Reauthorization

    The statute directs FDA to develop recommendations for 
BsUFA III for fiscal years 2023 through 2027. To develop these 
recommendations, FDA consulted with industry and public 
stakeholders, including scientific and academic experts, health 
care professionals, and patient and consumer advocates, as 
directed by Congress. In addition to meetings with industry 
organizations, FDA held two public meetings on November 19, 
2020, and November 2, 2021, to obtain input from public 
stakeholders. To ensure transparency in this work the Agency 
has posted the meeting minutes, including the two public 
meetings and the 13 negotiation sessions with industry. The 
recommendations for BsUFA III were transmitted to Congress on 
January 12, 2022.

                           BsUFA III Overview

    Based on successes of the BsUFA program, the BsUFA III 
commitment letter focuses on many of the top priorities 
identified by public stakeholders, regulated industry and FDA. 
The commitments build on the experience gained through the 
first and second iterations of BsUFA by expanding on existing 
successful enhancements, refining elements from the existing 
program, and including new enhancements. Highlights of the 
proposed commitments are summarized as follows.

   Enhancing pre-market review processes, procedures, and performance

    BsUFA III proposes to retain the majority of existing 
review performance goals FDA and industry agree are working 
well in the program. With 33 approved biosimilar products to 
date and more anticipated, FDA and industry expect companies 
will submit more supplements to FDA during BsUFA III for these 
products and others that may be approved during BsUFA III. As 
such, BsUFA III proposes new supplement categories, review 
timelines and performance goals to expedite the review of 
certain supplements, including the review of safety labeling 
updates. In addition, this proposal seeks to improve 
communication and feedback during the development process by 
modifying two formal meeting types, introducing a new meeting 
type to focus on a narrower set of issues than other formal 
meetings to enable faster responses to industry, and introduces 
a new follow-up opportunity for sponsors to submit clarifying 
questions after meetings or ``Written Response Only'' 
correspondence to ensure sponsor's understanding of FDA 
feedback.

   Enhancing biosimilar and interchangeable product development and 
                           regulatory science

    BsUFA III proposes to continue the framework established in 
BsUFA II by incorporating best practices in FDA-sponsor 
communication through updates to relevant guidances, Manual of 
Policies and Procedures (MAPPs), and Standard Operating Policy 
and Procedures (SOPPs).

    BsUFA III includes commitments for the Agency to:

         LIssue guidance on FDA's thinking on the use 
        of alternative tools to assess manufacturing facilities 
        named in pending applications (incorporating best 
        practices, including those in existing published 
        documents, from the use of such tools during the COVID-
        19 pandemic);

         LNotify sponsors in advance of facility 
        inspections where FDA needs to see the product being 
        manufactured; and

         LAdvance the development of review processes 
        for biosimilar biological-device combination products 
        by introducing new procedures and timelines for use-
        related risk analysis and human factor validation study 
        protocols.

    To further advance the development of safe and effective 
interchangeable biosimilar products, BsUFA III proposes a 
focused effort that includes issuing four foundational 
guidances for the development of interchangeable products; 
stakeholder engagement through a scientific workshop; and 
leveraging the new BsUFA III regulatory science program to 
advance product development, assist regulatory decisionmaking, 
and support guidance development for interchangeable biosimilar 
products.

    As proposed, the BsUFA III regulatory science pilot program 
would be broadly applicable to biosimilar and interchangeable 
product development. The pilot program would focus on two 
demonstration projects: (1) advancing the development of 
interchangeable products, and (2) improving the efficiency of 
biosimilar product development.

      Continuing enhancements for management of user fee resources

    Similar to PDUFA VII, BsUFA III proposes to continue to 
enhance management of user fee resources by advancing FDA's 
resource capacity planning function and adjustment methodology, 
including a third-party evaluation of the methodology by 2025. 
The proposal would continue financial transparency through 
issuance of a 5-year financial plan with annual updates and 
holding annual public meetings to discuss BsUFA finances.

 Improving FDA's hiring and retention of key scientific and technical 
                                 talent

    To accomplish the goals set out in the proposed commitment 
letter, the Agency would hire 15 new employees for fiscal year 
2023 and fiscal year 2024. Like PDUFA VII, BsUFA III proposes 
to further improve FDA's hiring and retention of key scientific 
and technical talent by providing transparency on hiring 
progress by reporting on progress toward meeting annual BsUFA 
III hiring goals on FDA's website and conducting a third-party 
assessment of FDA's hiring and retention.

                           Enhancing IT goals

    Similar to PDUFA VII, BsUFA III proposes to enhance 
transparency of IT activities and modernization plans, 
including by publishing a data and technology modernization 
strategy. The proposal would also modernize the Electronic 
Submission Gateway.

                                 MDUFA

    Enacted by Congress in 2002, MDUFA is a user fee program 
through which medical device companies pay fees to FDA when 
they submit a request for marketing authorization, or certain 
other submissions, or register their establishments with FDA. 
The program includes commitments between the U.S. medical 
device industry and FDA to improve the predictability, 
transparency, and consistency of regulatory processes, which 
are intended to reduce the time for FDA to make a decision 
about whether to authorize marketing of a device. MDUFA has 
been reauthorized every 5 years since Congress first 
established the program in 2002. As the program has evolved, 
FDA and industry have successfully negotiated agreements to 
improve patient access to medical devices and streamline 
regulatory processes, all while assuring the safety and 
effectiveness of devices that patients and healthcare providers 
depend upon.

    We have seen tremendous evolution and progress in FDA's 
medical devices program since inception of MDUFA. Prior to 
MDUFA enactment, FDA's devices program was in a far different 
place than the program we see today. We saw much longer review 
times, which led to less predictability and transparency for 
industry and patients. The investments made in the previous 
reauthorizations helped the MDUFA program make substantial 
progress. For example, we advanced more aggressive performance 
goals for 510(k) and premarket applications (PMA), including 
shared outcome goals; we added performance goals for Pre-
Submissions (which provide an opportunity for a sponsor to 
obtain FDA's feedback prior to an intended submission such as 
an Investigational Device Exemption (IDE) or marketing 
application), and De Novo requests; as well as added process 
improvements for real world evidence, digital health, patient 
engagement, and use of consensus standards. As a result of 
these developments, we have seen an increasing number of 
innovators bring their devices to the U.S. first, before 
seeking to market them in other nations. We are seeing the 
pipeline of innovative new devices in the U.S. continues to 
become more robust, improving patient access to medical devices 
overall--with access being an important indicator of success 
for patients who may not have approved/cleared/marketed 
alternatives. It also demonstrates that a strong MDUFA 
agreement enables patients to have access to more innovative 
and better performing devices--and therefore more options--than 
at any other time in our history.

    The draft MDFUA V reauthorization proposal was submitted to 
Congress on March 22, 2022. We expect to submit the final 
proposal following the close of public comments in April, and 
regret missing the statutory deadline to deliver the MDUFA V 
agreement this year. We take our obligation to provide the 
agreement to Congress in a timely manner very seriously, and 
know it is important for the Committees in both the House and 
Senate to have the opportunity to fully evaluate the agreement 
and engage with FDA and industry on the details because of how 
much is at stake, for FDA and our health care system. The 
deliberations on this agreement ran much longer than we 
intended, but it was critical that we took the time to 
deliberate and reach consensus on a strong, thoughtful 
agreement that assures the device program is appropriately 
resourced, and that we are supporting industry and innovators 
with a consistent, predictable, timely path to market for the 
safe and effective devices patients depend upon. We appreciate 
the patience of the Committee as we worked to reach an 
agreement that continues the progress made in the previous 
agreements toward advancement of medical device innovation, 
while maintaining FDA's standards. This is critical, as FDA and 
the device ecosystem face some of their greatest challenges. 
FDA's devices program continues to shoulder the unprecedented 
demands of the global COVID-19 pandemic, where the demand for 
medical devices has far exceeded anything we have seen in 
previous public health emergencies, while working hard to keep 
up with our MDUFA commitments as much as possible, and fulfill 
our ongoing mission of protecting public health and 
facilitating medical device innovation.

                                MDUFA IV

    The MDUFA IV agreement enabled FDA to continue making 
progress on reducing review times and bringing devices to 
patients more quickly, while also enabling FDA to move forward 
in critical areas including advancing our work to support 
innovation in digital health, strengthening our partnership 
with patients, enhancing our program to adopt consensus 
standards, and improving our ability to leverage real world 
evidence toward regulatory decisions. In terms of review goals, 
we had a strong performance during the first half of MDUFA IV, 
continuing to meet and exceed performance goals, working to 
reduce the time for patients to have access to safe, new, 
innovative devices. In fiscal years 2018 and 2019, FDA achieved 
all of our submission review goals, met 21 of 24 performance 
enhancement goals, and FDA and industry met three of four 
shared outcome goals. Though not perfect, this performance 
evidences a continually robust pipeline for new and innovative 
devices, which is a positive condition for U.S. patients and 
our health care providers on the front lines. And with a robust 
pipeline comes an increase in workload, which reached some of 
its highest levels in key areas and substantially impacted our 
Center.

         LPre-Submission requests grew substantially 
        beyond what was resourced in MDUFA IV. MDUFA IV assumed 
        that Pre-Submission volume would hold steady at 2,350 
        submissions per year. In fact, FDA received over 3,000 
        more Pre-Submissions than we were resourced to review 
        in MDUFA IV, including more than 1,000 submissions in 
        fiscal year 2020 alone. Growth in non-Breakthrough 
        related Pre-Submissions was steady and linear for 7 
        years prior to the pandemic (2013-2020), while growth 
        in Breakthrough-related Pre-Submissions has been much 
        more significant, increasing by an average of about 40 
        percent each of the last 3 years (FY 2019-fiscal year 
        2021). With significant growth driven primarily by the 
        popularity of the Breakthrough devices program, we 
        expect to receive approximately twice as many Pre-
        Submissions per year by the end of MDUFA V than what 
        was resourced in MDUFA IV.
        
        

         LSubmissions have and continue to become 
        increasingly complex and, as a result, review of 
        premarket submissions has become more resource-
        intensive. This rise in complexity is evidenced in 
        several ways

                Y LThroughout MDUFA III, the average size of a 
                510(k) submission held steady, at around 1,000 
                pages per submission. In MDUFA IV however, the 
                average size of a510(k) has steadily and 
                significantly increased, nearly doubling to an 
                average of2,000 pages per submission in 2021. 
                This increase occurred while FDA's requests for 
                industry to provide additional information 
                decreased or remained stable. This increase in 
                submission size is not just limited to 
                510(k)'s. Average submission size has also 
                increased in other important submission types 
                during MDUFA IV. For example, the average size 
                of an Original IDE grew by 1,300 pages (from 
                around1,700 pages per submission in 2018 to 
                more than 3,000 pages in 2021) and the average 
                size of a PMA Supplement doubled (from around 
                650 pages per submission in 2018 to more than 
                1,320 pages in 2021).
                
                

                Y LFDA has approved or authorized record 
                numbers of novel devices during MDUFAIV. In 
                2021, CDRH gave marketing authorization to 103 
                novel devices, an incredible achievement, 
                especially during a time of increased demand on 
                CDRH staff during the pandemic. Over the past 
                decade, in fact, there were four times as many 
                medical device approvals, authorizations, and 
                clearances of novel technologies as a result of 
                the innovative policies and approaches FDA has 
                developed and implemented.

                Y LSince fiscal year 2018, FDA has granted more 
                than 600 Breakthrough device designations--and 
                more than 200 in the last fiscal year alone (FY 
                2021). The majority of sponsors of these 
                products go on to submit multiple additional 
                requests for FDA feedback (via Pre-Submissions) 
                shortly after their designation is granted, 
                with roughly 1/3 submitting five Pre-
                Submissions or more. More than 50 percent of 
                companies receiving Breakthrough designations 
                are either small or startup companies (i.e., no 
                or less than $1M in annual sales).

                Y LFDA is also continuing to receive more 
                premarket submissions overall than it has in 
                previous years. For instance, in fiscal year 
                2015, we received nearly 13,900 total premarket 
                submissions, and in fiscal year 2016 received 
                nearly 14,300. In contrast, for fiscal year 
                2021, FDA received over 16,400. This is 
                approximately a 20 percent increase (or 
                ?2,500'submissions) since fiscal year 2015, and 
                a 10 percent increase (or ?1,400 
                submissions)'since the start of MDUFA IV.
                
                

    We also note another challenge of MDUFA IV was the rising 
payroll costs in CDRH and CBER, and the MDUFA inflation formula 
did not keep up. These payroll costs come from forces outside 
of the program's control--including government wide, mandatory 
cost-of-living adjustments; automatic ``step'' increases for 
employees; and increased contributions to the Federal 
retirement benefit. For CDRH, in fiscal year 2022, the 
accumulated payroll cost impact of these factors for the MDUFA 
program is $45.5M. However, CDRH received $8.7M from the MDUFA 
payroll inflation adjustment, leaving a gap of $36.8M. These 
increased costs likewise placed additional strain on the 
devices program.

                                COVID-19

    It is hard to overstate the impact the global pandemic has 
had on CDRH and the entire Agency, as it did for so many 
individuals, organizations, and communities around the world. 
Responding to this public health emergency (PHE) became central 
to our work and pushed us into a continuous all-hands-on-deck 
status, working oftentimes literally around the clock to 
facilitate the development and availability of pandemic-related 
devices as quickly and safely as possible. FDA's work to 
support access to devices for the COVID-19 response began in 
January 2020--before the PHE was declared in the U.S. and 2 
months before the pandemic was declared worldwide--due to the 
immediate need for COVID-19 tests and testing supplies, 
collection kits, personal protective equipment (PPE), 
ventilators, and other devices. To help combat the COVID-19 
pandemic, FDA and CDRH staff have continued to go well beyond 
normal operating procedures to help ensure the availability of 
appropriately safe and effective COVID-19-related devices as 
quickly as possible.

    From early in the pandemic, CDRH has actively reached out 
to and engaged other government agencies, medical device 
developers and international regulatory agencies, among other 
stakeholders. CDRH continues to hold weekly virtual town halls 
with industry to address COVID-19 test development and 
validation, as well as additional webinars and town halls 
addressing other policies and questions including PPE, 3D 
printed swabs and manufacturing disruptions during the public 
health emergency. CDRH staff have also interacted frequently 
with test developers and manufacturers through the Pre-
Emergency Use Authorization (PEUA) process, including rolling 
reviews of information that helped to further expedite 
emergency use authorization (EUA) of critical medical devices 
for patients and health care professionals on the front lines. 
Since the beginning of the pandemic, CDRH has prioritized at-
home tests, balancing speed with safety to ensure COVID-19 
tests are appropriately accurate and reliable as supported by 
valid scientific evidence. CDRH has authorized 19 over-the-
counter (OTC) at-home tests, resulting in hundreds of millions 
of additional OTC tests available monthly to American 
consumers. CDRH also took several additional steps, including: 
facilitating OTC COVID-19 test availability by issuing updated 
templates for EUA requests to streamline authorization of OTC 
tests; partnering with the National Institutes of Health (NIH) 
on the Independent Test Assessment Program (ITAP) to support 
FDA's evaluation of OTC COVID-19 tests that have the potential 
for manufacturing at significant scale, which resulted in five 
OTC authorizations of tests; and triaging our review efforts to 
focus on tests that ensure the biggest public health impact. We 
continue to grant EUA requests and take other actions, and we 
are proud that these contributions continue to help to 
facilitate the availability of critical devices and supplies 
for health care providers and patients.

    We also saw innovators across the device ecosystem mount a 
remarkable response--medical device manufacturers large and 
small turning their production lines to different types of 
devices, and non-traditional manufacturers who came forward to 
manufacture devices for the first time--all to meet the needs 
of an unforgiving pandemic. Our team worked closely with them, 
night and day, to review EUA and Pre-EUA submissions, and the 
volume of EUA requests quickly surpassed (by several orders of 
magnitude) that of any prior PHE or emergency. It is important 
to appreciate that this enormous addition to our workload to 
review EUA and Pre-EUA submissions could not be supported by 
MDUFA funds. FDA engaged in an unprecedented effort to engage 
with sponsors from the outset, to provide regulatory 
flexibility where appropriate, and to handle the influx of EUA 
submissions along with a simultaneously increasing volume of 
MDUFA work. In doing so, FDA contended with a workload that far 
exceeded our capacity.






         LFDA has received approximately 8,000 EUA and 
        Pre-EUA requests for devices since January 2020 
        (including over 900 so far in fiscal year 2022), and 
        continues to receive over130 EUA and PEUA submissions a 
        month.

         LTo date, we have granted EUAs or traditional 
        marketing authorizations to nearly 2,300medical devices 
        for COVID-19, including 15-times more EUAs for this PHE 
        than all other previous PHEs combined. This includes 
        ventilators and novel devices such as extra corporeal 
        blood purification devices, as well as novel 
        indications for devices such as continuous renal 
        replacement therapy devices, for which FDA had not 
        issued EUAs before. All in all, CDRH has reviewed and 
        cleared almost 1,400 510(k) devices for COVID-19 and 
        future pandemics.

         LWe also issued 28 guidance documents (as well 
        as 21 revisions) outlining policies to help expand the 
        availability of medical devices needed in response to 
        COVID-19.

         LFDA also supported authorization and patient 
        access to EUA devices and other devices through 
        monitoring safety signals and medical device reports, 
        publishing 23 letters to health care providers and 97 
        safety communications.

    During 2020 and 2021, we also experienced an increase in 
conventional premarket submissions, as noted above. The 
enormous COVID-19-related workload taken together with the 
increase in our ``regular'' workload inevitably led to some 
delays and a backlog in the medical device review process.

    FDA appreciates the impact this has had on companies across 
the country. This is why we have been transparent about the 
backlog of device submissions, issuing public communications 
and discussing expected impacts for sponsors during town halls, 
webinars, and in meetings with industry and other stakeholders. 
This is also why we have worked hard to reverse the backlog, 
for COVID-19 and non-COVID-19 devices, all while continuing to 
respond to the pandemic. Among other actions, we have adopted 
agile, interactive, and innovative approaches to review of EUA 
requests, published dozens of guidance documents and ``EUA 
templates'' to clarify agency recommendations and streamline 
review, implemented a front-end triage process to identify 
devices that would have the greatest impact on public health, 
reallocated our staff and resources from product areas less 
impacted by COVID-19 to those with increased submission volume, 
and made use of overtime. We greatly appreciate the support 
from Congress, particularly in the form of supplemental funding 
we used to leverage contractors and to hire temporary staff to 
help review EUAs.

                          MDUFA IV Performance

    The strain from the pandemic, as well as a workload that 
exceeded assumptions made in the MDUFA IV agreement, resulted 
in failure to meet some of our MDUFA IV goals. Specifically, we 
fell short of our goals, or are likely to, in the following 
areas:

         LFor fiscal year 2020, seven of 16 review 
        goals \35\ are still pending, six were met, and three 
        goals were missed. The missed goals include:
---------------------------------------------------------------------------
    \35\  MDUFA IV Commitment Letter (fda.gov)

---------------------------------------------------------------------------
                ` LThe substantive interaction goals for:

                   L180-day PMA supplements, and

                   L510(k)'s.

                ` LThe decision goal for Dual 510(k) and CLIA 
                Waiver by Applications with no advisory 
                committee input.

         LFor fiscal year 2021, seven of 16 review 
        goals \36\ are still pending, three have met the goal, 
        and six goals were missed. The missed goals include:
---------------------------------------------------------------------------
    \36\  MDUFA IV Commitment Letter (fda.gov)

---------------------------------------------------------------------------
                ` LThe substantive interaction goal for:

                   LOriginal PMAs and panel-track 
            supplements,

                   LPMA 180-Day supplements, and

                   L510(k)'s.

                ` LThe decision goals for:

                   LOriginal PMAs and panel-track 
            supplements with no advisory committee input,

                   L180-Day PMA supplements, and

                   L510(k)'s.

    FDA strives to meet all of our commitments, and we have 
built in additional transparency and accountability mechanisms 
in MDUFA V (which we will discuss in the next section). We also 
have statutory obligations to report to Congress on how we 
address and rectify missed performance goals. As we noted in 
the fiscal year 2021 MDUFA annual performance report, FDA will 
continue to prioritize COVID-19-related work to address the 
ongoing public health need for safe and effective medical 
devices. As the COVID-19 pandemic continues to evolve, the 
volume of new EUA submissions for COVID-19-related products 
should begin to lessen in non-in vitro diagnostic (IVD) 
offices. This reduction will allow FDA to begin focusing review 
resources back to MDUFA-related activities, bringing review 
performance back to ``pre-COVID-19'' levels for non-IVD 
offices. FDA has already begun to reverse submission delays, 
and review times have improved significantly. Submissions for 
non-IVD products under review continue to generally meet MDUFA 
goals. The IVD Office is hiring, and will continue to hire, 
additional staff and contractors to address the increased 
volume of work in the office.

                        MDUFA V Reauthorization

    MDUFA V supports both FDA's capacity to assess new medical 
device technologies and continues to provide a predictable, 
transparent path to market, while addressing critical resource 
gaps. The agreement strengthens our commitment to the 
foundation of the program--infusing more resources and people 
to review premarket device submissions. It also enhances 
accountability for FDA's performance and operations, and makes 
critical investments in the future of the program, to assure 
FDA has the resources to handle oversight and review of the 
robust pipeline of new technology and the innovations of 
tomorrow. It is an agreement that will ultimately lead to 
patients having timely access to new devices while upholding 
FDA's standards. Specifically, MDUFA V:

         LProvides FDA with $1,783,931,700 over 5 
        years, helping assure the CDRH and CBER has resources 
        it needs to handle a continually increasing workload 
        resulting from strong innovation in the U.S., which 
        impacted FDA before the COVID-19 pandemic.

         LSupports improved performance across device 
        types, to help assure U.S. patients have as rapid 
        access as possible to innovative devices that are safe 
        and effective.

         LIncreases accountability for the MDUFA 
        program, to help assure critical transparency for 
        industry, patients, and other stakeholders and helps 
        assure FDA continues to meet its commitments under 
        MDUFA V:

                Y LIncluding an innovative new mechanism for 
                add-on payments, unique to the MDUFA program, 
                where approximately $115 million will be 
                available for ``add-on'' funding during MDUFA 
                V. If specified goals for 510(k)'s, PMAs, De 
                Novo requests, and Pre-Submissions are met in 
                fiscal year 2023-2025, FDA would apply 
                additional user fees in fiscal year 2025-2027 
                to support improvements in those goals.

                Y LProviding for annual hiring targets for new 
                positions, for the first time in MDUFA's 
                history. If the target is missed by a specified 
                percentage, a formula will be applied to 
                calculate an offset of registration fees to be 
                applied in the next annual fee setting cycle.

                Y LProviding a cap for operating reserves in 
                the carryover balance, which brings MDUFA into 
                alignment with the other medical product user 
                fee programs. If the carryover operating 
                reserves grow beyond the prespecified level, 
                additional funds will be sent back to industry 
                in the form of offsets to registration fees.

                Y LRetaining an independent contractor to 
                conduct a MDUFA Workforce Data Assessment which 
                would include:

                  ` LAssessing current methodologies and data 
            and metrics available to represent MDUFA full time 
            equivalent (FTE) resources (e.g., FTE burn and 
            positions engaged in MDUFA process activities), 
            including the subset funded by user fees, for each 
            applicable Center and office; and

                  ` LDeveloping recommendations for improved 
            methodologies and data and metrics to represent 
            MDUFA FTE resources, including the subset funded by 
            user fees.

                Y LProviding additional transparency in the 
                form of new reporting to industry and the 
                public on use of MDUFA resources.

    The agreement supports advancement of the patient 
perspective in regulatory decisions, continuation and expansion 
of the use of consensus standards to support device development 
and testing, leveraging of real-world evidence for regulatory 
decisionmaking, and enhanced coordination with international 
regulators, among other priorities.

    MDUFA V pilots an innovative program to provide earlier, 
more frequent, and more strategic engagement with sponsors of 
products designated under the Breakthrough Devices Program and 
included in the Safer Technologies Program (STeP). The Total 
Product Lifecycle (TPLC) Advisory Program Pilot (TAP Pilot) 
will begin with a ``soft launch'' of up to 15 products in one 
CDRH Office of Health Technology (OHT) in fiscal year 2023, and 
will expand to enroll up to 325 products across multiple OHTs 
by the end of MDUFA V. The program has full accountability, 
starting with the fact that it is being implemented as a 
voluntary pilot where we will track over half-a-dozen metrics, 
and will assess the pilot program and provide a public report 
on progress during MDUFA V.

    TAP will build upon lessons learned from these programs, as 
well as FDA's experience during the COVID-19 pandemic response, 
of engaging with sponsors through the pre-EUA process, which 
was critical for facilitating availability and accessibility of 
important products. The program will help to assure that device 
developers have a clear, predictable path to market such that 
patients have timely access to new devices. We believe it will 
help innovators avoid pitfalls in early product development, 
better ensure a clear, predictable path to market from 
development to bedside so that devices actually reach patients, 
and will continue to foster the innovation pipeline.

                            MDUFA V Overview

    As we look toward efficient and expeditious implementation 
of our new agreement, FDA will continue to face significant 
challenges after two long years of a global pandemic that 
continues to significantly impact our day-to-day work:

         LFDA continues to receive a high volume of EUA 
        and Pre-EUA requests for tests and other devices.

         LAn increasing number of EUA-authorized 
        devices are being submitted for full marketing 
        authorization. This includes 15 EUA-authorized devices 
        that have already received full marketing authorization 
        and an additional 16 under review.

         LWe continue to see an increase in submissions 
        for devices that do not have EUAs, but are seeking 
        marketing authorization for use during COVID-19 and 
        future pandemics. These include various types of PPE, 
        tests and testing supplies, needles and syringes, 
        ventilators and respiratory assistive devices, dialysis 
        equipment, and infusion pumps, among others.

    We are committed to continuing the return to ``normal 
operations,'' but also know we will sustain some setbacks to 
our overall performance. This includes a continuing backlog of 
traditional device submissions for review. However, we have 
also begun to turn the corner--we have reduced the backlog of 
submissions by 45 percent. And even while in the middle of the 
pandemic, CDRH continued to authorize a record number of novel 
devices--over 100 each year--and we have been designating an 
increasing number of Breakthrough devices each year. FDA has 
demonstrated time and time again that we do our best to meet 
and exceed our commitments; and, the fact there are more safe 
and effective medical devices on the market--more options for 
patients--than at any other time in U.S. history is a testament 
to these ongoing efforts. This makes all the difference for 
U.S. patients, and relies in part on the resources our program 
has to fulfill our mission. The MDUFA V agreement will be 
instrumental in getting the program fully back on track, 
allowing patients to continue to benefit from the robust 
innovation pipeline for medical devices in the U.S. We 
appreciate patience and support as we worked toward an 
agreement and, with the support of Congress and the MDUFA 
reauthorization, we can continue to accelerate access to new 
technologies that meet FDA's regulatory standards.

                               CONCLUSION

    User fees are critical to ensuring that FDA has the 
resources needed to conduct reviews in a timely fashion without 
compromising the Agency's high standards--all part of getting 
safe and effective medical products to patients sooner. The 
user fee programs are an example of what FDA, Congress, 
industry, and other stakeholders can achieve when working 
together toward the same goal. While we have made demonstrable 
progress in bringing drug and biological products and medical 
devices to market as quickly as possible, we know that more 
work remains to continue to enhance our review processes, 
including investing in the hiring and retention of scientific 
talent (particularly in areas of rapid growth such as cell and 
gene therapy), maximizing the use of new tools and regulatory 
science, and investing in a bioinformatics infrastructure to 
support the evolving needs of the programs. The reauthorization 
of PDUFA, GDUFA BsUFA, and MDUFA will allow FDA to build upon 
the programs' demonstrated success, further benefiting patients 
and affirming our Nation's standing as a global leader in 
biomedical innovation.

    Thank you for the opportunity to testify today. We will be 
happy to answer your questions.

                         QUESTIONS AND ANSWERS

Response by Patrizia Cavazzoni to Questions From Senator Casey, Senator 
 Hassan, Senator Smith, Senator Paul, Senator Cassidy, Senator Scott, 
                         and Senator Tuberville


                             senator casey


     At our previous User Fee Agreements hearing with industry 
representatives, I asked about the role of patient voices in 
reviewing new therapies, particularly for rare diseases. I 
subsequently introduced S. 4071, the Helping Experts Accelerate 
Rare Treatments Act of 2022 with Senator Tim Scott. One of my 
aims with this legislation is to facilitate greater engagement 
with patients with rare diseases and specialized experts 
throughout the review process for therapies targeting their 
rare conditions. I have heard from patients with rare diseases 
who do not feel as though their voices are being heard, that 
the review and decision processes are sufficiently transparent, 
or that reviewers consistently have access to the specialized 
expertise necessary to appropriately consider these 
applications, due to the unique experiences of these patients 
and the challenges posed by necessarily small study population 
sizes.

    Question 1. How can the FDA integrate more patient and 
expert clinician perspectives into the review process--from 
pre-application to post-approval--to better inform the entire 
review process, particularly when evaluating treatments for 
rare diseases?

    Answer 1. FDA recognizes the importance of the patient and 
expert clinician perspective to inform drug development and 
regulatory decisionmaking. FDA incorporates the patient 
perspective in many ways, through patient listening sessions 
that focus on patient experiences, perspectives, and needs 
related to their health or a disease, patient focused drug 
development meetings that characterize the most significant 
symptoms of their condition and the impact of the condition on 
daily life and patients' approaches to treatment, and through 
public advisory committees that solicit independent expert 
advice where patients and expert clinicians often provide their 
expertise on rare diseases and conditions, which informs 
regulatory decisionmaking.

    In addition, FDA convenes rare disease stakeholders in 
public meetings to discuss and provide recommendations on 
common issues in development of medical products across the 
spectrum of rare diseases. FDA also utilizes public dockets, 
through which the public can submit electronic and written 
comments on specific topics to FDA.

    Patient experience data is an important part of the review 
process. Specifically, FDA reviewers assess a product's 
benefits and risks based, among other things, on data from 
patients. For patient experience data, this usually takes the 
form of Patient-Reported Outcomes (PROs) or other types of 
Clinical Outcome Assessments (COAs). In clinical trials, PROs 
or COAs can be primary, secondary, or supportive endpoints. In 
addition, patient experience data can provide contextual or 
supporting information (e.g., tolerability, patient priorities 
or concerns). Thus, patient experience data is an important 
component of a marketing application.

    Question 2. Are there opportunities to enhance CDER's 
review--for example, through improved biomarker or surrogate 
endpoint selection--by leveraging expertise beyond the FDA, 
such as the National Institutes of Health?

    Answer 2. FDA is exploring those opportunities. Recently, 
in May 2022, FDA and the Duke-Margolis Center for Health Policy 
convened a virtual public workshop to present best practices 
and use cases for successfully bringing forward evidence 
generated through translational science for regulatory 
submissions. The workshop presented efforts from FDA, NIH, 
academia, patient groups, and industry to support surrogate 
endpoint and other biomarker identification and development for 
use in therapeutic development and regulatory submissions. In 
addition, it provided successful examples of using 
translational science in the development of therapeutics. These 
types of engagements foster interaction and discussion among 
stakeholders who are developing these tools and implementing 
them in therapeutic development programs.


                             senator hassan


    Question 1. In April 2022, the House Committee on Oversight 
and Reform released an interim report detailing their findings 
into these conflicts of interest. The report revealed that at 
least 22 McKinsey consultants worked on related projects for 
both the FDA and opioid manufacturers, some at the very same 
time. It is clear that McKinsey took advantage of gaps in FDA's 
contracting procedures by failing to disclose its potential 
conflicts of interest during the contract application process.

    In light of these failures to disclose, is it appropriate 
for FDA to continue relying exclusively on contractors to self-
disclose their conflicts?

    Answer 1. FDA follows contracting regulations that apply 
across the entire Federal Government. FDA, as part of its 
solicitation and contract award process, includes 
Organizational Conflict of Interest (COI) language and clauses 
that outline what the contractor must do before, during, and 
after award. FDA relies on the Contractor to review the 
requirement and assure there is no actual or apparent COI on 
the part of either the Contractor's organization or its 
individual employees in performance of the contract. If so, the 
Contractor reports the potential COI and submits a mitigation 
plan for review and approval. This process is in compliance 
with the requirements regarding COI as delineated in the 
Federal Acquisition Regulations (FAR).

    The FAR applies governmentwide and sets out consistent 
policies and requirements for Federal contracts. Modifying 
those requirements for one agency would interfere with that 
consistent approach.


                             senator smith


    Question 1. Senator Braun and I have introduced 
legislation, the Expanding Access to Low-Cost Generics Act, 
which would address the issue of generic drug products 
``parking'' their 180-day market exclusivity and delaying entry 
to market. The Food and Drug Administration's fiscal year 2023 
budget includes a proposal to address ``parking'' by specifying 
that the FDA can approve subsequent applications unless a first 
applicant begins commercial marketing of the drug to ensure 
that exclusivity lasts 180 days rather than multiple years. Dr. 
Cavazzoni, what is FDA's perspective on the approach to address 
parking outlined in our Expanding Access to Low-Cost Generics 
Act? Would FDA be supportive of the policy outlined in our 
bill? Would this policy help bring more low-cost generic drugs 
to market?

    Answer 1. The Expanding Access to Low-Cost Generics Act 
would address the delayed access to generic drugs that 
currently occurs when unapproved first applicants who remain 
eligible for 180-day exclusivity block subsequent applicants 
who are otherwise ready for approval and marketing. FDA is 
supportive of the goals of this legislation, and the Agency 
anticipates it would bring low-cost generic drugs to the market 
more quickly than happens under current law in circumstances 
where a subsequent applicant who is otherwise ready for 
approval and marketing is blocked solely by an unapproved first 
applicant's eligibility for 180-day exclusivity (and certain 
other conditions are met).

    Question 2. I have been tracking a new challenge brought by 
Genus Medical Technologies v. FDA, in which the D.C. Circuit 
required the FDA to regulate products that meet both the drug 
and device definitions as medical devices. I believe the FDA 
should have the discretion to regulate combination products as 
drugs or medical devices. Dr. Cavazzoni, how would clarifying 
the regulation of products subject to the Genus decision help 
avoid delays in approvals of drugs? Can you list out the 
categories of products that would be subject to the Genus 
decision? Is it important to include all of these categories of 
products in clarifying legislation?

    Answer 2. We agree that FDA should be able to regulate 
combination products under the drug or device pathways, and the 
Genus decision does not impact our determination regarding 
which constituent part of a combination product provides the 
primary mode of action.

    Legislation clarifying that all contrast agents, 
radiopharmaceuticals, and OTC monograph products are drugs (as 
they were regulated before the Genus decision), would help 
avoid delays in approvals of these products. These categories 
capture nearly all the products that may be impacted by Genus. 
The one category of products not included in this list would be 
certain ophthalmic products that prior to Genus were regulated 
as drugs, but post-Genus would be regulated as drug-led 
combination products. We do not think it is necessary to 
clarify that these should be regulated as drugs instead of drug 
led combination products, because for the most part, this 
change is not likely to have a significant impact on these 
products, as explained in our March 2022 Guidance entitled 
Certain Ophthalmic Products: Policy Requiring Compliance with 
21 CFR Part 4. Additionally, there may be a few other products 
that do not fall within the categories described above, that 
may transition from being regulated as drugs to being regulated 
as devices as a result of the Genus decision. However, without 
expressly restoring the discretion FDA exercised prior to the 
Genus decision, it is not likely feasible to ensure that no 
products transition from being regulated as drugs to being 
regulated as devices as a result of Genus.

    Question 3. I have been working with Senator Cassidy on a 
proposal that would accelerate the therapeutic equivalence (TE) 
rating process for complex generic drugs. I appreciate the 
FDA's willingness to work with us on this policy proposal. 
Following up on your comments on the TE process during the 
hearing, I had some additional clarifying questions.

        Question 3(a). Does the 505(b)(2) pathway serve as a 
        suitable pathway for complex generic products?

    Answer 3. The 505(b)(2) pathway is generally not an 
appropriate pathway for a drug product that is a duplicate of 
another approved drug product, including a complex drug 
product, that is eligible for approval under section 505(j) of 
the FD&C Act. FDA generally refuses to file a 505(b)(2) NDA for 
a drug that is a duplicate of a listed drug and is eligible for 
approval under section 505(j) of the FD&C Act. See 21 CFR 
314.101(d)(9). However, in certain circumstances where FDA is 
unable to obtain information needed to ensure that a product is 
safe and effective because of the constraints of the 505(j) 
pathway and our current regulations, a 505(b)(2) NDA may be 
appropriate.

    Question 4. Has the FDA already approved and provided TE 
ratings for complex generics via the 505(b)(2) pathway? What 
additional information is provided in the subsequent citizen 
petitions?

    Answer 4. FDA has provided TE ratings for products approved 
via the 505(b)(2) pathway. However, the 505(b)(2) pathway is 
not designed to provide the information needed for the Agency 
to make a TE evaluation at approval. Rather, in approving a 
505(b)(2) NDA, FDA makes a finding that the 505(b)(2) NDA meets 
the statutory standards for approval, including those for 
safety and substantial evidence of effectiveness. The statutory 
and regulatory requirements for approval of a 505(b)(2) NDA are 
not aligned with the criteria for establishing therapeutic 
equivalence, and 505(b)(2) applications currently are not 
required to submit to FDA all the information needed to make 
these TE evaluations. For example, in order to a make TE 
evaluation FDA must determine, among other things, that the 
relevant products are bioequivalent in order to find the 
products to be therapeutic equivalents, but there is no 
statutory, regulatory, or scientific requirement that 505(b)(2) 
NDAs must establish bioequivalence to another listed drug as a 
requirement for approval. There are also many different types 
of 505(b)(2) applications, and the evidence needed to make a TE 
evaluation for these products can vary. For more complex 
505(b)(2) NDAs (e.g., drug-device combination products, 
products containing complex active ingredients), FDA would need 
to consider different scientific and regulatory issues in order 
to make a TE evaluation than those scientific and regulatory 
issues that were necessary to consider in determining whether 
the 505(b)(2) NDA met the applicable legal and regulatory 
requirements for approval. In general, a citizen petition for a 
TE evaluation would need to include information regarding the 
pharmaceutical equivalence and the bioequivalence of the drug 
product approved in a 505(b)(2) NDA and another listed drug 
product. The exact information to demonstrate these factors 
would likely differ depending on the complexity of the product 
involved.

    In contrast, the 505(j) pathway is designed to provide the 
data and information needed for a TE evaluation to be made at 
approval.

    Question 5. What resource demands would be placed on FDA if 
Congress directed FDA to make a TE determination at the time of 
approval rather than through a separate citizen petition 
process? How can Congress address these resource demands?

    Answer 5. FDA does not currently make TE evaluations for 
505(b)(2) NDAs at the time of approval. Because the statutory 
and regulatory requirements for approval of a 505(b)(2) NDA are 
not aligned with the criteria for establishing therapeutic 
equivalence, FDA would need to consider different scientific 
and regulatory issues to make a TE evaluation than those 
scientific and regulatory issues that were necessary to 
consider in determining whether the 505(b)(2) NDA met the 
applicable legal and regulatory requirements for approval. In 
addition, 505(b)(2) NDAs currently are not required to submit 
to FDA all the information needed to make a TE evaluation at 
the time of approval, meaning that FDA might not have all the 
necessary information to make a TE evaluation at the time of 
approval or 505(b)(2) applicants might have to generate 
additional information beyond that currently required by the 
statute and regulations to obtain a TE evaluation at the time 
of approval. As a result, we anticipate that there would be 
additional resource demands placed upon FDA if Congress 
directed the Agency to make TE evaluations for 505(b)(2) NDAs 
at the time of approval. The extent of those additional 
resource demands would likely depend, in part, on whether 
Congress directed FDA to make TE evaluations for all 505(b)(2) 
NDAs or only a subset of 505(b)(2) NDAs, as TE evaluations for 
more complicated 505(b)(2) NDAs would likely be more resource 
intensive. In addition, resources would be required for FDA to 
make recommendations on the type of information that should be 
submitted with a 505(b)(2) application to allow for a TE 
evaluation in specific circumstances.


                              senator paul


    Question 1. FDA recently released a direct-to-final 
guidance document changing the regulatory standard for 
ophthalmic drugs packaged with eye cups, eye droppers, or other 
dispensers to treat them as combination products. These 
products were previously regulated pursuant to 21 C.F.R. 
200.50, which stated that the eye cups, eye droppers, or other 
dispensers were part of the drug product and not device 
components. FDA stated in its guidance that it was implemented 
with immediate force and effect-and no opportunity for notice 
and comment--``given the urgency of these issues following the 
decision of the U.S. Court of Appeals for the District of 
Columbia Circuit in Genus Medical Technologies LLC v. U.S. Food 
and Drug Administration [Genus Decision].''

    Even though the Genus decision pertained only to medical 
imaging products, FDA appears to have conveniently expanded 
that opinion to other types of medical products. In doing so, 
FDA revoked a regulation that has been in place since 1975 with 
the infrequently used mechanism of direct-to-final guidance 
depriving the public of the notice and comment process. Please 
explain why FDA felt that the Agency had the authority to 
revoke a regulation through guidance, which is non-binding and 
does not have the force and effect of law, rather than revising 
or revoking its regulations through notice and comment 
rulemaking. Further, please explain why FDA concluded that the 
Genus decision applied to 21 C.F.R. 200.50, and why the Agency 
felt it was impossible to allow for notice and comment on the 
guidance document issued.

    Thank you.

    Answer 1. Although the product at issue in Genus involved a 
medical imaging product, the court in the Genus decision stated 
``[e]xcepting combination products, devices must be regulated 
as devices and drugs--if they do not also satisfy the device 
definition--must be regulated as drugs.'' In implementing the 
Genus decision, FDA determined that the language in 21 CFR 
Sec. 200.50(c) indicating that eye cups, eye droppers, and 
other dispensers intended for ophthalmic use are regulated as 
drugs when packaged with ophthalmic drugs was made obsolete, 
because these articles meet the device definition in section 
201(h) of the FD&C Act.

    In addition, we do not believe the change from regulating 
certain ophthalmic products as drug-led combination products 
rather than drugs is likely to have a significant impact on 
these products. As we explained in our March 2022 Guidance 
entitled Certain Ophthalmic Products: Policy Requiring 
Compliance with 21 CFR Part 4, we made the determination that 
prior public participation for this guidance document was not 
feasible or appropriate because FDA needed to communicate its 
compliance policy for certain ophthalmic products in a timely 
manner given the urgency of these issues following the decision 
of the U.S. Court of Appeals for the District of Columbia 
Circuit in Genus. However, even though we did not provide an 
opportunity for prior public participation, the guidance 
remains subject to comment in accordance with FDA's good 
guidance practices (GGP) regulation, and FDA will consider all 
comments received and determine whether revisions to the 
guidance document are appropriate. To date, we have not 
received any comments on the guidance in the docket.


                            senator cassidy


    Question 1. In recent months, FDA has issued more Complete 
Response Letters (CRLs) than approvals of applications for 
drugs to treat patients with chronic kidney disease [including 
CRLs on veverimer, taurolidine, tenapanor, roxadustat, 
bardoxolone and vadadustat]. How is FDA applying its benefit/
risk framework to new drugs to treat this chronically ill 
patient population at high risk of serious cardiovascular and 
other complications, and working with drug developers to ensure 
there are clear rules of the road to demonstrate safety and 
efficacy?

    Answer 1. FDA recognizes that patients with chronic kidney 
disease have significant unmet medical needs that would benefit 
from novel safe and effective therapies. Since 2012, FDA has 
been a close partner with the American Society of Nephrology in 
a public-private partnership, the Kidney Health Initiative 
(KHI), with a mission to catalyze innovation and the 
development of safe and effective patient-centered therapies 
for people living with kidney diseases. CDER, CBER, and CDRH 
have all been active participants in this partnership.

    FDA meets with sponsors regularly, including those 
developing drugs to treat patients with chronic kidney disease, 
to provide advice regarding the design of a development program 
that would have the potential to generate the data needed to 
demonstrate that a drug is safe and effective.

    Although FDA is not able to provide specific comment on 
unapproved applications, it is important to note that a 
marketing application might not be approved for a number of 
reasons. To the extent that a deficiency may relate to a 
determination that a drug has not been shown safe for a 
particular use, FDA applies a structured benefit-risk 
assessment framework, which involves making an informed 
judgment as to whether the benefits (with their uncertainties) 
of the drug outweigh the risks (with their uncertainties and 
approaches to managing risks). This assessment takes into 
account the evidence of safety and effectiveness submitted by a 
sponsor in an application as well as many other factors, 
including the nature and severity of the condition the drug is 
intended to treat or prevent, the benefits and risks of other 
available therapies for the condition, and any risk management 
tools that might be necessary to ensure that the benefits of 
the drug outweigh its risks.

    Question 2. Historically, the nephrology division at the 
FDA had one of the lowest rates of new drug applications 
submitted, particularly compared to oncology and cardiology. 
How does the FDA ensure that the legal standards are being 
applied equally by each division?

    Answer 1. Many drug products for kidney diseases are 
regulated by the same division as those for heart disease 
(currently, the Division of Cardiology and Nephrology; 
formerly, the Division of Cardiovascular and Renal Products); 
FDA does not believe there is a different application of legal 
and regulatory standards within that division that would be 
responsible for differences in the number of submissions across 
these therapeutic areas. Instead, a variety of factors would be 
expected to influence the level of interest product developers 
may have in any given therapeutic area. A key driver of 
interest in drug development is often the advancement of 
scientific knowledge about the pathophysiology of disease; for 
example, as scientific research led to increasingly specific 
understanding of how certain cancers develop and grow, novel 
specific drug targets were revealed that allowed for a dramatic 
increase in interest in drug development for the field of 
oncology. Furthermore, scientific advances often generate the 
information needed to support novel surrogate endpoints for use 
in clinical trials, especially for diseases that progress 
slowly.

    As an example of FDA's involvement in facilitating drug 
development in kidney disease through advancing the science, 
FDA nephrologists co-led a project of the aforementioned Kidney 
Health Initiative (KHI) to identify endpoints that could be 
used as a basis for approval for IgA nephropathy, a disease for 
which there had been little progress in its treatment with no 
licensed or approved therapies. Collaborating with an 
international group of academic and industry scientists in the 
pre-competitive space, a review of the available evidence led 
to support for the use of a surrogate endpoint in this disease; 
in December 2021, FDA approved Tarpeyo (budesonide), using 
accelerated approval, for certain patients with IgA nephropathy 
on the basis of the surrogate endpoint supported by the KHI 
project.

    Examples of drug approvals during 2021 that are important 
to patients with kidney disease include Lupkynis (voclosporin) 
to treat active lupus nephritis; Farxiga (dapagliflozin) to 
reduce the risk of kidney and heart complications in adults 
with chronic kidney disease at risk of progression; Kerendia 
(finerenone) to reduce the risk of kidney and heart 
complications in chronic kidney disease associated with type 2 
diabetes; and Korsuva (difelikefalin) to treat moderate-to-
severe itching associated with chronic kidney disease in adults 
undergoing hemodialysis. With advancements in the science of 
kidney diseases, FDA is hopeful that additional safe and 
effective therapies will be discovered to help patients with 
chronic kidney disease.

    Question 2. A pillar of the PDUFA VII commitment letter is 
greater communication between FDA and drug sponsors to ensure 
that drug development programs have clear metrics, including 
for safety and clinical end points. How will these new 
commitments reduce unexpected analyses or standards introduced 
late in the development or application process for therapies 
developed to treat patients with kidney disease?

    Answer 2. As noted, one of the goals for PDUFA VII 
commitments is to increase communication between FDA and 
sponsors to enable more effective and efficient drug 
development, including for drugs intended to treat kidney 
disease. A few examples include:

    Question 3. Rare Disease Endpoint Advancement (RDEA) pilot 
program: endpoint development for rare diseases has been 
historically challenging due to lack of regulatory precedent, 
small trial populations, and limited understanding of disease 
natural history. To help address these challenges, the new 
pilot program is intended to provide a mechanism for sponsors 
to have increased, focused, and repeated interactions and 
communication with FDA to identify better ways to develop novel 
clinical endpoints for rare diseases, including rare kidney 
diseases. The learnings from this pilot will be shared with the 
public to promote innovation and evolving science that can 
advance the development of novel endpoints and methodologies 
for use in rare disease clinical trials.

        Question 3(a). Communicating Anticipated Postmarketing 
        Requirements (PMRs): to provide more predictability in 
        the marketing application review stage, PDUFA VII 
        includes a new communication timeline for anticipated 
        PMRs. This timeline is based on earlier assessment of 
        the product safety data, and the timeline also allows 
        for thoughtful consideration of any anticipated 
        postmarketing studies that may be required.

        Question 3(b). Type D and INTERACT meetings, Follow-up 
        Opportunities: The new Type D meeting allows for 
        focused discussion of critical issues in a sponsor's 
        drug development program and for timely feedback from 
        FDA. INTERACT meetings allow for early interaction with 
        the Agency, before IND-enabling studies are conducted, 
        to discuss issues that may be critical to the success 
        of those studies, thus potentially reducing uncertainty 
        and wasted resources. Finally, the follow-up 
        opportunity provides a chance for sponsors to clarify 
        their understanding of feedback received during a 
        formal meeting with the Agency. This should also help 
        to reduce unexpected issues later in development.

    Answer 3. There are many other opportunities for sponsors 
to engage with FDA to obtain recommendations for a robust drug 
development program. While these examples of increased 
communication are intended to lead to increased predictability 
in drug development and review, it is important to point out 
that it is always possible that scientific questions could 
arise during our independent review of the full data sets that 
will generate a need for further analyses and engagement with 
the applicant, for example, on discovery of an unexpected 
safety event.

    Question 4. Another pillar of the commitment letter is 
building on a focus of Patient Focused Drug Development to 
ensure that the patient voice in incorporated into drug 
development decisionmaking. How can we ensure that FDA takes 
into consideration patient preferences and potential 
acceptability of tradeoffs between treatment benefit and risk 
outcomes in high risk diseases like kidney disease?

    Answer 4. FDA recognizes that the patient and expert 
clinician perspectives may be very important to inform drug 
development and regulatory decisionmaking. FDA provides 
opportunities to incorporate the patient perspective in many 
ways, including through patient listening sessions that focus 
on patient experiences, perspectives, and needs related to 
their health or a disease, and patient focused drug development 
meetings that characterize the most significant symptoms of 
their condition and the impact of the condition on daily life 
and patients' approaches to treatment. Some patient focused 
drug development meetings relevant to kidney disease have 
focused on: Alport Syndrome, focal segmental glomerulosclerosis 
(FSGS), C3 glomerulonephropathy, IgA nephropathy, membranous 
nephropathy, and primary hyperoxaluria. FDA also receives input 
through public advisory committees that solicit independent 
expert advice where patients and expert clinicians often 
provide their expertise on the diseases and conditions under 
discussion, which informs regulatory decisionmaking.

    In addition, FDA convenes stakeholders in public meetings 
to discuss and provide recommendations on common issues in 
development of medical products across the spectrum of 
diseases. For example, in December 2020, FDA and the National 
Kidney Foundation co-sponsored a scientific workshop on 
clinical trial considerations in developing treatments for 
early stages of chronic kidney disease. A survey of patients, 
which solicited how much risk versus potential benefit they 
would be willing to accept, informed the discussions at this 
workshop.

    Patient experience data may play an important role in the 
review process. Specifically, FDA reviewers assess a product's 
benefits and risks based, in part, on data from patients. For 
patient experience data, this can take the form of Patient-
Reported Outcomes (PROs) or other types of Clinical Outcome 
Assessments (COAs). In clinical trials, PROs or COAs can be 
primary, secondary, or supportive endpoints. In addition, 
patient experience data can provide contextual or supporting 
information (e.g., tolerability, patient priorities or 
concerns). Patient experience data is frequently a valuable 
source of data in a marketing application.


                             senator scott


    Question 1. Patients have expressed concerns that not all 
review divisions within FDA understand or apply the accelerated 
pathway appropriately. Some have even likened the experience to 
that of a ``lottery'' as to whether they'll be assigned a 
division with experience in ultra-rare conditions with well 
under 20,000 patients in the U.S.--and oftentimes only 2,000 or 
even 200 patients.

        Question 1(a). How is FDA using external expertise to 
        appropriately make risk-benefit decisions for rare and 
        ultra-rare diseases when safety is established, there 
        are no other treatment options, and the condition is 
        life threatening or significantly impacting quality of 
        life?

    Answer 1. FDA recognizes that there is significant unmet 
need for patients and families living with rare diseases as 
most rare diseases do not have approved therapies at this time. 
As further discussed below, these circumstances are considered 
and incorporated into FDA's approach to rare diseases, 
regardless of the regulatory pathway used or available for a 
particular development program.

    It is important to understand that FDA considers safety and 
clinical benefit in its review and this benefit-risk assessment 
takes into account the seriousness of the disease. Benefit-risk 
assessment is integrated into FDA's regulatory review of 
marketing applications. The benefit-risk assessment includes 
many factors, such as the nature and severity of the condition 
the drug is intended to treat or prevent, the benefits and 
risks of other available therapies for the condition, and any 
risk management tools that might be needed. As articulated in 
our 2019 draft guidance that addresses demonstrating 
substantial evidence of effectiveness, \1\ FDA recognizes that 
some patients and their caregivers are willing to accept less 
certainty about effectiveness in return for earlier access to 
much needed medicines. For example, for a life-threatening 
disease without any available treatment, FDA might accept the 
results of adequate and well-controlled investigations with 
less rigorous designs, such as historically controlled studies. 
FDA has approved many drugs for rare diseases by applying these 
principles, using both traditional and accelerated approval 
pathways, when there is evidence that the drug is effective. 
Importantly, rare disease drug development spans therapeutic 
areas. FDA has mechanisms and initiatives, such as policy 
councils and the Rare Diseases Team, to facilitate consistency 
across divisions around rare disease product development 
considerations, such as the use of accelerated approval and 
considerations related to regulatory flexibility.
---------------------------------------------------------------------------
    \1\  https://www.fda.gov/media/133660/download. When finalized, 
this will represent FDA's current thinking on this issue.

    FDA's clinical review staff take advantage of a multitude 
of resources to gain knowledge on rare diseases when the agency 
determines such advice would be helpful as FDA considers the 
risks and benefits of medical products, including those 
intended for rare diseases based on the statutory definition 
---------------------------------------------------------------------------
(i.e., <200,000 in the U.S.).

    Development and review of rare disease applications 
frequently involves challenging considerations that may benefit 
from discussion with external experts, such as at advisory 
committee meetings. FDA uses this authority to consult with 
external experts and to solicit their participation in advisory 
committee meetings as needed. FDA also communicates with 
relevant patient groups through our various patient listening 
sessions, patient and caregiver connection resource, and 
patient focused drug development meetings.

    In addition, FDA convenes rare disease stakeholders in 
public meetings to hear different perspectives, on common 
issues in development of medical products across the spectrum 
of rare diseases. Recognizing these existing structures and 
mechanisms to facilitate rare disease product development, FDA 
agrees that there is value in external input on rare disease 
product development considerations, including through advisory 
committee meetings and other for a (e.g., workshops) and will 
continue to optimize strategies to leverage and obtain diverse 
expertise in the science and challenges of working with small 
populations.

    When needed for rare diseases for which there is relevant 
expertise across the Agency, the Center for Drug Evaluation and 
Research (CDER), the Center for Devices and Radiological Health 
(CDRH), and the Center for Biologics Evaluation and Research 
(CBER) regularly consult the review staff in other centers. 
Beside the many available cross-Agency training and information 
sharing opportunities about rare diseases, extensive online 
medical information resources are available to FDA review staff 
through FDA's library for obtaining the most up-to-date medical 
literature about specific rare diseases.

    Question 2. Has the review division consulted with patients 
about any safety signals or the benefit-risk assessment it is 
making before removing the accelerated approval pathway from 
consideration?

    Answer 2. FDA recognizes the importance of the patient 
perspective to inform drug development and regulatory 
decisionmaking, regardless of the approval pathway utilized.

    The Agency uses a variety of mechanisms to obtain the 
patient and caregiver perspective on safety issues and the 
balance of benefits and risks. Such mechanisms include patient 
listening sessions and patient focused drug development 
meetings, which are typically planned and held by or in 
collaboration with patient advocacy organizations, and public 
advisory committee meetings. Often, review staff hear first-
hand from patients on their experiences in living with a 
specific rare disease during patient focused drug development 
meetings and listening sessions. During public advisory 
committee meetings, FDA solicits independent advice from 
external experts, which often includes patients, who provide 
their expertise on their condition to inform regulatory 
decisionmaking. Patient perspectives obtained from these 
different mechanisms often include the acceptability of certain 
risks given a drug's demonstrated benefits.

    With respect to the accelerated approval pathway, 
accelerated approval requires a determination that the product 
has an effect on a surrogate endpoint--or an intermediate 
clinical endpoint--that is reasonably likely to predict 
clinical benefit. The assessment that a surrogate endpoint is 
reasonably likely to predict clinical benefit depends on the 
state of the science, including, for example, the depth of 
understanding of the pathogenesis of the disease. . The 
pathophysiology of some rare diseases remains incompletely 
understood, such that there may be considerable uncertainty in 
whether a drug's effect on a biomarker, for example, is 
reasonably likely to predict clinical benefit. Rare disease 
drug development is a dynamic and rapidly advancing field, so 
the optimal development pathway for a given product for a 
certain rare disease may evolve over time and we work closely 
with sponsors to consider the current state of science. The 
above mentioned patient and caregiver perspectives are 
carefully considered in decisions regarding accelerated 
approval of marketing applications.

    Question 2. Beyond advancements in science, what are the 
most significant barriers that slow our ability to review 
applications for rare and ultra-rare therapies more 
expeditiously? Are there process or system improvements at the 
FDA that could enable the agency to further strengthen and 
accelerate its work reviewing therapies for these populations?

    Answer 2. Development and review of rare disease 
applications frequently involve challenging considerations. For 
example, the natural history of a given rare disease may be 
poorly understood, there may be phenotypic and genotypic 
diversity within a disorder, drug development tools (e.g., 
outcome measures and biomarkers) often are lacking, and there 
may be a need to develop novel, clinically meaningful endpoints 
to facilitate drug development in many rare diseases.

    These challenges necessitate a renewed focus on scientific 
research into rare diseases. Nevertheless, FDA remains 
committed to doing what it can to facilitate the review of 
proposed therapies for rare diseases. As an example, CDER 
recently launched the Accelerating Rare disease Cures (ARC) 
Program to harness our collective expertise and activities to 
provide strategic overview and coordination of the Center's 
rare disease activities. This program will help address some of 
the common and significant barriers in rare disease product 
development. Although ARC is a CDER program, by strengthening 
CDER connections and collective vision it will enhance FDA's 
ability to continue work across the Agency. Enhancing these 
current partnerships and collaborations will broadly benefit 
rare disease product development.

    Further, FDA's review of applications can be slowed when 
more information needs to be submitted by the applicant for FDA 
to continue its review and make a regulatory action. Although 
specific to each application, issues typically can be lumped 
under common topics or categories, such as certain aspects of 
manufacturing, product testing or safety data among many other 
topics. FDA continues to develop and issue guidance on a vast 
array of topics related to product development and application 
submission, including topics specific to rare diseases, to help 
applicants avoid pitfalls and submit the best possible 
applications to FDA for an expeditious review. FDA also 
provides outreach to stakeholders on such topics via 
presentations in various venues and on FDA webpages, all with 
the goal of improving the content and quality of submissions. 
Continued support of these outreach efforts will contribute to 
FDA's expeditious review of applications for new therapies 
including those for rare diseases.

        Question 2(a). What approaches are there to help build 
        FDA's knowledge on issues relevant to therapy 
        development for rare and ultra-rare diseases, such as 
        working with small populations and limited clinical 
        trials data, and ensuring this knowledge can be applied 
        agency-wide?

    Answer 2. FDA's approach to building knowledge to 
facilitate the development of medical products for rare 
diseases, regardless of prevalence, is robust and 
collaborative, both across the Agency and with external 
stakeholders.

    The Rare Diseases Team in CDER, Office of New Drugs (OND) 
coordinates with CBER, CDRH, and OOPD to collaborate on annual 
staff training to share learning and promote rare disease 
education regarding policy and review across the Agency. In 
addition, the Rare Diseases Team hosts quarterly seminars 
presented by internal and external experts to train and inform 
staff on timely and important aspects of rare disease drug 
development relevant to their work on rare disease 
applications. OND has also established a new Rare Disease Drug 
Development Council comprised of leaders from across CDER's OND 
and from CDER's Office of Translational Sciences with expertise 
and experience in rare disease drug development to promote 
organizational cohesion across rare disease issues and drug 
development programs. CBER and other Centers also participate 
in this new council. In spring 2022, CDER also launched the 
Accelerating Rare disease Cures (ARC) Program, which will drive 
scientific and regulatory innovation and engagement to 
accelerate the availability of treatments for patients with 
rare diseases. ARC Program initiatives support the needs of 
CDER's drug review programs and associated CDER offices to 
foster scientific and regulatory innovation and engagement to 
enhance rare disease product development and advance rare 
disease regulatory science.

    These types of approaches will further enhance 
collaboration, consistency, and knowledge sharing between OND 
divisions and across CDER and FDA, while ensuring that each 
rare disease drug development program is evaluated by staff 
that have the disease-specific expertise needed to 
appropriately design and evaluate these programs.

    CBER's Rare Disease Program facilitates the Center's active 
participation in efforts with other rare disease partners 
across FDA to continue to build knowledge to advance 
development of therapies for rare diseases including those with 
very low prevalence. Collaborative activities include 
development and implementation of training for review staff, 
information sharing via stakeholder outreach and engagement 
activities (including patient engagement activities such as 
Patient Focused Drug Development meetings and Patient Listening 
Sessions), routine dialog with other regulatory authorities, 
guidance development, and FDA supported initiatives not 
specific to CBER. These activities focus on common issues and 
challenges faced in the development of medical products for 
rare diseases. CBER's Rare Disease Coordinating Committee, 
comprised of representatives from across the Center's Offices, 
provides a forum for information exchange on these efforts and 
rare disease related issues in general. CBER staff also 
participate and share information with other staff from across 
the agency in routine rare disease-related meetings such as the 
Rare Disease Council meetings led by OOPD and the Rare Disease 
Roundtable meetings led by CDER. CBER also collaborates with 
external stakeholders in efforts to address specific challenges 
encountered in development of CBER-regulated products such as 
cell and gene therapies and regenerative medicine therapies for 
rare diseases. Examples include partnering with NIH, joint 
public meetings with their National Center for Advancing 
Translational Science (NCATS), partnering with the Foundation 
for NIH, and working with others in establishing the Bespoke 
Gene Therapy Consortium to help advance development of gene 
therapies for rare diseases that affect one or a small number 
of individuals.

    Question 3. How has patient engagement or patient-focused 
drug development supported innovation and what more can be done 
to ensure FDA is factoring the patient perspective into its 
regulatory activities?

    Answer 3. Listening to the patients' perspectives through 
patient-focused drug development (PFDD) meetings or other 
venues supports identification of the benefits and risks that 
matter most to patients and helps identify new endpoints for 
innovative therapies.

    Examples of CDER's ongoing efforts include the PFDD Meeting 
Program, conduct and participation in Patient Listening 
Sessions, conduct and participation in scientific round tables, 
and other activities that allow us to better understand the 
patient perspective. Additionally, the PFDD Guidance Series 
describes how stakeholders (patients, caregivers, researchers, 
medical product developers, and others) can collect and submit 
patient experience data and other relevant information from 
patients and caregivers to be used for medical product 
development and regulatory decisionmaking. This guidance series 
has encouraged innovation by providing drug developers and 
patients with clarity on FDA's current thinking related to the 
quality of patient experience data that is submitted to FDA. 
Through programs such as the Standard Core Clinical Outcome 
Assessments and Related Endpoints Grant Program, CDER works 
cooperatively with grantees to develop core sets of clinical 
outcome assessments that include significant input from 
patients; several focus on rare diseases. This input is 
intended to help ensure that the endpoints being measured in 
clinical trials are endpoints that are meaningful to patients. 
When development is complete, CDER expects that these core sets 
will be made publicly available to medical product developers 
and others, potentially obviating the need for them to develop 
measures of their own. In addition, as part of our ongoing 
effort to ensure that CDER is factoring the patient perspective 
into our regulatory activities, under PDUFA VII we will be 
conducting internal trainings on patient-focused methodologies 
at least twice annually, and will issue a guidance document 
that focuses on patient preference studies.

    The Centers also interact with patient groups on Center-
specific topics and actively engage in Agency programs, 
initiatives, and events to gather patient input and share best 
practices for involving patients in medical product development 
and regulation. Patient engagement staff across the Agency 
including staff in the Center for Biologics Evaluation and 
Research (CBER), the Center for Drug Evaluation and Research 
(CDER), the Center for Devices and Radiological Health (CDRH), 
and the Office of the Commissioner, work closely with staff 
from other FDA offices and programs, to coordinate patient 
engagement activities and patient-focused medical product 
development efforts, and to share best practices.

    Examples of CBER efforts that support advancement of 
patient engagement and patient-focused medical product 
development include the Center's Science of Patient Input (SPI) 
initiative, its Rare Disease program, and patient-focused 
outreach on regenerative medicine product development. SPI 
initiative activities include supporting studies on methods and 
tools to obtain robust patient input to support biological 
product regulatory reviews and providing CBER reviewers with 
assistance in the regulatory review of patient input and 
patient-reported outcomes data. CBER's Rare Disease program 
works to facilitate the incorporation of the patient 
perspective into regulatory decision making for biologics for 
rare diseases. CBER's recent outreach efforts to facilitate 
patient engagement in development of regenerative medicine 
products, many of which are for rare diseases, include two 
public workshops for patient advocates (5/6/2021 and 5/24/2022) 
and the educational webinar series, RegenMedEd, which launched 
in November 2021 for patients, caregivers, and other 
stakeholders.

    FDA also notes that CDRH has a robust Patient Science and 
Engagement Program that is committed to engaging with patients, 
understanding their experiences, and proactively integrating 
patient perspectives into medical device decisions and 
regulatory activities where appropriate. The Center has created 
forward-leaning mechanisms to facilitate patient involvement in 
regulatory activities as well as fostered innovative approaches 
to supporting the science of patient input. By collaborating 
with patients, healthcare providers, the research community, 
and industry, CDRH has fostered the creation of well-defined 
outcome measures and structured assessments of patient 
preferences that directly impact medical device decisions and 
assure that these devices include the evidence patients and 
providers depend upon rare disease regulatory science.

    CDRH at the forefront of describing ways that structured 
collection of patient preference information can be used as 
scientific evidence in the evaluation of medical products. 
Since CDRH issued guidance on patient preference information in 
2016, industry has been increasingly including this information 
in medical device submissions, growing from initially none to 
26 studies that are completed or in the pipeline. In addition, 
patient-reported outcomes are being collected consistently in 
more than 50 percent of medical device submissions with 
clinical studies. \2\ To better work hand-in-hand with patients 
to incorporate their values and perspectives into all aspects 
of the medical device total product life cycle, CDRH 
established the first advisory committee comprised solely of 
patients, caregivers and representatives of patient 
organizations called the Patient Engagement Advisory Committee 
(PEAC). The PEAC provides formal recommendations to FDA on 
general scientific matters related to medical devices such as 
patient involvement in the design and conduct of clinical 
trials, communicating cybersecurity vulnerabilities and medical 
device recalls, as well as the ways in which patient-generated 
health data can provide insights on medical device performance 
in real-world use. CDRH integrates the PEAC recommendations 
into regulatory actions like the recently issued final guidance 
\3\ on the ways patients can engage as advisors in the design 
and conduct of clinical studies.
---------------------------------------------------------------------------
    \2\  https://jpro.springeropen.com/articles/10.1186/s41687--022--
00444--z
    \3\  https://www.fda.gov/medical-devices/workshops-conferences-
medical-devices/webinar--patient--engagement--design--and--conduct--
medical--device--clinical--studies--final--guidance

    Question 4. Dr. Cavazzoni--According to cancer researchers, 
there is no one novel therapy that will be the magic bullet to 
cure all cancer patients. Many children and adults with cancer 
will need combinations of cancer therapies to achieve cures. 
However, unlike adults, childhood cancer provides little market 
incentive to develop new therapies because of its small 
population. As a result, current treatments for children are 
---------------------------------------------------------------------------
largely based on adult indications.

        Question 4(a). What are some of the challenges the FDA 
        faces as it tries to encourage companies to make 
        combination therapies for children?

    Answer 1. Section 504 of the FDA Reauthorization Act of 
2017 (FDARA) amended section 505B of the FD&C Act to require--
for original applications submitted on or after August 18, 
2020--pediatric investigations of certain targeted cancer drugs 
with new active ingredients, based on molecular mechanism of 
action rather than clinical indication. Specifically, if an 
original new drug application (NDA) or biologics license 
application (BLA) is for a new active ingredient, and the drug 
that is the subject of the application is intended for 
treatment of an adult cancer and directed at a molecular target 
FDA determines to be substantially relevant to the growth or 
progression of a pediatric cancer, reports on the molecularly 
targeted pediatric cancer investigation (required under section 
505B(a)(3) of the FD&C Act) must be submitted with the 
marketing application, unless FDA waives or defers the 
requirement. Importantly, this requirement applies to an 
original NDA or BLA for a new active ingredient for use in an 
oncology drug combination regimen with a previously approved 
product (provided that the other criteria in section 
505B(a)(1)(B) of the FD&C Act are satisfied). FDARA thus 
created a mechanism to require evaluation of certain novel 
drugs that may have the potential to address an unmet medical 
need in the pediatric population, specifically, in pediatric 
cancer patients. FDA has fully implemented the FDARA amendments 
to section 505B of the FD&C Act, which has resulted in 
substantially increased numbers of timely pediatric 
investigations of novel cancer drugs potentially applicable to 
the treatment of children based on the molecular mechanism of 
action and the specific molecular targets to which the drugs 
are directed. Early evidence of activity also can support 
earlier incorporation of these novel agents into known 
effective combinations to evaluate further improvements in 
outcome. In addition, recent, histology-agnostic approvals of 
cancer drugs for different types of cancer in both adults and 
children based on the specific molecular driver or cause of a 
particular cancer predicts that the requirement for early 
pediatric investigation based on the molecular mechanism of 
action of a new drug, rather than indication, may result in 
approval for use of drugs for specific pediatric cancers, 
distinct from those adult cancers.

    Despite these advancements, however, FDA does lack explicit 
authority to require study of combination drug regimens to 
treat cancer (including pediatric cancers) unless an 
application for such combination regimen has been submitted 
consistent with section 505B(a)(1) of the FD&C Act. There also 
is currently no statutory requirement for pre-clinical 
investigation of novel combinations of drugs in pediatric-
specific tumor models to provide the evidence base to support 
clinical investigation of combinations in the pediatric 
population.

    Question 5. There have been recent incidents where FDA has 
failed to meet agreed upon PDUFA dates with little 
justification or information given as to when a decision should 
be expected. This backlog is concerning as therapies are 
delayed from coming to market and patients are delayed access 
to new treatments that they have been eagerly waiting for. It 
is important for the FDA to prioritize meeting these timelines 
to ensure innovation and improved health outcomes for patients 
are not jeopardized.

        Question 5(a). What is causing these delays that 
        prevent the FDA from meeting these agreed upon product 
        review deadlines and what is being done to clear the 
        current backlog?

    Answer 5. Since March 2020 when inspections were first 
impacted, FDA has generally continued to meet PDUFA user fee 
goal dates and has acted upon 90 percent or more of PDUFA 
applications each quarter throughout the pandemic. Delays in 
application performance goals may occur for multiple reasons. 
Some examples include when there are deficiencies that must be 
corrected before an application can be approved, or where 
logistical challenges prevent FDA from conducting or completing 
necessary activities. An example of these latter logistical 
challenges brought on, or exacerbated by the pandemic, is 
traveling and safely conducting inspections, including in 
geographic locations where travel is restricted or limited.

    During the pandemic, we increased our communication with 
sponsors and informed them if there was a need for inspection, 
if we expected to encounter delays in completing the 
inspection, and if we may not be able to complete the 
application review by the PDUFA goal date. Please see FDA's 
guidance for industry, Manufacturing, Supply Chain, and Drug 
and Biological Product Inspections During COVID-19 Public 
Health Emergency Questions and Answers. \4\
---------------------------------------------------------------------------
    \4\  https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/manufacturing-supply chain-and-drug-and-biological-
product-inspections-during-covid-19-public-health

    While continuing to conduct mission-critical and 
prioritized inspections, due to practical constraints, such as 
travel limitations, quarantine and social distancing 
requirements or lockdowns, we have increasingly relied on 
alternative approaches to inspections, including:
         LReviewing the inspection history of 
        facilities to assess feasibility of relying on records 
        or trusted partner inspections
         LUsing information shared by trusted foreign 
        regulatory partners
         LRequesting records directly from facilities 
        in lieu of drug and biological product inspections
         LPerforming remote interactive evaluations in 
        which we remotely evaluate live streamed video of 
        facility operations and engage in other remote, live 
        interactions with facility operators

    FDA has found that, historically, only around 20 percent of 
applications warrant a pre-approval inspection (PAI) or pre-
license inspection (PLI). FDA has used these alternative 
approaches to further reduce the need for PAIs/PLIs.

    Where alternate tools are not available, insufficient, or 
otherwise will not satisfy the need for an inspection, FDA will 
use a risk-based approach to prioritize inspections, which 
includes consideration for (a) how product availability could 
impact public health; (b) investigator safety; and (c) travel 
restrictions or advisories associated with the location of the 
facility or site (e.g., country or region/state/province within 
the country, U.S. state, county, or territory).

    As reported in the Resiliency Roadmap and the Roadmap 
Update, \5\ between March 2020 and September 30, 2021, of the 
thousands of applications and supplements submitted, decisions 
on only 60 submissions were delayed solely due to a pending 
inspection that was postponed during the pandemic. Submissions 
under the PDUFA review program accounted for 35 of the delayed 
actions, but only 7 of these were for new drug applications The 
remaining were for supplements to already approved drug 
applications. Since September 30, 2021, 10 additional 
submissions had a delayed action due to inspections, only 3 of 
which were new drugs. It is important to note that to date, we 
have not denied, and do not intend to deny, approval of a 
product application solely because we have been unable to 
complete a pre-approval inspection of a manufacturing facility 
or clinical trial site due to the COVID-19 pandemic.
---------------------------------------------------------------------------
    \5\  https://www.fda.gov/media/154293/download.

    With respect to new drug applications pending action due to 
inspections, all delayed mission critical submissions have now 
---------------------------------------------------------------------------
been acted upon.

    Question 6. We know that certain ethnic and racial 
populations are underrepresented in biomedical research yet 
have a disproportionate disease burden for certain diseases. 
Recently, FDA released guidance titled: ``Diversity Plans to 
Improve Enrollment of participants from Underrepresented Racial 
and Ethnic Populations in Clinical Trials.''

        Question 6(a). Can you describe the Agency's strategy 
        to address diversity in clinical trials beyond this 
        guidance and how the Agency will engage patient groups 
        representative of ethnic and racial populations 
        currently underrepresented?

    Answer 6. FDA is committed to encouraging diverse 
participation in research used to support marketing 
applications for regulated medical products and has made 
progress in this area over the years. Physicians' ability to 
extrapolate results from clinical investigations to their own 
patients is dramatically improved when the participants in a 
clinical investigation reflect the product's intended patient 
population as closely as possible.

    FDA is currently engaging in significant policy work 
relating to diversity in clinical investigations. We view 
modernizing clinical investigation design, conduct, and use of 
innovative technologies as ways to: enhance enrollment of 
diverse populations; facilitate the development of drugs, 
biological products, and devices; and improve efficiencies.

    FDA has numerous efforts underway to encourage sponsors to 
increase the diversity of research participants in clinical 
investigations. These efforts are designed to help ensure that 
participants in clinical investigations reflect the population 
that ultimately may use the approved medical product. For 
example, FDA issued final guidance in November 2020, titled 
Enhancing the Diversity of Clinical Trial Populations--
Eligibility Criteria, Enrollment Practices, and Trial Designs. 
The publication of this guidance followed a congressionally 
mandated public meeting on eligibility criteria that was held 
in April 2018 to help inform the content of the guidance. FDA 
also held Patient Engagement Advisory Committee (PEAC) meetings 
in 2017 and 2018 which focused on ways to engage diverse 
patients in the design and conduct of medical device clinical 
investigations. Based on the discussions held during both PEAC 
meetings and with consideration of comments submitted to a 
public docket, FDA issued final guidance in January 2022, 
titles Patient Engagement in the Design and Conduct of Medical 
Device Clinical Studies.

    FDA's Office of Women's Health (OWH) conducts outreach on 
this important topic through the Diverse Women in Clinical 
Trials (DWCT) Initiative. This campaign was developed in 
collaboration with the NIH Office of Research on Women's Health 
to raise awareness about clinical investigation participation 
among women of different ages, races, ethnic backgrounds, 
disabilities, chronic illnesses, and health conditions. FDA's 
Office of Minority Health and Health Equity developed a 
Diversity in Clinical Trials Initiative which includes an 
ongoing, multi-media, public education and outreach campaign to 
help address some of the barriers preventing diverse groups 
from participating in clinical investigations through a variety 
of culturally and linguistically tailored strategies, tools, 
and resources, such as educational materials in multiple 
languages, a dedicated webpage with public service 
announcements and videos, social media outreach, and ongoing 
stakeholder engagement. FDA's Oncology Center of Excellence 
(OCE) has an active program to help improve diversity in 
clinical trials. Project Equity is a public health initiative 
established by OCE to ensure that the data submitted to FDA for 
approval of oncology medical products adequately reflects the 
demographic representation of patients for whom the medical 
products are intended. Project Equity works to improve access 
to clinical trials of oncology medical products for populations 
that have historically been underrepresented in clinical 
research such as racial and ethnic minorities, individuals who 
live in rural areas, sexual and gender minorities, and 
individuals with economic, linguistic, or cultural barriers to 
healthcare services.

    FDA has ongoing efforts to promote the use of technology 
and innovative trial designs, such as decentralized 
investigations that bring the investigation to the 
participant's location, which may address some of these 
barriers. Decentralizing clinical trial activities may include 
the use of telehealth so patients can participate in trial 
visits from their homes. Direct distribution of medical 
products to patients' homes and the use of local clinical 
facilities near where patients live are other approaches to 
reduce the burden of trial participation. This can improve 
diversity of trial participants by reducing the time and 
expense of missing work, avoiding the need to arrange 
childcare, and eliminating the costs of travel, all which 
significantly impact minorities with less socio-economic 
resources. Additionally, FDA has published guidance encouraging 
sponsors to avoid excessively restrictive eligibility criteria 
which can be an additional barrier to clinical investigation 
participation.

    Question 7. Given the impact of the COVID-19 pandemic on 
these patient groups, can you share any lessons learned from 
the pandemic that could be leveraged to improve clinical trial 
diversity?

    Although progress has been made to increase the enrollment 
of diverse populations, there is still significant room for 
improvement. The current public health emergency further 
catalyzed FDA's efforts in this space. One strategy that needs 
to be scaled up in a sustainable way is engaging community 
clinicians in the clinical trial research efforts. There is 
considerable evidence that clinician recommendations play an 
important role in helping patients to consider participating in 
clinical investigations. \6\
---------------------------------------------------------------------------
    \6\  https://www.nejm.org/doi/full/10.1056/NEJMp2107331

    The COVID-19 pandemic has highlighted the ability of 
technology to enable remote assessment of safety and efficacy 
outcomes in clinical trials. Such technology allows 
decentralized investigations that bring the investigation to 
the participant's location, thus decreasing the financial and 
time or logistical burden of clinical trial participation. 
Therefore, more patients with fewer resources may be able to 
participate in clinical trials and improve the diversity of the 
study populations.


                           senator tuberville


    Question 1. The User Fee Agreements are a big deal here in 
DC. They represent the product of years of discussion and 
negotiation between the FDA, industry, and other stakeholders. 
But, most regular Americans do not pay attention to these 
negotiations. I hear from my constituents all the time about 
rising prescription drug costs, but no one ever mentions the 
FDA User Fee agreements. How would you explain to my 
constituents back home how these new agreements are going to 
help them?

    Answer 1. The User Fee agreements provide FDA with 
necessary resources, establish priorities and review structure, 
and foster new and innovative programs which facilitate 
development and approval of medical products. For example, FDA 
has seen a sustained increase in development program 
activities, including investigational new drug applications and 
formal meeting requests. A number of these development programs 
have the potential to bring new therapies to meet unmet medical 
needs for serious and life-threatening diseases.

    Generally, the User Fee agreements will allow the Agency to 
produce multiple guidances; host public meetings to examine new 
technologies and approaches; host patient-focused drug 
development meetings to better understand patient perspectives 
on gene therapy products; and conduct public outreach to 
facilitate product development and approval.

    Below are specifics for each program:
         LPDUFA--Now in its seventh authorization, 
        PDUFA has proven to be an extremely effective program 
        that has transformed U.S. drug review process to the 
        fastest in the world, while setting the global gold 
        standard for quality, efficacy, and safety. As 
        reflected in the PDUFA commitment letter, PDUFA VII, 
        when enacted, will also provide for additional 
        resources for the cell and gene therapy program. New 
        allergenic extract products are also included in PDUFA 
        VII, and the program will provide needed resources to 
        facilitate the timely development and approval of new 
        medical products critical for the diagnosis and 
        treatment of allergies, including serious food 
        allergies.
         LGDUFA--Now in its third authorization, GDUFA 
        aims to put FDA's generic drug program on a firm 
        financial footing and ensure timely access to safe, 
        high-quality, affordable generic drugs. GDUFA enables 
        FDA to assess user fees to fund critical and measurable 
        enhancements to the performance of FDA's generic drugs 
        program, bringing greater predictability and timeliness 
        to the review of generic drug applications.
         LBsUFA--Now in its third authorization, BsUFA 
        aims to expedite the review process for biosimilar 
        biological products. Biosimilar biological products 
        represent an important public health benefit, with the 
        potential to offer life-saving or life-altering 
        benefits at reduced cost to the patient. BsUFA 
        facilitates the development of safe and effective 
        biosimilar products for the American public.
         LMDUFA--Now in its fifth authorization, MDUFA 
        has enabled patients to have timely access to more 
        innovative and better performing devices--and therefore 
        more options--than at any other time in our history. 
        MDUFA supports FDA's capacity to assess new medical 
        device technologies, provides a predictable, 
        transparent path to market, and upholds FDA's rigorous 
        review standards. MDUFA also promotes accountability 
        for the Center's performance and operations, and makes 
        critical investments in the future of the program, to 
        assure FDA has the resources to handle review of the 
        robust pipeline of new technology and the innovations 
        of tomorrow.

    Question 2. I hear from constituents who are concerned 
about the FDA's draft guidance on homeopathic products. The 
guidance takes a different position than the FDA has 
historically taken on the regulation of homeopathic medicines. 
Since inclusion in the Food, Drug, and Cosmetic Act of 1938, 
homeopathic medicines have been recognized as a unique and 
separate category of drugs. The FDA stated in the past that 
``the law gives the FDA no premarket review of true homeopathic 
dilutions.'' Yet, the draft guidance takes a new position 
deeming all homeopathic products as unapproved new drugs 
subject to pharmaceutical-specific premarket approval.

        Question 2(a). Is FDA is seeking a revised regulatory 
        framework with regard to homeopathic medicines?

        Question 2(b). If so, how does the Agency's 
        reinterpretation of longstanding law and corresponding 
        regulations and policies fall within the purview of 
        guidance documents?

    Answer 2. FDA appreciates the opportunity to clarify the 
Agency's approach to its regulation of homeopathic drug 
products.

    We first note that as described in the Agency's October 
2019 revised draft Guidance, Drug Products Labeled as 
Homeopathic, \7\ the definition of ``drug'' in section 
201(g)(1) of the FD&C Act, 21 U.S.C. 321(g)(1), includes 
articles recognized in the Homeopathic Pharmacopeia of the 
United States. As such, homeopathic drugs are subject to the 
same statutory requirements as other drugs; nothing in the FD&C 
Act exempts homeopathic drug products from any of the 
requirements related to approval, adulteration, or misbranding, 
including labeling requirements.
---------------------------------------------------------------------------
    \7\  https://www.fda.gov/media/131978/download

    There are currently no homeopathic drug products that are 
approved by FDA. Products labeled as homeopathic and currently 
marketed in the U.S. have not been reviewed by the FDA for 
safety and effectiveness to diagnose, treat, cure, prevent or 
---------------------------------------------------------------------------
mitigate any diseases or conditions.

    On October 24, 2019, FDA withdrew Compliance Policy Guide 
(CPG) 400.400, entitled ``Conditions Under Which Homeopathic 
Drugs May be Marketed,'' because it was inconsistent with our 
risk-based approach to regulatory and enforcement action. FDA 
also issued the revised draft guidance: Drug Products Labeled 
as Homeopathic, for public comment. This revised draft guidance 
proposes a comprehensive, risk-based enforcement approach to 
homeopathic products marketed without FDA approval. When 
finalized, this guidance will help provide transparency 
regarding the categories of homeopathic drug products that we 
intend to prioritize under our risk-based enforcement approach. 
In the meantime, FDA is applying its general approach to 
prioritizing regulatory and enforcement action, which involves 
risk-based prioritization considering all the relevant facts of 
a given situation. We note that the draft guidance, when 
finalized, would not represent a change in the legal 
obligations that currently apply to homeopathic drugs under the 
statutes FDA administers.

    FDA sought broad public input as the Agency evaluated its 
enforcement policies for homeopathic products to better promote 
and protect the public health. \8\ Our top concern is patient 
safety.
---------------------------------------------------------------------------
    \8\  April 2015, FDA held a public hearing to obtain information 
and comments from stakeholders about the current use of homeopathic 
drug products, as well as the Agency's regulatory framework for such 
products (Docket No. FDA-2015-N-0540; available at https://
www.regulations.gov/docket/FDA-2015-N-0540). In October 2019, FDA 
issued revised draft guidance (``Drug Products Labeled as 
Homeopathic''), as noted above, in response to public comments received 
on the initial December 2017 draft version.

    FDA is currently working to finalize the revised draft 
guidance on homeopathic drug products and has reviewed comments 
submitted to the docket. You can review these comments online 
at: https://www.regulations.gov/document/FDA-2017-D--6580--
4828/comment (Docket No. FDA-2017-D-6580). When finalized, this 
guidance will represent the Agency's current thinking. The 
Agency is unable to comment at this time on the pending content 
of the final guidance. When it is posted and the Notice of 
Availability publishes in the Federal Register, we will be able 
---------------------------------------------------------------------------
to publicly discuss the contents.

    Question 3. Legislation and policy ideas around improving 
the Accelerated Approval pathway are focused on what sponsors 
can do better with respect to confirmatory trials. However, I 
am also concerned that, aside from oncology, FDA hasn't been 
using this pathway as actively as it could be in rare diseases. 
I'm also concerned that not all review divisions understand or 
apply the accelerated pathway appropriately.

        Question 3(a). How is FDA ensuring that expertise about 
        the use of the accelerated approval pathway is being 
        shared within the Agency's divisions?

    Answer 3. We recognize that collaboration and information 
sharing are important aspects of facilitating rare disease 
product development. This collaboration and information sharing 
occurs with external stakeholders and within FDA. In terms of 
internal collaboration, we are committed to information 
sharing, both through formal and informal mechanisms.

    For example, we routinely share information and discuss 
challenging issues in rare disease product development across 
review divisions through multiple mechanisms. FDA has several 
widely attended internal forums for discussion, including 
CDER's Medical Policy and Program Review Council and the Rare 
Disease Drug Development Council (RDDDC), with the latter being 
dedicated to discussing development programs for rare diseases. 
The RDDDC facilitates not only cross-division discussion and 
sharing of expertise, which could include topics such as the 
use of accelerated approval, but also invites staff from other 
Centers to participate as well. Both of these councils include 
leaders across the Office of New Drugs and the Office of 
Translational Sciences, which helps bring cross-disciplinary, 
senior Agency expertise to advise review divisions regarding 
challenging issues that arise in drug development. As another 
example of information sharing, important regulatory decisions 
on rare disease marketing applications are shared by rare 
disease staff through internal communications in both CDER and 
CBER.

    Further, to ensure expertise about the use of the 
accelerated approval pathway is shared, training on expedited 
programs including accelerated approval is provided to FDA 
review staff on a regular basis and is available in recorded 
format for review at any time.

        Question 3(b). How is FDA using external expertise to 
        appropriately make risk-benefit decisions for rare and 
        ultra-rare diseases when safety is established, there 
        are no other treatment options, and the condition is 
        life threatening or significantly impacting quality of 
        life?

    Answer 3(b). FDA recognizes that there is significant unmet 
need for patients and families living with rare diseases as 
most rare diseases do not have approved therapies at this time. 
As further discussed below, these circumstances are considered 
and incorporated into FDA's approach to rare diseases, 
regardless of the regulatory pathway used or available for a 
particular development program.

    It is important to understand that FDA considers safety and 
clinical benefit in its review and this benefit-risk assessment 
takes into account the seriousness of the disease. Benefit-risk 
assessment is integrated into FDA's regulatory review of 
marketing applications. The benefit-risk assessment includes 
many factors, such as the nature and severity of the condition 
the drug is intended to treat or prevent, the benefits and 
risks of other available therapies for the condition, and any 
risk management tools that might be needed. As articulated in 
our 2019 draft guidance that addresses demonstrating 
substantial evidence of effectiveness, \9\ FDA recognizes that 
some patients and their caregivers are willing to accept less 
certainty about effectiveness in return for earlier access to 
much needed medicines. For example, for a life-threatening 
disease without any available treatment, FDA might accept the 
results of adequate and well-controlled investigations with 
less rigorous designs, such as historically controlled studies. 
FDA has approved many drugs for rare diseases by applying these 
principles, using both traditional and accelerated approval 
pathways, when there is evidence that the drug is effective. 
Importantly, rare disease drug development spans therapeutic 
areas. FDA has mechanisms and initiatives, such as policy 
councils and the Rare Diseases Team, to facilitate consistency 
across divisions around rare disease product development 
considerations, such as the use of accelerated approval and 
considerations related to regulatory flexibility.
---------------------------------------------------------------------------
    \9\  https://www.fda.gov/media/133660/download. When finalized, 
this will represent FDA's current thinking on this issue.

    FDA's clinical review staff take advantage of a multitude 
of resources to gain knowledge on rare diseases when the agency 
determines such advice would be helpful as FDA considers the 
risks and benefits of medical products, including those 
intended for rare diseases based on the statutory definition 
---------------------------------------------------------------------------
(i.e., <200,000 in the U.S.).

    Development and review of rare disease applications 
frequently involves challenging considerations that may benefit 
from discussion with external experts, such as at advisory 
committee meetings. FDA uses this authority to consult with 
external experts and to solicit their participation in advisory 
committee meetings as needed. FDA also communicates with 
relevant patient groups through our various patient listening 
sessions, patient and caregiver connection resource, and 
patient focused drug development meetings.

    In addition, FDA convenes rare disease stakeholders in 
public meetings to hear different perspectives, on common 
issues in development of medical products across the spectrum 
of rare diseases. Recognizing these existing structures and 
mechanisms to facilitate rare disease product development, FDA 
agrees that there is value in external input on rare disease 
product development considerations, including through advisory 
committee meetings and other for a (e.g., workshops) and will 
continue to optimize strategies to leverage and obtain diverse 
expertise in the science and challenges of working with small 
populations.

    When needed for rare diseases for which there is relevant 
expertise across the Agency, the Center for Drug Evaluation and 
Research (CDER), the Center for Devices and Radiological Health 
(CDRH), and the Center for Biologics Evaluation and Research 
(CBER) regularly consult the review staff in other centers. 
Beside the many available cross-Agency training and information 
sharing opportunities about rare diseases, extensive online 
medical information resources are available to FDA review staff 
through FDA's library for obtaining the most up-to-date medical 
literature about specific rare diseases.

        Question 3(c). What is FDA's oversight of its own 
        divisions, especially when departing from earlier 
        openness to a pathway that would promise much earlier 
        access to treatments where patients lack any other 
        treatments?

    Answer 3(c). Use of the accelerated approval pathway 
requires a determination that the product has an effect on a 
surrogate endpoint--or an intermediate clinical endpoint--that 
is reasonably likely to predict clinical benefit. The 
assessment that a surrogate endpoint is reasonably likely to 
predict clinical benefit reflects a scientific decision based 
on numerous considerations, including the depth of 
understanding of the pathogenesis of the disease. 
Unfortunately, many diseases, including many rare diseases, are 
poorly understood, which may complicate assessment of proposed 
surrogate endpoints. FDA has several forums and mechanisms for 
considering these scientific issues, such as policy councils, 
including the Medical Policy and Program Review Council and the 
Rare Disease Drug Development Council.

    In addition, FDA is committed to having meetings with 
sponsors to discuss challenging product development issues. For 
example, product developers can request Type C meetings to 
discuss surrogate endpoints. Such meetings will allow FDA to 
engage with sponsors who would like to employ a biomarker as a 
surrogate endpoint that has not been used previously as the 
primary basis for product approval in the proposed context of 
use. Sponsors who request these meetings may benefit from a 
discussion about whether a surrogate endpoint could support a 
traditional or accelerated approval. The meetings also allow 
for early identification of any gaps in scientific knowledge 
(e.g., of the disease being treated) and discussion of how they 
might be addressed. Early consultation in the drug development 
program allows the review team to consult with FDA leadership 
and subject matter experts, as necessary, to evaluate the 
sponsor's proposal before providing advice regarding the 
proposed surrogate endpoint to support accelerated or 
traditional approval. In addition, product developers are 
encouraged to consult with FDA should new information become 
available that could affect the assessment of the likelihood 
that a surrogate endpoint predicts clinical benefit (either 
positively or negatively).

        Question 3(d). How does FDA evaluate its own review 
        divisions' decisions to withdraw the accelerated 
        pathway in a way that is applied uniformly across 
        divisions or is defensible?

    Answer 3(d). The process and grounds for withdrawal of 
approval of a product or indication approved under accelerated 
approval are well defined in statute (Section 506(c) of the 
FD&C Act), FDA regulations (21 CFR 601.43 and 314.530), and the 
Expedited Programs Guidance. The process includes written 
notification to the applicant for an opportunity for a hearing, 
a Federal Register notice of the hearing, and an advisory 
committee constituted under 21 CFR part 14.

    FDA has a number of mechanisms to discuss and evaluate 
scientific considerations, including those related to whether 
the accelerated approval pathway is appropriate for a given 
drug development program.

    For example, although there are currently 27 clinical 
review divisions in CDER's Office of New Drugs, these divisions 
report to only eight clinical offices that align interrelated 
disease areas. Thus, office leadership is well-positioned to 
facilitate the sharing of knowledge and experience between 
review divisions. Input of other leaders is often sought, 
however, especially for challenging issues in drug development. 
CDER has several councils that may discuss and advise review 
divisions on scientific and regulatory considerations, such as 
the Medical Policy and Program Review Council and the Rare 
Disease Drug Development Council. CDER also has a Rare Diseases 
Team that facilitates, supports, and accelerates the 
development of drugs and therapeutic biologics for rare 
diseases. This includes providing advice to review divisions on 
their rare disease programs as requested and promoting rare 
disease considerations across CDER's Office of New Drugs. 
Similarly, CBER's products are organized into three product 
offices. Their leadership facilitates knowledge sharing and 
experience within their Offices and across the Center. Within 
CBER, Councils have been established where challenging 
scientific and clinical issues can be discussed. CBER also 
participates in many CDER Councils and groups and Centers may 
also consult each other on specific issues.

   Response by Peter Marks to Questions From Senator Casey, Senator 
    Collins, Senator Cassidy, Senator Scott, and Senator Tuberville


                             senator casey


    Pennsylvania is home to a thriving life sciences industry 
pioneering promising new fields of medicine. I have been 
particularly excited to hear about tremendous progress in the 
area of cell and gene therapy and the promise they hold in 
curing devastating diseases and transforming the lives of 
patients. Since many of these advanced therapies are cutting-
edge and hold the potential to address unmet medical needs, my 
understanding is that these companies are often entitled to 
pre-application meetings with the FDA. In setting up these 
expedited programs and authorizing previous PDUFA agreements, 
Congress intended for these meetings to help facilitate their 
applications and streamline the review process, ultimately 
delivering treatments that prove safe and effective to patients 
as quickly as possible.

    I have heard from companies working on next-generation 
therapies that the FDA frequently responds to their meeting 
requests with so-called ``written response only'' (WRO). 
Understandably, these written responses do not allow the same 
opportunities for exchanges and context that make the meetings 
as useful as possible to both parties. I am concerned that 
progress on these technologies could be slowed by insufficient 
face-to-face communication--the intention for these meetings--
and an overreliance on WROs.

    Question 1. Why have WROs become so common in responding to 
meeting requests? Is CBER able to meet the demands of these 
congressionally mandated programs with its current resources 
and staff?

    Answer 1. Written response only (WRO) is one of three 
formats for formal meetings with FDA (see: https://www.fda.gov/
regulatory-information/search-fda-guidance-documents/formal-
meetings-between-fda-and-sponsors-or-applicants-pdufa-products-
guidance-industry). WROs are an important and efficient tool to 
respond to drug developer questions that only require 
straightforward responses, questions that are already addressed 
in published FDA guidance, or other questions that can be 
readily addressed in writing. CBER has experienced increased 
workload especially in the areas of Cellular and Gene Therapies 
which is regulated by the Office of Tissues and Advanced 
Therapies (OTAT). OTAT currently has over 3,000 active 
Investigational New Drug Applications (INDs). Over the past 5 
years, there has been a rapid increase in the number of meeting 
requests, with a related rapid increase in the number of 
meetings granted, exceeding the rate of increase in OTAT review 
staff. OTAT has seen a sustained increase in development 
program activities, including an 85 percent increase in INDs, 
and a 158 percent increase in formal meeting requests. Thus, 
OTAT does not currently have the manpower to hold face-to-face 
communications for every meeting request for a face-to-face 
meeting and must be selective in order to be most efficient 
with available resources. Meetings, while important, are only 
one aspect of developing innovative products to address unmet 
medical needs and resources must be applied to other areas 
(e.g., review, guidance).

        Question 1(a). How does the FDA determine which meeting 
        requests receive live engagements and which are 
        relegated to WROs?

    Answer 1(a). For each meeting request, CBER carefully 
considers the specific questions posed by the drug developer, 
as well as the context (e.g., stage of development, product 
complexity, clinical indication and unmet need). Considerations 
include whether the questions and associated responses are 
straight-forward or nuanced and complex, can be easily 
addressed in writing, are already addressed in our published 
guidance documents, or have been previously discussed with the 
drug developer. If we expect that our responses will be 
straight-forward (e.g., referral to content of a specific 
guidance document) or will reiterate points made in previous 
discussions with the sponsor, then we are more likely to 
provide written responses. If the questions are complex, with a 
product that raises new scientific questions, or an innovative 
trial design, we are more likely to communicate on a telecon. 
In addition, CBER prioritizes meeting requests for products 
that have Breakthrough Therapy Designation or Regenerative 
Medicine Advanced Therapy (RMAT) Designation.

        Question 1(b). What steps does the FDA take to ensure 
        that programs which address the most pressing unmet 
        medical needs receive prioritized attention to ensure 
        their review is not unnecessarily delayed?

    Answer 1(b). Fast Track designation and Breakthrough 
Therapy designation are expedited drug development and review 
programs that provide sponsors with prioritized attention 
through earlier and more frequent interactions with FDA for 
drug development programs that meet certain criteria. In 
addition, biological products identified as regenerative 
medicine therapies and intended to address an unmet medical 
need may be eligible for Regenerative Medicine Advanced Therapy 
(RMAT) designation, an expedited development program 
established under the 21st Century Cures Act that provides 
similar and additional benefits. A drug development program 
granted designation under any one of these three programs, may 
be eligible for priority review designation and a rolling 
review, each of which may help speed review. Sponsors submit a 
separate request for each of these programs and may be granted 
designation for more than one program. FDA guidance on these 
programs is available. (See Expedited Programs for Regenerative 
Medicine Therapies for Serious Conditions Guidance for Industry 
at https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/expedited-programs-regenerative-medicine-
therapies-serious-conditions and Expedited Programs for Serious 
Conditions--Drugs and Biologics at https://www.fda.gov/
regulatory-information/search-fda-guidance-documents/expedited-
programs-serious-conditions-drugs-and-biologics).


                            senator collins


    Question 1. CBER will receive significant new resources 
under the new agreement in exchange for meeting specific 
performance goals, including improvements to how the Center 
engages with sponsors. The commitment letter gives FDA 
discretion to choose the format of necessary meetings between 
the agency and drug sponsors, but I have heard serious concerns 
that FDA is responding to some meeting requests with a 
``written response only.''

    The written response counts as a meeting for purposes of 
tracking whether FDA is upholding its commitments, but it is 
actually effectively declining a meeting, because the written 
response ends the interaction. There is no opportunity for 
dialog on key issues, which can result in miscommunications 
that delay research and the development process--and can have a 
negative impact for patients involved in clinical trials.

    This is particularly problematic in the cell and gene 
therapy space, which may promise cures to vexing diseases like 
Type 1 diabetes and Duchenne Muscular Dystrophy, but also 
introduces new questions for regulatory science. How does CBER 
plan to improve the quality of interaction with sponsors given 
the new resources provided under the agreement?

    Answer 1. Sponsors will have access to additional 
engagement and communication with FDA's expert scientific staff 
via some of the enhancements under PDUFA VII, once it is 
enacted. The PDUFA VII commitment letter includes a new Type D 
meeting, INTERACT meeting, and a follow-up opportunity 
following sponsor meetings to confirm understanding of the 
communications that took place. Similar enhancements with 
respect to biosimilar and interchangeable biological products 
are described in the BsUFA III commitment letter. For example, 
the BsUFA III commitment letter includes a new Type 2a meeting, 
increased flexibility in requesting Biosimilar Initial Advisory 
meetings, and the same post-meeting follow-up opportunity as in 
PDUFA.


                            senator cassidy


    Question 1. In recent months, FDA has issued more Complete 
Response Letters (CRLs) than approvals of applications for 
drugs to treat patients with chronic kidney disease [including 
CRLs on veverimer, taurolidine, tenapanor, roxadustat, 
bardoxolone and vadadustat]. How is FDA applying its benefit/
risk framework to new drugs to treat this chronically ill 
patient population at high risk of serious cardiovascular and 
other complications, and working with drug developers to ensure 
there are clear rules of the road to demonstrate safety and 
efficacy?

    Answer 1. Please see FDA response in CDER section above.

    Question 2. Historically, the nephrology division at the 
FDA had one of the lowest rates of new drug applications 
submitted, particularly compared to oncology and cardiology. 
How does the FDA ensure that the legal standards are being 
applied equally by each division?

    Answer 2. Please see FDA response in CDER section above.

    Question 3. A pillar of the PDUFA VII commitment letter is 
greater communication between FDA and drug sponsors to ensure 
that drug development programs have clear metrics, including 
for safety and clinical end points. How will these new 
commitments reduce unexpected analyses or standards introduced 
late in the development or application process for therapies 
developed to treat patients with kidney disease?

    Answer 3. Please see FDA response in CDER section above.

    Question 4. Another pillar of the commitment letter is 
building on a focus of Patient Focused Drug Development to 
ensure that the patient voice in incorporated into drug 
development decisionmaking. How can we ensure that FDA takes 
into consideration patient preferences and potential 
acceptability of tradeoffs between treatment benefit and risk 
outcomes in high risk diseases like kidney disease?

    Answer 4. Please see FDA response in CDER section above.


                             senator scott


    Question 1. Patients have expressed concerns that not all 
review divisions within FDA understand or apply the accelerated 
pathway appropriately. Some have even likened the experience to 
that of a ``lottery'' as to whether they'll be assigned a 
division with experience in ultra-rare conditions with well 
under 20,000 patients in the U.S.--and oftentimes only 2,000 or 
even 200 patients. How is FDA using external expertise to 
appropriately make risk-benefit decisions for rare and ultra-
rare diseases when safety is established, there are no other 
treatment options, and the condition is life threatening or 
significantly impacting quality of life?

        Question 1(a). Has the review division consulted with 
        patients about any safety signals or the benefit-risk 
        assessment it is making before removing the accelerated 
        approval pathway from consideration?

    Answer 1. Please see FDA response in CDER section above.

    Question 2. Beyond advancements in science, what are the 
most significant barriers that slow our ability to review 
applications for rare and ultra-rare therapies more 
expeditiously? Are there process or system improvements at the 
FDA that could enable the agency to further strengthen and 
accelerate its work reviewing therapies for these populations?

        Question 2(a). What approaches are there to help build 
        FDA's knowledge on issues relevant to therapy 
        development for rare and ultra-rare diseases, such as 
        working with small populations and limited clinical 
        trials data, and ensuring this knowledge can be applied 
        agency-wide?

        Question 2(b). How has patient engagement or patient-
        focused drug development supported innovation and what 
        more can be done to ensure FDA is factoring the patient 
        perspective into its regulatory activities?

    Answer 2. Please see FDA response in CDER section above.

    Question 3. According to CBER's PDUFA performance metrics 
from October 2019 to present, despite the pandemic workload, 
CBER has largely been getting meeting summaries to sponsors on 
time (0-6 percent late per quarter). However, a lot of these 
summaries are written responses to the sponsor for meetings 
that were not held, leading to stakeholder concerns that this 
could mean CBER is focused more on checking the box for 
meetings with sponsors by using written responses only.

        Question 3(a). With the large influx of resources--both 
        people and money--for CBER under PDUFA VII--what is the 
        industry's expectation regarding CBER's use of Written 
        Response Only versus live meetings?

    Answer 3. CBER will continue to use all available resources 
to communicate effectively with stakeholders. CBER will 
continue to carefully prioritize each meeting request with 
regard to written responses only versus live meetings, based on 
a variety of factors, including complexity of the question, 
whether the request involves new scientific questions, ability 
to answer the question in a written form or by referencing 
guidance, and changes in the workload relative to the 
availability of resources. If we expect that our responses will 
be straight-forward (e.g., referral to content of a specific 
guidance document) or will reiterate points made in previous 
discussions with the sponsor, then we are more likely to 
provide written responses. If the questions are complex, with a 
product that raises new scientific questions, or an innovative 
trial design, we are more likely to communicate on a telecon.

    Of note, CBER is also planning to increase other forms of 
communication (e.g., webinars, guidances), which we believe 
will help decrease the need for individual sponsor meetings. 
Meetings with industry, while important, are only one aspect of 
developing innovative products (e.g., review, guidance) for 
which PDUFA resources are applied.

    Question 4. There have been recent incidents where FDA has 
failed to meet agreed upon PDUFA dates with little 
justification or information given as to when a decision should 
be expected. This backlog is concerning as therapies are 
delayed from coming to market and patients are delayed access 
to new treatments that they have been eagerly waiting for. It 
is important for the FDA to prioritize meeting these timelines 
to ensure innovation and improved health outcomes for patients 
are not jeopardized.

        Question 4(a). What is causing these delays that 
        prevent the FDA from meeting these agreed upon product 
        review deadlines and what is being done to clear the 
        current backlog?

    Answer 4. Please see FDA response in CDER section above.

    Question 5. We know that certain ethnic and racial 
populations are underrepresented in. Can you describe the 
Agency's strategy to address diversity in clinical trials 
beyond this guidance and how the Agency will engage patient 
groups representative of ethnic and racial populations 
currently underrepresented? biomedical research yet have a 
disproportionate disease burden for certain diseases. Recently, 
FDA released guidance titled: ``Diversity Plans to Improve 
Enrollment of participants from Underrepresented Racial and 
Ethnic Populations in Clinical Trials.'' biomedical research 
yet have a disproportionate disease burden for certain 
diseases. Recently, FDA released guidance titled: ``Diversity 
Plans to Improve Enrollment of participants from 
Underrepresented Racial and Ethnic Populations in Clinical 
Trials.''

    Answer 5. Please see FDA response in CDER section above.


                           senator tuberville


    Question 1. The User Fee Agreements are a big deal here in 
DC. They represent the product of years of discussion and 
negotiation between the FDA, industry, and other stakeholders. 
But, most regular Americans do not pay attention to these 
negotiations. I hear from my constituents all the time about 
rising prescription drug costs, but no one ever mentions the 
FDA User Fee agreements. How would you explain to my 
constituents back home how these new agreements are going to 
help them?

    Answer 1. Please see FDA response in CDER section above.

    Question 2. I hear from constituents who are concerned 
about the FDA's draft guidance on homeopathic products. The 
guidance takes a different position than the FDA has 
historically taken on the regulation of homeopathic medicines. 
Since inclusion in the Food, Drug, and Cosmetic Act of 1938, 
homeopathic medicines have been recognized as a unique and 
separate category of drugs. The FDA stated in the past that 
``the law gives the FDA no premarket review of true homeopathic 
dilutions.'' Yet, the draft guidance takes a new position 
deeming all homeopathic products as unapproved new drugs 
subject to pharmaceutical-specific premarket approval.

        Question 2(a). Is FDA seeking a revised regulatory 
        framework with regard to homeopathic medicines?

        Question 2(b). If so, how does the Agency's 
        reinterpretation of longstanding law and corresponding 
        regulations and policies fall within the purview of 
        guidance documents?

    Answer 2. Please see FDA response in CDER section above.

    Question 3. Legislation and policy ideas around improving 
the Accelerated Approval pathway are focused on what sponsors 
can do better with respect to confirmatory trials. However, I 
am also concerned that, aside from oncology, FDA hasn't been 
using this pathway as actively as it could be in rare diseases. 
I'm also concerned that not all review divisions understand or 
apply the accelerated pathway appropriately.

        Question 3(a). How is FDA ensuring that expertise about 
        the use of the accelerated approval pathway is being 
        shared within the Agency's divisions?

        Question 3(b). How is FDA using external expertise to 
        appropriately make risk-benefit decisions for rare and 
        ultra-rare diseases when safety is established, there 
        are no other treatment options, and the condition is 
        life threatening or significantly impacting quality of 
        life?

        Question 3(c). What is FDA's oversight of its own 
        divisions, especially when departing from earlier 
        openness to a pathway that would promise much earlier 
        access to treatments where patients lack any other 
        treatments?

        Question 3(d). How does FDA evaluate its own review 
        divisions' decisions to withdraw the accelerated 
        pathway in a way that is applied uniformly across 
        divisions or is defensible?

    Answer 3. Please see FDA response in CDER section above.

Response by Jeffrey Shuren to Questions From Senator Scott, and Senator 
                               Tuberville


                             senator scott


    Question 1. Patients have expressed concerns that not all 
review divisions within FDA understand or apply the accelerated 
pathway appropriately. Some have even likened the experience to 
that of a ``lottery'' as to whether they'll be assigned a 
division with experience in ultra-rare conditions with well 
under 20,000 patients in the U.S.--and oftentimes only 2,000 or 
even 200 patients.

        Question 1(a). How is FDA using external expertise to 
        appropriately make risk-benefit decisions for rare and 
        ultra-rare diseases when safety is established, there 
        are no other treatment options, and the condition is 
        life threatening or significantly impacting quality of 
        life?

        Question 1(b). Has the review division consulted with 
        patients about any safety signals or the benefit-risk 
        assessment it is making before removing the accelerated 
        approval pathway from consideration?

    Answer 1. Please see FDA response in CDER section above.

    Question 2. Beyond advancements in science, what are the 
most significant barriers that slow our ability to review 
applications for rare and ultra-rare therapies more 
expeditiously? Are there process or system improvements at the 
FDA that could enable the agency to further strengthen and 
accelerate its work reviewing therapies for these populations?

        Question 2(a). What approaches are there to help build 
        FDA's knowledge on issues relevant to therapy 
        development for rare and ultra-rare diseases, such as 
        working with small populations and limited clinical 
        trials data, and ensuring this knowledge can be applied 
        agency-wide?

        Question 2(b). How has patient engagement or patient-
        focused drug development supported innovation and what 
        more can be done to ensure FDA is factoring the patient 
        perspective into its regulatory activities?

    Answer 2. Please see FDA response in CDER section above.

    Question 3. There have been recent incidents where FDA has 
failed to meet agreed upon PDUFA dates with little 
justification or information given as to when a decision should 
be expected. This backlog is concerning as therapies are 
delayed from coming to market and patients are delayed access 
to new treatments that they have been eagerly waiting for. It 
is important for the FDA to prioritize meeting these timelines 
to ensure innovation and improved health outcomes for patients 
are not jeopardized.

        Question 3(a). What is causing these delays that 
        prevent the FDA from meeting these agreed upon product 
        review deadlines and what is being done to clear the 
        current backlog?

    Answer 3. Please see FDA response in CDER section above.

    Question 4. We know that certain ethnic and racial 
populations are underrepresented in biomedical research yet 
have a disproportionate disease burden for certain diseases. 
Recently, FDA released guidance titled: ``Diversity Plans to 
Improve Enrollment of participants from Underrepresented Racial 
and Ethnic Populations in Clinical Trials.''

        Question 4(a). Can you describe the Agency's strategy 
        to address diversity in clinical trials beyond this 
        guidance and how the Agency will engage patient groups 
        representative of ethnic and racial populations 
        currently underrepresented?

        Question 4(b). Given the impact of the COVID-19 
        pandemic on these patient groups, can you share any 
        lessons learned from the pandemic that could be 
        leveraged to improve clinical trial diversity?

    Answer 4. Please see FDA response in CDER section above.


                           senator tuberville


    Question 1. The User Fee Agreements are a big deal here in 
DC. They represent the product of years of discussion and 
negotiation between the FDA, industry, and other stakeholders. 
But, most regular Americans do not pay attention to these 
negotiations. I hear from my constituents all the time about 
rising prescription drug costs, but no one ever mentions the 
FDA User Fee agreements. How would you explain to my 
constituents back home how these new agreements are going to 
help them?

    Answer 1. Please see FDA response in CDER section above.

    Question 2. I hear from constituents who are concerned 
about the FDA's draft guidance on homeopathic products. The 
guidance takes a different position than the FDA has 
historically taken on the regulation of homeopathic medicines. 
Since inclusion in the Food, Drug, and Cosmetic Act of 1938, 
homeopathic medicines have been recognized as a unique and 
separate category of drugs. The FDA stated in the past that 
``the law gives the FDA no premarket review of true homeopathic 
dilutions.'' Yet, the draft guidance takes a new position 
deeming all homeopathic products as unapproved new drugs 
subject to pharmaceutical-specific premarket approval.

        Question 2(a). Is FDA seeking a revised regulatory 
        framework with regard to homeopathic medicines?

        Question 2(b). If so, how does the Agency's 
        reinterpretation of longstanding law and corresponding 
        regulations and policies fall within the purview of 
        guidance documents?

    Answer 2. Please see FDA response in CDER section above.

    Question 3. Legislation and policy ideas around improving 
the Accelerated Approval pathway are focused on what sponsors 
can do better with respect to confirmatory trials. However, I 
am also concerned that, aside from oncology, FDA hasn't been 
using this pathway as actively as it could be in rare diseases. 
I'm also concerned that not all review divisions understand or 
apply the accelerated pathway appropriately.

        Question 3(a). How is FDA ensuring that expertise about 
        the use of the accelerated approval pathway is being 
        shared within the Agency's divisions?

        Question 3(b). How is FDA using external expertise to 
        appropriately make risk-benefit decisions for rare and 
        ultra-rare diseases when safety is established, there 
        are no other treatment options, and the condition is 
        life threatening or significantly impacting quality of 
        life?

        Question 3(c). What is FDA's oversight of its own 
        divisions, especially when departing from earlier 
        openness to a pathway that would promise much earlier 
        access to treatments where patients lack any other 
        treatments?

        Question 3(d). How does FDA evaluate its own review 
        divisions' decisions to withdraw the accelerated 
        pathway in a way that is applied uniformly across 
        divisions or is defensible?

    Answer 3. Please see FDA response in CDER section above.

                                ------                                

    [Whereupon, at 11:44 a.m., the hearing was adjourned.]

                                 [all]