[House Hearing, 117 Congress]
[From the U.S. Government Publishing Office]
FDA USER FEE REAUTHORIZATION: ENSURING
SAFE AND EFFECTIVE DRUGS AND BIOLOGICS
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HYBRID HEARING
BEFORE THE
SUBCOMMITTEE ON HEALTH
OF THE
COMMITTEE ON ENERGY AND COMMERCE
HOUSE OF REPRESENTATIVES
ONE HUNDRED SEVENTEENTH CONGRESS
SECOND SESSION
__________
FEBRUARY 3, 2022
__________
Serial No. 117-65
[GRAPHIC NOT AVAILABLE IN TIFF FORMAT]
Published for the use of the Committee on Energy and Commerce
govinfo.gov/committee/house-energy
energycommerce.house.gov
__________
U.S. GOVERNMENT PUBLISHING OFFICE
57-563 PDF WASHINGTON : 2026
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COMMITTEE ON ENERGY AND COMMERCE
FRANK PALLONE, Jr., New Jersey
Chairman
BOBBY L. RUSH, Illinois CATHY McMORRIS RODGERS, Washington
ANNA G. ESHOO, California Ranking Member
DIANA DeGETTE, Colorado FRED UPTON, Michigan
MIKE DOYLE, Pennsylvania MICHAEL C. BURGESS, Texas
JAN SCHAKOWSKY, Illinois STEVE SCALISE, Louisiana
G. K. BUTTERFIELD, North Carolina ROBERT E. LATTA, Ohio
DORIS O. MATSUI, California BRETT GUTHRIE, Kentucky
KATHY CASTOR, Florida DAVID B. McKINLEY, West Virginia
JOHN P. SARBANES, Maryland ADAM KINZINGER, Illinois
JERRY McNERNEY, California H. MORGAN GRIFFITH, Virginia
PETER WELCH, Vermont GUS M. BILIRAKIS, Florida
PAUL TONKO, New York BILL JOHNSON, Ohio
YVETTE D. CLARKE, New York BILLY LONG, Missouri
KURT SCHRADER, Oregon LARRY BUCSHON, Indiana
TONY CARDENAS, California MARKWAYNE MULLIN, Oklahoma
RAUL RUIZ, California RICHARD HUDSON, North Carolina
SCOTT H. PETERS, California TIM WALBERG, Michigan
DEBBIE DINGELL, Michigan EARL L. ``BUDDY'' CARTER, Georgia
MARC A. VEASEY, Texas JEFF DUNCAN, South Carolina
ANN M. KUSTER, New Hampshire GARY J. PALMER, Alabama
ROBIN L. KELLY, Illinois, Vice NEAL P. DUNN, Florida
Chair JOHN R. CURTIS, Utah
NANETTE DIAZ BARRAGAN, California DEBBIE LESKO, Arizona
A. DONALD McEACHIN, Virginia GREG PENCE, Indiana
LISA BLUNT ROCHESTER, Delaware DAN CRENSHAW, Texas
DARREN SOTO, Florida JOHN JOYCE, Pennsylvania
TOM O'HALLERAN, Arizona KELLY ARMSTRONG, North Dakota
KATHLEEN M. RICE, New York
ANGIE CRAIG, Minnesota
KIM SCHRIER, Washington
LORI TRAHAN, Massachusetts
LIZZIE FLETCHER, Texas
------
Professional Staff
TIFFANY GUARASCIO, Staff Director
WAVERLY GORDON, Deputy Staff Director
NATE HODSON, Minority Staff Director
Subcommittee on Health
ANNA G. ESHOO, California
Chairwoman
G. K. BUTTERFIELD, North Carolina BRETT GUTHRIE, Kentucky
DORIS O. MATSUI, California Ranking Member
KATHY CASTOR, Florida FRED UPTON, Michigan
JOHN P. SARBANES, Maryland, Vice MICHAEL C. BURGESS, Texas
Chair H. MORGAN GRIFFITH, Virginia
PETER WELCH, Vermont GUS M. BILIRAKIS, Florida
KURT SCHRADER, Oregon BILLY LONG, Missouri
TONY CARDENAS, California LARRY BUCSHON, Indiana
RAUL RUIZ, California MARKWAYNE MULLIN, Oklahoma
DEBBIE DINGELL, Michigan RICHARD HUDSON, North Carolina
ANN M. KUSTER, New Hampshire EARL L. ``BUDDY'' CARTER, Georgia
ROBIN L. KELLY, Illinois NEAL P. DUNN, Florida
NANETTE DIAZ BARRAGAN, California JOHN R. CURTIS, Utah
LISA BLUNT ROCHESTER, Delaware DAN CRENSHAW, Texas
ANGIE CRAIG, Minnesota JOHN JOYCE, Pennsylvania
KIM SCHRIER, Washington CATHY McMORRIS RODGERS, Washington
LORI TRAHAN, Massachusetts (ex officio)
LIZZIE FLETCHER, Texas
FRANK PALLONE, Jr., New Jersey (ex
officio)
C O N T E N T S
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Page
Hon. Anna G. Eshoo, a Representative in Congress from the State
of California, opening statement............................... 2
Prepared statement........................................... 4
Hon. Brett Guthrie, a Representative in Congress from the
Commonwealth of Kentucky, opening statement.................... 6
Prepared statement........................................... 8
Hon. Frank Pallone, Jr., a Representative in Congress from the
State of New Jersey, opening statement......................... 12
Prepared statement........................................... 14
Hon. Cathy McMorris Rodgers, a Representative in Congress from
the State of Washington, opening statement..................... 16
Prepared statement........................................... 19
Witnesses
Patrizia Cavazzoni, M.D., Director, Center for Drug Evaluation
and Research, U.S. Food and Drug Administration\1\
Prepared statement........................................... 23
Answer to submitted questions................................ 174
Peter Marks, M.D., Ph.D., Director, Center for Biologics
Evaluation and Research, U.S. Food and Drug Administration\1\
Prepared statement........................................... 25
Answer to submitted questions................................ 191
Lucy Vereshchagin, Ph.D., Vice President, Science and Regulatory
Advocacy, Pharmaceutical Research and Manufacturers of America. 75
Prepared statement........................................... 78
Answer to submitted questions................................ 204
Cartier Esham, Ph.D., Chief Scientific Officer, Executive Vice
President, Emerging Companies, Biotechnology Innovation
Organization................................................... 88
Prepared statement........................................... 90
Answer to submitted questions................................ 207
Juliana M. Reed, President, Biosimilars Forum.................... 103
Prepared statement........................................... 105
Answer to submitted questions................................ 213
David Gaugh, Senior Vice President, Science and Regulatory
Affairs, Association for Accessible Medicines.................. 107
Prepared statement........................................... 109
Answer to submitted questions................................ 215
Reshma Ramachandran, M.D., Chair, Doctors for America FDA Task
Force, Physician-Fellow, Yale National Clinician Scholars
Program,....................................................... 119
Prepared statement........................................... 121
Answer to submitted questions................................ 217
H.R. the Biosimilar User Fee Amendments of 2022 \2\
H.R. the Generic Drug User Fee Amendments of 2022 \2\
H.R. the Prescription Drug User Fee Amendments of 2022 \2\
Article ``Accelerated Approval is not Conditional Approval:
Insights From International Expedited Approval Programs'',
JAMA, Viewpoint, submitted by Ms. Eshoo........................ 155
----------
\1\ Patrizia's testimony has been retained in committee files and
also is available at https://docs.house.gov/meetings/IF/IF14/
20220203/114371/HHRG-117-IF14-Wstate-CavazzoniP-20220203.pdf.
\2\ Legislation has been retained in committee files and also is
available at https://docs.house.gov/Committee/Calendar/
ByEvent.aspx?EventID=114371.
Submitted Material
Article ``Comparison International Expedited Approval Programs'',
JAMA Network, January 20,2022, submitted by Ms. Eshoo.......... 157
Article ``Scott Gottlieb criticizes CMS in feud over Aduhelm
coverage, calls out their lack of expertise'', by Paul
Schloesser, Endpoint News, January 27, 2022, submitted by Ms.
Eshoo.......................................................... 158
Statement of February 3, 2022, by Randall L. Rutta, Chief
Executive Officer, National Health Council, submitted by Ms.
Eshoo.......................................................... 161
Statement of February 3, 2022, Alzheimer's Association and
Alzheimer's Impact Movement, submitted by Ms. Eshoo............ 165
Statement of February 3, 2022, American College of Physicians,
submitted by Ms. Eshoo......................................... 169
HEARING ON; FDA USER FEE REAUTHORIZATION: ENSURING SAFE AND EFFECTIVE
DRUGS AND BIOLOGICS
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THURSDAY, FEBRUARY 3, 2022
House of Representatives,
Subcommittee on Health,
Committee on Energy and Commerce,
Washington, DC.
The subcommittee met, pursuant to call, at 10:02 a.m., in
the John D. Dingell Room 2123, Rayburn House Office Building
and remotely via Cisco Webex online video conferencing, Hon.
Anna G. Eshoo, (chairman of the subcommittee) presiding.
Members present: Representatives Eshoo, Butterfield,
Matsui, Castor, Sarbanes, Welch, Schrader, Cardenas, Ruiz,
Dingell, Kuster, Kelly, Barragan, Blunt Rochester, Craig,
Schrier, Trahan, Fletcher, Pallone (ex officio); Guthrie
(subcommittee ranking member), Upton, Burgess, Griffith,
Bilirakis, Long, Bucshon, Carter, Dunn, Curtis, Crenshaw,
Joyce, and McMorris Rodgers (ex officio).
Also present: Representative Schakowsky.
Staff present: Elizabeth Ertel, Office Manager; Waverly
Gordon, Deputy Staff Director and General Counsel; Tiffany
Gutierrez, Staff Member; Stephen Holland, Health Counsel;
Mackenzie Kuhl, Press Assistant; Una Lee, Chief Health Counsel;
Meghan Mullon, Policy Analyst; Kaitlyn Peel, Digital Director;
Caroline Rinker, Press Assistant; Chloe Rodriguez, Clerk; Kylea
Rogers, Staff Assistant; Andrew Souvall, Director of
Communications, Outreach and Member Services; Kimberlee
Trzeciak, Chief Health Advisor; Asad Ramzanali, Legislative
Director; and Vincent Amatrudo, FDA Detailee; Sarah Burke,
Minority Deputy Staff Director; Grace Graham, Minority Chief
Counsel, Health; Nat Hodson, Minority Staff Director; Peter
Kielty, Minority General Counsel; Emily King, Minority member
Services Director; Clare Paoletta, Minority Policy Analyst,
Health; Kristin Seum, Minority Counsel, Health; Kristen
Shatynski, Minority Professional Staff Member, Health; Olivia
Shields, Minority Communications Director; Michael Taggart,
Minority Policy Director.
Ms. Eshoo. Good morning, colleagues. The Subcommittee on
Health will now come to order.
Due to COVID-19, today's hearing is being held remotely as
well as in person. For members and witnesses taking part in
person, we are following the guidance of the CDC and the Office
of the Attending Physician. So please wear a mask when you are
not speaking.
For members and witnesses taking part remotely, microphones
will be set on mute to eliminate background noise. Members and
witnesses, you will need to unmute your microphone when you
wish to speak.
Since members are participating from different locations at
today's hearing, recognition for members for questions will be
in the order of subcommittee seniority.
Documents for the record should be sent to Meghan Mullon at
the email address we have provided to your staffs, and all
documents will be entered into the record at the conclusion of
the hearing.
OPENING STATEMENT OF HON. ANNA G. ESHOO, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF CALIFORNIA
The Chair now recognizes herself for 5 minutes for an
opening statement.
Our Health Subcommittee today is holding its first hearing
on the FDA Medical Product User Fee Programs, each of which
must be reauthorized every five years.
The current User Fee Programs need to be reauthorized by
September 30th of this year, and the focus of today's hearing
will center on reauthorizing three of the four User Fee
Programs for fiscal years 2023 through 2027, prescription
drugs, generic drugs, and biosimilars.
The creation of the Prescription Drug User Fee Act, or
PDUFA, in 1992 came at a time in our country when HIV and AIDS
had reached epidemic proportions. In the late 1980s, Americans
with HIV, AIDS, and cancer had to wait years for lifesaving
medicines to work their way through the notoriously backlogged
approval process at the FDA.
Thousands of patients were dying yearly because the agency
simply did not have the resources nor the staff to review human
drug applications.
PDUFA introduced a new opportunity for the FDA to take a
transformative approach and vastly expedite its drug review
process.
By authorizing the collection of user fees from industry,
PDUFA provided the FDA with an additional revenue source to
hire more staff and meet ambitious review deadlines for new
medicines to treat the deadliest of diseases.
Prior to PDUFA the average review time for standard new
drug applications and biologics' license applications was 29
months. Today, PDUFA's timeline for standard review is ten
months, and the timeline for priority review is only six
months.
Following the success of the PDUFA Program, Congress
enacted the Generic Drug User Fee Act, or GDUFA, and the
Biosimilar User Fee Acts, or BsUFA. I do not know quite how to
pronounce that abbreviation. That was in 2012, to clear
additional backlogs and ensure patients have timely access to
safe and effective generic drugs and biosimilars.
These user fee agreements have successfully led to the
development of more lifesaving products at reduced cost for the
American people.
The user fees of each of these programs are strictly used
to accelerate the FDA's drug and biologics review processes,
and they supplement but do not supplement congressional
appropriations to the FDA.
Every five years Congress reassesses the User Fee Programs
to ensure that each program has a fresh chance to improve its
goals of getting critical medicines to patients who need them.
Improvements to these programs are made with input from
industry, regulators, and patient advocates while working in
agreement with the FDA to ensure the agency is appropriately
equipped to assess the next wave of diagnostics, vaccines, and
therapeutics.
Today we are going to hear from representatives from the
FDA, industry, and public health who have worked, I know, very
hard together on negotiations for the User Fee Programs.
I am pleased that the parties have reached an agreement on
the three that we are taking up today and the negotiated
recommendations for each of these programs actually builds upon
the successes of the existing programs and refined elements in
light of the pandemic.
With these new programs, the FDA estimates that user fees
for PDUFA will average $1.4 billion per year. That is a hefty
amount of money.
The user fees for GDUFA will average over $600 million per
year, and the user fees for the biologics program will average
$51 million per year.
So as we discuss the sixth reauthorization of PDUFA and the
third of the other two, it is my hope that Congress will act
quickly to reauthorize these User Fee Programs to ensure that
companies can continue to innovate and FDA can quickly assess
the next wave of lifesaving medications.
[The prepared statement of Ms. Eshoo follows:]
Prepared Statement of Hon. Anna Eshoo
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[GRAPHIC] [TIFF OMITTED] T7563.002
Ms. Eshoo. With that, the Chair now recognizes our
wonderful ranking member, Mr. Guthrie, for 5 minutes for his
opening statement.
OPENING STATEMENT OF HON. BRETT GUTHRIE, A REPRESENTATIVE IN
CONGRESS FROM THE COMMONWEALTH STATE OF KENTUCKY
Mr. Guthrie. Thank you, Madam Chair, and thanks to our
witnesses for being here with us today.
Today marks the last stretch of a more than two-year
process to reauthorize the four critical FDA user fee
agreements that are foundational building blocks for medical
innovation in the United States. These agreements ensure safe
and effective lifesaving treatments and devices are approved
and eventually reach patients.
We are here today to examine three of these four programs,
PDUFA, the Prescription Drug User Fee Act; GDUFA, the Generic
Drug User Fee Amendments--and I am going to go with the BsUFA--
BsUFA, the Biosimilar User Fee Act.
The U.S. Food and Drug Administration, or the FDA, industry
and other key stakeholders have been meeting regularly since
2020 to identify barriers to bringing drugs to market.
Although we will not be discussing medical devices today, I
look forward to discussing the Medical Device User Fee Act with
industry and FDA before this committee once an agreement is
reached.
Congress originally passed PDUFA in 1992 to address
significant delays in the drug review process at the FDA. The
law authorized FDA to collect from companies who were
submitting drug applications.
These fees helped ensure a timely review of drug
applications by the FDA drug reviewers. As a result of the
early successes of PDUFA, Congress in 2002 passed the Medical
Device User Fee Act, and 2012 passed the Generic Drug User Fee
Amendments and the Biosimilar Drug Fee Act to enhance
competition in other parts of the life science industry.
These must pass agreements are reauthorized by Congress
every five years on a strong bipartisan basis. For example, the
FDA Reauthorization Act of 2017 passed under suspension in the
House and by a 94-to-one vote in the Senate.
Since Congress established the first User Fee Program three
decades ago, the FDA has approved over 1,700 drugs. By
approving more drugs and generic options, Americans have more
options and more affordable lifesaving medications.
User fees have also given the United States pharmaceutical
industry a competitive advantage globally. In 2021, 38 out of
50 novel drugs approved globally in 2021 were first approved in
the United States.
Another success of these programs has been the ability to
bring more generic biosimilars to market, providing lower cost
options for patients. In the first five years after the
authorization of generic or the GDUFA in 2012, the FDA reviewed
98 percent of abbreviated new drug applications, or generic
drug application, that had been backlogged.
Further, since reauthorizing the Biosimilar or BsUFA the
same year, the U.S. healthcare system is modeled to save $100
billion in analyzed savings resulting from increased
marketplace competition due to the availability of FDA approved
biosimilars over the next five years, according to a report
by--and I will spell this one out--IQVIA.
Since passage of 2017 FDA Reauthorization Act, which
reauthorized all four user fee agreements, members of this
committee have been building on a policy this bipartisan
legislation established.
For example, Mr. Schrader and I introduced the Protecting
Access to Safe Protective Medicines Act, and it was signed into
law last year. This law helps increase competition in the
marketplace by taking a technical clarification to the drug
application process to prevent drug companies from gaming the
system for more market exclusivity and in some case eliminating
generics from coming to the market sooner.
I look forward to finding more opportunities to create
bipartisan solutions to bring more drugs to the marketplace as
quickly and safely as possible.
And looking ahead to the next few months, this committee
will have a unique opportunity to help shape the drug and
medical device approval process for years to come. Members will
be given a chance to raise questions directly with industry
leaders and regulators about past reauthorization agreements or
specific policy priorities designed to increase innovation.
A top priority for me will be to ensure the FDA approved
drugs or devices receive coverage by both public and private
insurers as quickly as possible. This will be possible by
allowing drug or device companies to share real time economic
and clinical data with payers which will allow payers to plan
ahead for formulary placement.
This policy ensures patients would receive timely access to
new and novel treatments once approved by the FDA. Timely
coverage of a drug will not only address critical care gaps,
but will also further incentivize innovation.
Above all, I can underscore how critical it is for this
committee and for Congress to reauthorize these agreements
before September 30th. Doing so is imperative for patients to
have access to lifesaving treatments.
I thank you for the time, and I yield back.
[The prepared statement of Mr. Guthrie follows:]
Prepared Statement of Hon. Brett Guthrie
[GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT
Ms. Eshoo. The gentleman yields back. A wonderful and
important opening statement.
The Chair is now pleased to recognize the chairman of the
full committee, Mr. Pallone, for his 5 minutes for an opening
statement.
OPENING STATEMENT OF HON. FRANK PALLONE, Jr., A REPRESENTATIVE
IN CONGRESS FROM THE STATE OF NEW JERSEY
Mr. Pallone. Thank you, Chairwoman Eshoo.
Today the Health Subcommittee is beginning the critical
process of reauthorizing the FDA's User Fee Program for
prescription drugs, generic drugs, and biosimilars.
We will also discuss FDA's agreements with industry
stakeholders on improvements to the review and development of
important medicines.
The fees collected from these programs support the timely
review of drug applications and other activities needed to
support drug development, and as such, these programs are
essential to FDA's mission to ensure that the agency has the
resources and personnel it needs to review and approve safe and
effective medical treatments in a timely fashion.
The current user fee authorizations expire later this year
on September 30th, and it is critical that we pass these
reauthorizations well ahead of the deadline so that FDA can
continue its operations without interruption.
Over the past two years as we have confronted the COVID-19
pandemic, the American people have witnessed the important work
the FDA does every day. The agency has led the critical review
process and supported the development of lifesaving vaccines
that are essential to our efforts to once day end this terrible
virus.
The FDA has also reviewed and approved important therapies
that are helping people fight the virus, and it has also helped
to respond to medical supply chain issues that have led to
shortages of some medical products.
The unprecedented nature of the pandemic has stretched FDA
to its limit over the last two years, and the entire FDA
workforce should be commended for their outstanding work not
only in responding to this pandemic, but also for continuing to
do all the other important work they are charged to do.
As we continue to face the COVID-19 pandemic, we simply
cannot put FDA's funding in jeopardy, and that is why we must
act expeditiously to reauthorize these important user fees.
It is also why Ranking Member Rodgers and I, along with our
counterparts on the Senate Health Committee, sent a letter last
week to Acting Commissioner Woodcock expressing concern that
the FDA and industry have not yet reached agreement on the
Medical Device User Fee Program.
This is troubling because we are now more than two weeks
past the statutory deadline for Congress to receive the
agreement, and this deadline is set by law. It is not a mere
suggestion.
It is in everyone's interest for FDA and industry to reach
an agreement, and I look forward to receiving a status update
soon.
The proposed legislation and performance goals of the drug
programs before us today show the progress and improvements
that can be made with these user fee agreements. The
performance goals include new policies that will help increase
the consistency, efficiency, and effectiveness of drug reviews.
The proposed legislation strengthens staff capacity for the
review of cell and gene therapies; improves review timelines
for complex generic products; and develops the more competitive
biosimilar markets.
So it is my hope that these proposals from FDA will lead to
a more efficient and effective review of drugs and biosimilars
while maintaining the agency's highest standards for safety and
efficacy.
The focus on safe and effective development should
ultimately provide for a greater number of approvals of
lifesaving drugs and improved competition in a way that will
help lower costs for our healthcare system and the American
people.
And, Madam Chair, if I just may ask for a moment of
privilege and address the subcommittee on a different topic.
For those of you who have not yet heard, Kim Trzceciak, the
subcommittee's Chief Public Health Advisor, will be departing
after nearly seven years on my staff. Kim was one of the first
hires when I became the Democratic leader of the committee in
2015, handling the FDA portfolio first and then being promoted
to lead the public health team in the majority, and she has
shined throughout.
This committee and Congress have taken so much action over
the last seven years in the public health space and Kim's
fingerprints are on each of these laws.
She has been a trusted member of my team who has dedicated
her career to public health, and I am incredibly grateful to
her for her service to our country and for her counsel over the
years, and I wish her nothing but the best.
And with that, Madam Chair, I yield back.
[The prepared statement of Mr. Pallone follows:]
Prepared Statement of Hon. Frank Pallone Jr.
[GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT
Ms. Eshoo. I often say we really are nothing without great
staff.
So, Kim, we are all grateful to you for the incredible work
that has taken place and your leadership in working with both
sides of the aisle over all of these years.
I am sure it has been a rich experience for you, but you
have made it even richer for all of us. So God bless you on
your continuing journey.
Did you say where she is going?
Mr. Pallone. She is going to the FDA.
Ms. Eshoo. She is going to the FDA. How is that?
Do not forget us. Always remember your roots in this
family. So I guess we will look forward to seeing you on the
other side of the dais.
But thank you and bravo.
The Chair now is pleased to recognize the ranking member of
the full committee, Represent Cathy McMorris Rodgers, for her
opening statement.
And, Cathy, remember to unmute.
Mrs. McMorris Rodgers. All right.
Ms. Eshoo. There you are. I am looking at the screen. I did
not see you come in.
Mrs. McMorris Rodgers. Madam Chair, yes.
Ms. Eshoo. That is great. It is great to see you.
Mrs. McMorris Rodgers. And I agree. Kim, do not forget us
when you get over at the FDA.
Thank you, Madam Chair.
OPENING STATEMENT OF HON. CATHY McMORRIS RODGERS, A
REPRESENTATIVE IN CONGRESS FROM THE STATE OF WASHINGTON
Today we are discussing the critical task of reauthorizing
several key FDA User Fee Programs.
Thank you to the FDA and industry for submitting these
agreements, these three agreements, before January's deadline
and for your engagement over the last year.
These programs are designed to innovate as fast as possible
while maintaining the FDA's gold standard of safety.
The goal is to provide FDA with the resources necessary to
conduct timely and efficient reviews of human medical products,
investing cutting edge technologies, and hire and retain agency
experts to carry out these tasks.
These recommendations reflect a shared commitment to
America leading the world in medical innovation, spurring
competition, and ensuring timely access to safe and effective
drugs.
The committee is in the process of reviewing the proposed
agreements for the three User Fee Programs before us today.
These agreements include provisions that will support emerging
areas of drug discovery and streamlining the review and
approval of treatment for rare diseases.
The PDUFA agreement also directs significant investments
for the development, review, and approval of gene and cell
therapy products.
The next five years can be game-changing with one-time
curative therapies for diseases such as hemophilia, sickle
cell, and rare pediatric diseases. That innovation means hope
for patients and their families, as well as lower overall
healthcare costs required to treat those diseases today.
The new Star Pilot Program also proposed in PDUFA will
expedite the delivery of promising therapeutics for diseases
with unmet clinic needs.
I look forward to hearing from our witnesses on how PDUFA
and GDUFA--that is what I was told--will bring competition to
the market, increasing options and lowering cost for patients.
Competition, not price controls, has demonstrated the
ability to lower drug prices, and these agreements are key to
bringing more lower cost generics and biosimilar drugs to
market. I am pleased to see proposals in both packages that
will enhance approval of these complex generics and
interchangeable products.
Over the course of the negotiation process we have heard
from FDA, industry, and stakeholders on how the COVID-19
pandemic has impacted new treatments and cures to the American
people. FDA gave rolling reviews to expedite the review of
treatments and vaccines while not lowering the bar on safety.
Can FDA continue those process improvements for other
diseases?
I also want to discuss today how the FDA is planning for an
orderly transition from emergency use authorizations to full
approvals and how we can get back to normal.
We clearly have more supply of vaccines than demand. So why
do we not transition to routine distribution?
Rumor is that the Biden administration may ask for more
COVID-19 funding, and I want to know how long the
administration plans to be the sole purchaser of COVID-19
vaccines in the country.
At some point, and I hope it can be soon, the public health
emergency will end. When that happens, American patients need
to continue to have access to necessary vaccines, and we need
to improve access to tests and treatment.
FDA plays a large role in that transition, and I want to
learn more about what that takes and how these agreements will
play a role.
FDA also works with companies designing critical trials for
approval, including a number of treatments for Alzheimer's
disease. I was shocked to find out that at the CMS proposed
national coverage determination severely restricts Medicare
coverage for a whole class of Alzheimer's treatments, including
the recently FDA-approved Aduhelm, to only cover these drugs in
CMS-approved clinical trials.
It also excludes those with Down's Syndrome from
participating in covered trials, even though Alzheimer's may
affect greater than 90 percent of those with Down's Syndrome
over the age of 60.
This is wrong. We need clinical trials that more closely
reflect the diversity of Americans, including those with
disabilities.
Further, just because they may be excluded from trials
today, it should also not hurt their access to FDA-approved
drugs if their doctor determines it is the best decision for
their health.
We are committed to moving these User Fee Agreements
through Congress on time and through regular order. Now more
than ever let's work together in a bipartisan way to promote
innovation, to lower cost with more competition, and deliver
safe and effective drugs to Americans.
Thank you, and I yield back.
[The prepared statement of Mrs. McMorris Rodgers follows:]
Prepared Statement of Hon. Cathy McMorris Rodgers
[GRAPHIC(S) NOT AVAILABLE IN TIFF FORMAT
Ms. Eshoo. The gentlewoman yields back.
I now would like to introduce our witnesses for our first
panel. I would say two stars from the FDA.
The first, Dr. Patrizia Cavazzoni. She is the Director of
the Center for Drug Evaluation and Research at the FDA. She has
testified many times before our subcommittee, and we welcome
her here today and thank her for the work, the ongoing work
which has been an extraordinary workload given the pandemic.
And Dr. Peter Marks, who is the Director of the Center for
Biologics Evaluation and Research at the FDA.
We welcome you. We thank you for your leadership and work
that you are doing, as I said, the really heavy load that has
fallen on the FDA during the pandemic. Your service to the
American people is nothing sort of extraordinary.
So thank you, again, for joining us today. We look forward
to your testimony. I think you are familiar with our system of
lights: 5 minutes for each.
Dr. Cavazzoni, you are recognized for 5 minutes .
STATEMENT OF PATRIZIA CAVAZZONI, M.D., DIRECTOR, CENTER FOR
DRUG EVALUATION AND RESEARCH, U.S. FOOD AND DRUG
ADMINISTRATION; AND PETER MARKS, M.D., Ph.D., DIRECTOR, CENTER
FOR BIOLOGICS EVALUATION AND RESEARCH, U.S. FOOD AND DRUG
ADMINISTRATION
STATEMENT OF PATRIZIA CAVAZZONI, M.D.
Dr. Cavazzoni. Madam Chair, Ranking Member Guthrie, and
members of the subcommittee, I am Dr. Patrizia Cavazzoni,
Director of the Center for Drug Evaluation and Research at the
Food and Drug Administration.
I appreciate the opportunity to appear before you today,
along with my colleague, Dr. Marks, to discuss reauthorization
of the User Fee Program covering brand name drugs, generic
drugs, and biosimilars.
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.
As 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 people who
otherwise could not afford them. Facilitating access of
lifesaving medicine for all Americans is a top priority for
FDA.
Since its creation more than ten years ago, GDUFA has
allowed the agency to approve thousands of generic medicines
resulting in significant cost savings for consumers. By some
accounts, generic drugs saved the U.S. healthcare 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 healthcare system.
We are committed to building on the 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 will build on the agency's prior success by
introducing new measures that allow for earlier approvals and
ensure that we have appropriate staff expertise to deliver on
our goals year after year.
Let me now turn to the Biosimilar User Fee Program.The
abbreviated biosimilar approval pathway saves the developers
time and resources, thus encouraging competition and
potentially lowering healthcare costs.
Since the enactment of BsUFA II five years ago, the number
of approved biosimilar products has grown from five to 33
today, including an interchangeable insulin product.
BsUFA III proposed 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
for 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 disease could not
exist as they are today.
PDUFA's revolutionary impact on innovation and the flow of
new medicines is matched by PDUFA's impact on 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 PDUFA 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 Dr. Cavazzoni follows:] \1\
[Please see footnote.]
Ms. Eshoo. Thank you, Dr. Cavazzoni.
Now I would like to recognize Dr. Peter Marks.
Welcome back to the committee, Dr. Marks. Thank you for
your really extraordinary leadership, and you have 5 minutes to
make your presentation to us.
STATEMENT OF PETER MARKS, M.D., Ph.D.
Dr. Marks. Thanks very much.
Madam Chair, Ranking Member Guthrie, and the members of the
subcommittee, I am Peter Marks, Director of the Center for
Biologic Evaluation and Research at the Food and Drug
Administration.
We are excited to be here today to work with you to
initiate the congressional reauthorization of the User Fee
Program. For my portion of the testimony, I will focus on the
Prescription Drug User Fee Program, or PDUFA.
Both CDER and CBER implement the commitments contained in
the PDUFA commitment letter, which are referred to as PDUFA
VII. So know that while I am presenting the elements of the
PDUFA VII letter, both Dr. Cavazzoni and I share the
responsibility to oversee 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 launched first 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 therapies to
patients in a much more timely manner.
So it began with a general focus on shortening review times
through successive five-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 approval and giving safe and effective drugs to patients
sooner.
These interactions also enable sponsors to incorporate the
advances in regulatory science so their development programs
are expediting drug development and facilitating timely
regulatory decisions.
Reauthorization of PDUFA will enable the agency to collect
fees to support the review of new, innovative drugs. The PDUFA
VII commitment letter includes the following categories, among
others: enhancing CBER support for the development, review, and
approval of cell and gene therapy products and new allogeneic
extract products; advancing applied scientific research to
expedite drug development; continued enhancement and
modernization of the drug safety system; advancing the
utilization of innovative manufacturing technologies; and
improving 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 enhancements to CBER support the development, review, and
approval of cell and gene therapy products and new allogeneic
extract products.
FDA has experienced exponential growth in cellular and gene
therapy submissions over the past seven 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 investigation of new drug applications and
a 158 percent increase in formal meeting requests.
A number of these programs have the potential to bring new
therapies to meet unmet medical needs to serious and life-
threatening diseases. Since December 2016, 68 of 180 requests
have received regenerative medicine advanced therapy, or RMAT,
designation, which was enacted by Congress as part of the 21st
Century Cures Act, and three of these designated products have
received approval in 2021. These include two allogeneic
cellular products, one for children with a rare immune
disorder, one for wound healing, and a third, CAR T-cell gene
therapy product for B-cell lymphoma.
To meet the demands of this 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, both public meetings to examine new
technologies and approaches, patient-focused drug development
meetings to better understand patient perspectives on gene
therapy products, and public outreach to facilitate product
approval and development and approval.
New allogeneic 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.
Enhanced cell and gene therapy and allogeneics are just two
examples of the important enhancements proposed under PDUFA
VII, and we will be happy to answer your questions regarding
the others.
Thank you, again, for your time today.
[The prepared statement of Dr. Marks follows:] \1\
Dr. Marks. Thank you, Dr. Marks.
A little housekeeping issue. Since our witnesses are
virtual today, I am asking members to mute their mikes after
they ask their question so we can hear the witnesses more
clearly. When you are unmuted, it, I think, drains away some of
the power and the clarity of whomever is speaking.
So thank you for that.
All right. I think that we will now move to questions of
our witnesses, and I recognize myself for 5 minutes .
I leaned over and said to our ranking member that these
programs have all worked. Members from both sides of the aisle
support these programs, and they continue under your direction
and your leadership to keep producing good things for the
American people.
PDUFA was first passed 1992. Congress has successfully,
reauthorized the program five times since then. For anyone that
is tuned in today listening to our hearing, they have already
heard a real alphabet soup of acronyms.
What I want to ask each one of you is what are the
highlights of the reauthorization of these three programs. What
is brand new?
Is there a commitment of more dollars for each program?
Does it remain the same?
And how long does it take for you to negotiate these
agreements, as well, in meeting with industry partners?
So if you could just highlight what is new, what you are
excited about that has been brought forward by both the FDA and
industry, and also the resources.
Dr. Cavazzoni. Madam Chair, thank you.
I am happy to start and focus on the generic and the
biosimilar programs and let Dr. Marks speak more to PDUFA.
First, to your question about resources, all three
reauthorization proposals entail incremental resources for FDA,
and those resources are largely overwhelmingly pointed to
incremental staff to meet the additional enhancements and
commitments in the proposals.
When it comes to the generic program, the agreement is
really focused on increasing the efficiency of the review
process and trying to make the most out of every single review
process so that we can increase the proportion of generic drugs
that are approved with only one cycle of review.
And to that effect, there are a number of incremental
elements in the proposals to achieve those goals.
The other big focus in the generic program is enhancements
to facilitate and accelerate the development of complex
generics, which are those complex generic drugs that are more
difficult to make.
And to that effect, the agreement includes commitments to
issue product-specific guidances to increase communication with
the manufacturers who are developing these complex generics and
also to ensure that there is communication in situations where
we have to issue a complete response letter and move the
application to review.
With biosimilars, the focus of the proposal is really about
increasing the efficiency of the biosimilar development, and
within that is the approvals of interchangeable biosimilars,
which are those biosimilars that can be switched at the
pharmacy like generics.
And we have already seen some gains there with the approval
of interchangeable biosimilar insulin this past year.
I am going to yield the time to Dr. Marks to speak to
PDUFA.
Ms. Eshoo. OK. Dr. Marks.
Dr. Marks. Thanks very much.
I will try to be brief, but these commitments take a lot of
time to work through, and approximately two years has gone into
leading up to arriving at the agreements.
In the PDUFA commitment, some really important enhancements
include an early meeting type called the Interact Program for
both the Center for Drugs and the Center for Biologics, which
will allow manufacturers to get early input on their
development programs.
It also includes and we have already heard about the STAR
Program which will be a way that supplements can be split and
reviewed in a somewhat more timely manner, hopefully bringing
them towards approval for additional indications for already
approved drugs at least a month earlier.
And we also have an incremental increase in our cell and
gene therapy staff which is desperately needed to allow those
products to move ahead and progress in a very timely manner.
Thanks.
Ms. Eshoo. Thank you very much.
The Chair nowrecognizes our ranking member, Mr. Guthrie,
for his 5 minutes of questions.
Mr. Guthrie. Thank you, Madam Chair.
I really appreciate it, and it is great to be here to get
these moving forward.
Just before the committee started, we had a discussion up
here with the Chair and Dr. Burgess, and we were just talking
about how do we get drugs out quicker to the marketplace which
we know are safe and effective and out to the marketplace
quicker.
And since we do not really have the chance to get FDA
before us too often, Dr. Cavazzoni, I just want a question
about Aduhelm, and my question is was FDA asked to consult with
CMS.
The situation with Aduhelm is that FDA had an approval and
CMS said send it back for more analysis. So I just wondered if
150 makes the approval, why the coverage determination asks for
more analysis.
And so my question for you, Dr. Cavazzoni, just to put the
background, was FDA asked to consult with CMS, ensure its
analysis of Aduhelm when the decision was made to cover the
drug only with evidence development?
Dr. Cavazzoni. So thank you for that question.
The FDA and the CMS decisions are independent of each
other. FDA makes a determination that a drug is safe and
effective, and in this case we did so by approving Aduhelm, and
then once that decision is made, CMS makes their own decision
on coverage on the basis of their parameters and standards and
process.
The data that served as the basis for the approval of
Aduhelm was available to CMS and the public, in fact, because
we have shared all the reviews and the memos at the time or
shortly after approval. And so those data were, you know, well
known.
CMS, you know, makes their own decision based on their
criteria and their thinking about the data.
FDA is the agency that determines that a drug is safe and
effective.
Mr. Guthrie. You answered my question on that. So I
understand what you are saying is they are independent and
should be. But if the FDA says it is safe and effective and CMS
says, ``No, we are going to need more data to understand
that,'' do you think that the mandated trials that CMS is
asking for are duplicative?
Dr. Cavazzoni. I was not part of nor were we part of the
thinking by CMS in making these determinations. What I can say
is that based on FDA standards, we determined that the drug
should be approved using accelerated approval, which is a
pathway that inherently has [audio malfunction].
Mr. Guthrie. OK. Just one question on that, if I could ask
you a question on that. I am sorry.
So because we have had other things that have been
accelerated approvals, and it is important that people
understand this.
So what is the difference between FDA accelerated approval
standard, safety standards and additional approval process?
Dr. Cavazzoni. Thank you.
That is a very, very important question. The accelerated
approval is based on some surrogate endpoints that predict
clinical benefit or some intermediate clinical measures.
And because of that, we often, if not all the time, require
post-approval studies or confirmatory trials. So in the
situation, in the instance of Aduhelm, we determined that the
data met the criteria for using accelerated approval as opposed
to traditional approval, which normally does not require the
confirmational additional post-market studies except for safety
in some instances.
Mr. Guthrie. So if I am a patient in that, what was the
difference in safety?
Is the drug going to be safe if you do accelerated
approval? Because we have that currently in our country right
now.
Dr. Cavazzoni. Yes. So when we make the determination that
the drug can be approved under accelerated approval, we
determine that the benefits outweigh the risks for the drug and
that the drug can be marketed and used by prescribers with
information that is provided in the prescriber information or
the label.
Mr. Guthrie. Do not have but about 20 seconds left. So do
you believe that CMS' decision to not accept accelerated
approvals in that way will hurt other further research in
Alzheimer's moving forward?
Dr. Cavazzoni. There have been some concerns raised about
this. Our focus is to review these drugs. There is a very, very
rich pipeline for Alzheimer's, and we expect to have a lot of
work ahead in advancing the development of these drugs.
Mr. Guthrie. Thank you.
My time has expired, and I yield back.
Ms. Eshoo. The gentleman yields back.
The Chair recognizes the chairman of the full committee,
Mr. Pallone, for his 5 minutes of questions.
Mr. Pallone. Thank you, Chairwoman Eshoo.
As I mentioned in my opening statement, it is critical that
Congress reauthorize User Fee Programs on time, well ahead of
the September 30th funding deadline. So my question is to help
all committee members understand the importance of passing
these agreements, Dr. Cavazzoni and Dr. Marks, can each of you
describe briefly what would happen to your centers at FDA if we
enter August or even September and Congress has not acted.
And what would that also mean for patients, if you would?
Dr. Cavazzoni. Thank you, Chairman Pallone.
I am able to start.
I am not exaggerating by saying that not reauthorizing
these programs will be disastrous for FDA and for patients.
These programs represent the funding for the bulk of, well
over 80 percent of our medical product staff, and that
represents well over 5,000 staff in the agency.
And these staff are, of course, critical for reviewing
applications and for making sure that we continue to have this
incredible flow of new drugs or new, affordable generic drugs
for the American people, which these programs have been able to
bring to us over the years.
I will yield to Dr. Marks for some additional comments.
Dr. Marks. Thanks, Dr. Cavazzoni.
I would just echo what Dr. Cavazzoni said. Basically our
ability to review novel cell gene therapies and innovative
products would be basically devastated. It would be an
incredible blow to our gene therapy leadership.
The United States is generally considered the global leader
in innovation in gene therapy, using novel technologies such as
genome editing, et cetera. And our ability to provide advice to
sponsors to move those programs forward would be really
crippled.
Mr. Pallone. Thank you both.
I wanted to ask Dr. Cavazzoni about one specific area of
the Prescription Drug User Fee Agreement which relates to
confirmatory studies for drugs approved through the accelerated
approval pathway.
Unfortunately, the confirmatory study may take months or
years to get off the ground if it ever gets started at all, and
in PDUFA, FDA has committed to getting the process started
earlier on its end by telling sponsors about its expectations
for post-marketing requirements earlier, before the PDUFA
action goal date.
So, Dr. Cavazzoni, explain how these pre-approval
communications will help post-marketing studies start earlier.
And then what more could be done to ensure confirmatory
trials begin on time and are completed?
For example, would it be helpful if manufacturers were
required to begin enrollment in post-marketing studies before
FDA approves their product?
Dr. Cavazzoni. Thank you, Chairman Pallone, for that
excellent question.
So you mentioned PDUFA introduces some new performance
goals for FDA to review proposals for post-marketing
requirements and to communicate to the manufacturers in a
timely fashion when those post-marketing requirements are
needed.
When it comes to confirmatory trials, those are an inherent
component of the accelerated approval program, and we do agree
that whenever possible the confirmatory trials should be
underway by the time the approval takes place and ideally
should have started recruitment.
There may be some instances where that may not be possible.
The other very important aspect of accelerated approval is
our ability to quickly and efficiently withdraw the drug from
market in those situations where the confirmatory trials do not
confirm clinical benefit.
And right now the process that we have is very cumbersome
and can take months to years because it is heavily dependent on
the manufacturer's willingness to withdraw the drug when we ask
them, and if they do not, then we have to engage in a very
cumbersome administrative process that takes time and a lot of
resources.
Ms. Eshoo. The gentleman yields back.
It is a pleasure to recognize Mrs. McMorris Rodgers, the
ranking member of the full committee, for her 5 minutes of
questions.
Mrs. McMorris Rodgers. Thank you, Madam Chair.
We need to get our lives back. We have vaccines available
with a second fully approved this week, and part of that
transition is ending the public health emergency.
However, it is imperative that the tools we have to fight
COVID-19 remain available for those who need and want them as
we look to the end of the public health emergency.
So I had a few questions in that vein. Does FDA have the
authority to continue authorizing vaccines and treatments for
emergency use if the public health emergency were to end?
Dr. Cavazzoni. Thank you, Congresswoman.
I will get us started, and then Dr. Marks can.
So when the public health declaration ends, the department,
HHS, has the ability to keep the emergency use declaration in
place, and by law there is also a requirement for public
notice, a Federal Register notice, before stopping the
emergency use declaration.
And so when the emergency use declaration ends after all of
these tests and determinations that it should end, we also
anticipate that there will be a need for some patients to
continue to have access to these drugs even if once the
emergency declaration ends they are considered not approved.
And so we recognize a period sort of, of transition to
ensure that drugs remain available for patients.
Mrs. McMorris Rodgers. OK. OK. Thank you.
I have a few more questions here.
So are you planning, are you making plans now to make sure
that the vaccines and therapeutics, which do not yet have full
FDA approval, are able to seek approval in a timely manner?
Dr. Cavazzoni. Yes. And this is, in fact, the way we work
with all manufacturers. From the very beginning----
Mrs. McMorris Rodgers. OK.
Dr. Cavazzoni [continue]. They come in for emergency use.
Mrs. McMorris Rodgers. Thank you, thank you.
Dr. Cavazzoni [continue]. For approval.
Mrs. McMorris Rodgers. OK. Well, so these products will not
have to start back at zero with new reviewers and teams?
Dr. Cavazzoni. No, they will not.
Mrs. McMorris Rodgers. OK. Has FDA communicated those plans
to drug and vaccine manufacturers who have products authorized
for emergency use?
Dr. Marks. This is Peter Marks.
Yes, we have, and in fact, we have guidance out that
actually specifically notes that as these products receive
their emergency use, the sponsors should be prepared that they
all will need to transition to biologics license applications
for the vaccine.
Mrs. McMorris Rodgers. OK. What is the status of the FDA
workforce in terms of returning to normal?
I have heard some concerns that FDA is still communicating
with drug sponsors exclusively through written correspondence
or conference calls, not even Zoom or virtual calls.
In-person meetings offer the opportunity for a more robust
dialogue between the agency and the sponsors. Do you have a
plan to resume these in-person meetings?
Dr. Cavazzoni. Right now we are still making them remote,
and we have the ability to conduct meetings via teleconference
or video conference, which have greatly increased our
efficiency and effectiveness at a time when our staff are
dealing with an unprecedented increase in volume of work during
the pandemic.
So we recognize that once the situation normalized that
we----
Mrs. McMorris Rodgers. OK. Well----
Dr. Cavazzoni [continue]. Resume some meetings, but will
continue potentially to have some remote meetings.
Mrs. McMorris Rodgers. Sooner rather than later would be
great.
I heard the FDA had a good meeting with LuMind, the IDSC
Foundation, Down's Syndrome Foundation, on what is needed and
how to encourage more studies so that we know how the drugs and
biologics work for those with Down's Syndrome.
I appreciate that, and I want to know if and how the
programs in the User Fee Agreements support the development and
validation of tools that take into account unique populations
like those with Down's Syndrome.
Dr. Marks. If you would like I can.
There are specific arrangements in the USER Fee
Reauthorization, such as the Rare Disease Endpoint Pilot
Program, that are put there to try to help facilitate the more
rapid development of medical products for specific populations,
and some of those tools can also be applied to more common
diseases as well.
Ms. Eshoo. The gentlewoman yields back.
The Chair is now pleased to recognize the gentleman from
North Carolina, Mr. Butterfield for his 5 minutes of questions.
Mr. Butterfield. Thank you, Madam Chair, for convening this
very important hearing today, and thank you for your
leadership.
Madam Chair, further delay should not be an option, and
thank you to our witnesses for your testimony. As other members
have said, thank you so much for your service to our country.
As the co-chair of the Rare Disease Caucus and the
Childhood Cancer Caucus, I was pleased to see that the
commitment letter addresses the importance of increasing review
of combination products and advancing the development of drugs
for rare diseases.
And so my first question, and I guess I will start with
you, Dr. Marks; my first question regards pediatric cancer.
Without question, we are accelerating cancer drug development
for children. It is a good thing.
What impact has the Race for Children Act had?
And looking forward, can you explain the importance of
including combination studies in the pediatric assessment?
Dr. Marks. Yes. So thank you for that question.
So it is obviously critical that cancer drugs be studied in
pediatric populations as soon as they possibly can be, and that
is a critical piece of this.
Our center has worked, as has the Center for Drugs and the
Oncology Center for Excellence, have all worked to try to move
forward drug development programs as fast as they can to be
able to move towards appropriately studying these in children
to alleviate the pediatric burden of cancer.
Mr. Butterfield. Thank you for that.
And just to let my colleagues know that my fellow co-chair
of the Childhood Cancer Caucus, Mike McCaul, and I have
introduced H.R. 5416, the Give Kids a Chance Act. It is H.R.
5416. Please give it some attention.
This bill would authorize the FDA to direct companies
developing cancer drugs to undertake pediatric study plans of
combinations of new drugs, and so I look forward to working
with this committee and all of you and the FDA on our shared
goal of bringing hope, treatment, and cures to kids and
families across the country.
Let me next go to Dr. Cavazzoni. Thank you for your
testimony today, and thank you for all of the work that you do
for all of us.
My next question is it pertains to the Rare Disease Input
Advancement Pilot Program. As you know, most rare diseases do
not have an FDA approved therapy, which is why I applaud you at
the FDA for the creation of this pilot program.
Rare disease advocates have anxiously awaited for a program
like this, but have raised several issues that I would like you
to address.
With over 7,000 rare diseases, why is the pilot limited to
one proposal per quarter?
Dr. Cavazzoni. Thank you, Congressman.
This new pilot that was introduced in PDUFA will allow us
to work with sponsors very early in development to develop or
identify endpoints that can be used to study treatments for
rare diseases.
This is a pilot. It is a start, and we recognize that as a
pilot it will be only a certain amount of programs that we
might be able to engage with sponsors on.
Having said so, we really see that is a very important
start, and all of this is complementary with all the other
elements in the PDUFA VII proposal that will facilitate the
development of rare diseases.
For instance,----
Mr. Butterfield. Just remember we have over 7,000 rare
diseases that we are dealing with, more than 7,000. So please
take a look at possibly increasing that number.
Many rare diseases do not have clinical data, which has
remained a significant barrier in clinical trial design and
therapy development.
How will the FDA work with industry and advocates to ensure
rare diseases without robust clinical data are not left out of
this pilot?
Dr. Cavazzoni. So we have a number of elements in PDUFA
that includes our ongoing patient full constructed element
work, including patient-focus constructive element meetings.
We also have an established program that we are continuing
to advance to develop a standard set off clinical outcome
assessments for therapies for rare diseases.
And so this new pilot in PDUFA VII on endpoint development
really is part of a multiprong approach to continue to advance
and accelerate the development of drugs for the many rare
diseases.
Mr. Butterfield. Thank you to both of you.
Madam Chair, I yield back.
Ms. Eshoo. The gentleman yields back.
The Chair is pleased to recognize the gentleman from
Michigan, Mr. Upton, former chairman of the full committee, for
your 5 minutes of questions.
Mr. Upton. Well, thank you, Madam Chair.
A very important hearing, and I look forward to this
legislation moving forward.
I really have two questions I would like to focus on. Let
me first commend our colleagues, former colleague on this
committee, Richard Burr, and his partner, Senator Murray, for
releasing a comprehensive pandemic preparedness package in the
last couple of days. I look forward to working with them in
this Congress for sure.
I would note that in the testimony presented, you stated as
of December 31st, 2021, there were more than 670 drug
development programs in the planning stages, and you all
reviewed more than 470 trials of potential therapies for COVID-
19.
It is good to hear. I commend you for work speeding up
vaccines to the U.S. population, for sure, but what areas of
drug development from your vantage point do you see as
inadequate to meet the possible pandemics of the future?
I am worried about lack of new antibiotics. I would just
note maybe you want to comment on our colleague, Mr. Doyle's
PASTEUR Act, which was included in the H.R. 6000 Cures 2.0,
which helps spur development of novel new drugs to prevent
pandemics.
It has support, you know, broad support. I would urge this
committee to take action on it a little bit later this year,
but I am interested in your constructive ideas on how we deal
with these future pandemics.
Either one of you is fine.
Dr. Cavazzoni. Dr. Marks?
Dr. Marks. Yes, I am happy to start with vaccines and say
that obviously what we have learned is we have to have constant
surveillance and constantly work to do our best to have medical
countermeasures at the ready.
In some cases, this will mean working our way toward
vaccines that are probably more broadly admissible for certain
things; work toward obtaining a coronavirus vaccine just like
there has been long-term work on a pan influenza vaccine.
So we will have to continue to work very diligently on
vaccines and continuing our ability to bring forward rapid
vaccine development. That was one of the advantages that have
been on the mRNA platform, the ability to rapidly move a
vaccine into development against a specific pathogen.
And I will turn to Dr. Cavazzoni for the drug development
piece for antiviral.
Dr. Cavazzoni. Thank you, Dr. Marks, and thank you,
Congressman.
When it comes to therapeutics, the situation is really not
dissimilar to vaccines. We need to continue to do surveillance
for emerging new variants or viruses.
And when it comes to therapeutics, we need to continue to
advance the development of antiviral drugs and specifically
antiviral drugs that are less prone to lose utility or efficacy
when a new variant emerges.
And we have seen some advances to that effect in the recent
authorizations of oral antiviral, for instance, that have a
mechanism that tends to be more sort of resilient to the
emergence of new variants.
And we also have to continue to advance technology, such as
platform technologies even for therapeutics in addition to
vaccines that might allow us to learn from drugs or types of
drugs that have been determined to be safe and effective, and
apply some of what we know about those drugs to advance the
development within the same platform.
Mr. Upton. That leads right into my next question relating
to real world evidence. As you may know, we have that included
in Cures 2.0. It provides for advancing the use of RWE as we
look down the road.
Is this going to help us ten years from now if we are able
to get this thing done?
And just as a quick follow-up, would it be useful to
include that as part of the pilot program, sort of building on
what we heard in a question a little bit earlier?
Dr. Marks. I can start on that one. So real world evidence
is something that is clearly going to make a difference moving
forward, particularly when it is used Fit-for-Purpose.
We are still early on in the days of real-world evidence
because to use real world evidence, one has to have reliable
data. It has to be based on reliable evidence that one is
drawing from, and we are still developing computer systems from
the medical record to do that reliably.
Nonetheless, it has already helped us in the vaccine world
to understand the efficacy and the safety of various vaccines.
There are provisions within the current PDUFA commitment
letter to continue and expand upon and build upon the world on
real world evidence, and the agency has had a longstanding
commitment in both centers, the Center for Biologics and the
Center for Drugs, for moving ahead using real world evidence
taken, for instance, from things like the Sentinel System.
Dr. Cavazzoni, do you want to add anything to that?
Mr. Upton. I think my time has expired. I appreciate that.
I look forward to following up with you. Thank you for the work
that you do.
Ms. Eshoo. The gentleman yields back.
It is a pleasure to recognize the gentlewoman from
California, Ms. Matsui, for your 5 minutes of questions.
Ms. Matsui. Thank you very much, Madam Chair, for this very
important hearing.
And I want to thank the witnesses for being here with us
today.
Dr. Cavazzoni and Dr. Marks, thank you for CDER's and
CBER's work on patients for this drug development in recent
years. Highly rigorous clinical research around the safety and
effectiveness of therapies in development is critical, but does
not always consider the full picture of the potential impact of
a new treatment.
And that is especially true for rare conditions, such as
Duchenne Muscular Dystrophy. With a spectrum of presentation in
patients, as well as many comorbidities, the potential effects
for the therapy are not always linear, nor are the risks and
benefits.
Therefore, it is equally critical to include this patient
experience data when you are viewing a potential new treatment,
and that is why I have introduced the BENEFIT Act. That is
legislation to strengthen patient-focused drug development, or
the PFDD approach.
Dr. Cavazzoni and then Dr. Marks, patients and drug
developers are interested in working in this space, but the
clear communication about how FDA considers PFDD in making
regulatory decisions, what is FDA's plan to explain to
stakeholders how data related to patient experience and
perspective can be found in the drug review process?
Dr. Cavazzoni. Thank you, Congresswoman.
I am happy to start. The PDUFA VII agreement entails a
number of enhancements that build upon the Patient-Focused Drug
Development Program that has been part of PDUFA in the current
cycle.
So we are planning to continue to hold patient-focused drug
development meetings, to continue listening sessions and
engagement with patients, developers, and the communities to
work to find ways to increase the inclusion of patient
experience and endpoints that are meaningful to patients in
clinical trials.
And one of the important vehicles that we are going to be
using is to issue guidance. We have four guidances that are
currently in development and will be issued in the near future
that will provide developers and patient communities
information and advice on the development of endpoints and core
outcome assessments.
Ms. Matsui. Thank you.
Dr. Marks, do you have any more to add to this?
Dr. Marks. No, I think Dr. Cavazzoni covered it well.
Ms. Matsui. OK. Thank you.
Now, I have heard concerns from providers about recent
modifications of the risk evaluation and mitigation strategies,
or REMS, for Clozapine, and it is an important medication used
to treat patients with schizophrenia.
Now, implementation issues with the new Clozapine REMS this
past November posed excessive burdens on healthcare providers
and put patients at risk, leaving FDA to suspend the provisions
after just four days of operation.
Stakeholders are now seeking clarity on how long the
suspension will be continued and what steps FDA is taking to
incorporate stakeholder participation in REMS' development.
Dr. Cavazzoni and then Dr. Marks, unless Dr. Marks should
go first, how is FDA communicating its plans on REMS with
stakeholders, including prescribing physicians and pharmacies?
Dr. Marks, do you want to go first?
Dr. Marks. So in our case the REMS affected in our center
was one for a medication that is used to actually treat
complications that relate to the administration of chimeric
antigen receptor T-cells.
And the way we communicated that was through guidance in
terms of a modification to the REMS that will be in effect
during the pandemic. It is a little bit of a different
situation than Dr. Cavazzoni's, and I will turn it over to her.
Ms. Matsui. Yes. Dr. Cavazzoni?
Dr. Cavazzoni. Yes. Thank you. I really appreciate the
question.
We are very well aware of the challenges that have been
encountered with the Clozapine REMS, and this was due to the
sponsor deciding to transition the technical platform that
supported it.
We engaged extensively with stakeholders, patients,
professional associations, and other groups before the change
and after the change, and we decided to suspend some elements
because of that ongoing dialogue that allowed us to learn very
quickly that there were problems.
So we will continue to communicate, and we will determine
when these REMS, all the elements can be reinstated, and we
will only do so when we are sure that the sponsors have
fulfilled their responsibilities to get this new platform
working as it should because we do not want patients with
schizophrenia to go without their medication.
Ms. Matsui. Well, absolutely, because that can cause
extreme problems, as you know.
Ensuring patients have access to this medication is
necessary to really prevent adverse outcomes, such as
hospitalizations or loss of life, and so I encourage you to
address this issue expeditiously.
So thank you, Madam Chair, and I yield back.
Ms. Eshoo. The gentlewoman yields back.
It is a pleasure to recognize Dr. Burgess of Texas for his
5 minutes of questions.
Mr. Burgess. I thank the Chair.
And, Dr. Marks, let me thank you for the last two years of
this pandemic. You have always been responsive to my questions,
and I appreciate you coming and talking to our Doctors Caucus
at least virtually on more than one occasion. So thank you for
your leadership during this time.
Now, Chairwoman Eshoo to kick us off said she wanted to see
us get back to normal. I do want the country to get back to
normal, but I am not sure I want to see the FDA get back to
business as usual. I do not know that the status quo prior to
the pandemic would necessarily be to anyone's advantage.
So over the past two years, we have seen the FDA work with
this historic capability that was granted under Operation Warp
Speed. Let me just ask you, and this may be a longer question
that is going to require a written answer, but are there any
authorities or flexibilities granted under Operation Warp Speed
that the agency could incorporate into the regular processes
outside of a public health emergency?
Dr. Marks. So I am happy to start.
Thank you very much for that question, Congressman.
Probably the most important piece that I would say is
actually one that is a resource intense one, but that has been
the dialogue that we have had with sponsors starting very early
on and going on continuously through the drug development
process.
I can tell you that the vaccine development process often
had back-and-forth with the vaccine sponsors where in 24 hours
there has been turnaround of multiple questions. Now, normally
in development that same process might take over a month.
So that type of turnaround is not something that we need
new authority for, per se, but one where it is incredibly
resource intense.
And I will turn it over to Dr. Cavazzoni.
Dr. Cavazzoni. You know, the best time [audio malfunction]
the emergency use authorization will not be in place at some
point. We have continuously been taking stock of what we have
learned during the pandemic and the experiences, and we intend
to carry forward some of those lessons learned.
So, for instance, when it comes to----
Mr. Burgess. Let me just interrupt you there because my
time is limited, and I am going to ask you to respond to that
in writing because that is a critical part of this, and quite
honestly, I am not sure that our language we are proposing in
the user fee agreements is going to cover that, but I think it
is important that it needs to.
One of the other issues is the acknowledgement of risk in
the process, and I think it has been really powerful that the
Federal Government has been willing to assume some of the risk
in the development. There was actually, once getting through
the approval process, there was actually a product on the shelf
if we did have a breakthrough, if something was effective.
And, again, I just want to stress that it is important we
develop the language in the user fee agreements that will allow
that to happen.
But let me just ask a question on the emergency use
authorization since that came up, and my concern is that you
have something that may be effective, and so it is going to
undergo an emergency use authorization evaluation.
But there are instances. For example, a patient in the ICU,
sick with coronavirus, there are no medicines on the shelf.
Remdesivir does not work that late in the course of the
illness. Steroids if they are going to have worked will have
already worked, and now they are past their utility.
But there are some newer products, what are called
vasoactive intestinal peptides that are showing a great deal of
promise.
The difficulty right now is they cannot even get to the
emergency use authorization stage because they are still
collecting data in the Phase 3 trials. The question is you have
got an ICU population who is terribly sick; a disease that is
taking 3,300 patients a day in this country right now. We are
just fixing to have another candlelight vigil for all of the
people that we have lost.
What can you do to make that emergency use authorization
process a little more straightforward when there is obviously
indication that the product is going to be useful?
Dr. Cavazzoni. So when it comes to the emergency
authorization, while the [audio malfunction] may be different
from approval, we still need to have some data that show that
the known and potential benefits outweigh the known and
potential risks.
Mr. Burgess. Yes. Let me just interrupt you there for a
second because my time is going to expire. This is critically
important.
You already got an indication because it is in a Phase 3
trial. So it is already showing some efficacy, and again, we
are talking about a population of patients that has virtually
no other recourse.
So this is the difficulty that I am encountering. We talk
about real world stuff. In an ICU earlier this week, this very
question was posed to me, and I do not have an answer for it,
but I know we need one.
So I am asking you two at the agency to help us develop an
answer for this.
Dr. Marks. The answer----
Mr. Burgess. Yes, sir.
Dr. Marks. The answer is probably the use of our expanded
access provisions, which we have actually used quite
effectively, and the Expanded Access Program both in a patient
and intermediate treatment size population allows us to give
investigation [audio malfunction] to thousands of individuals
potentially with very simple protocols, such as informed
consent and capturing safety information.
Mr. Burgess. Well, currently these patients are being
treated under right to try. It does not seem ideal.
Thank you, Madam Chair, I will yield back.
Ms. Eshoo. The gentleman's time has expired.
The Chair nowrecognizes the gentlewoman from Florida, Ms.
Castor, for your 5 minutes of questions.
Ms. Castor. Well, thank you very much, Chair Eshoo, and
thank you to our witnesses for appearing today and to your
service to the country.
The user fee reauthorization process really provides the
Congress with an opportunity every five years to review FDA's
authorities to determine what is working well, what can be
improved, and how Congress can better provide the agency with
the tools and resources for innovation and keep the American
people safe.
The FDA's enforcement authorities are a critical component
of this mission to ensure that American consumers can have
confidence in the products regulated by the agency, that they
are safe to use, and this includes FDA's ability to issue
warning letters, to conduct inspections, issue fines, and begin
legal proceedings when appropriate.
In the case of certain products, including food products or
medical devices, controlled substances and vaccines, FDA has
the authority to issue mandatory recall to remove a product
from the market should the agency determine that it is
necessary to protect health and safety.
However, many may be surprised to know that the agency
lacks this authority for the majority of drugs that Americans
take every day, including prescriptions and over-the-counter
drugs. Instead FDA and the American people must rely on the
manufacturers themselves to voluntarily recall drug products
when the agency determines that they are no longer safe or they
are adulterated or they have been mislabeled.
And this has become a high-profile topic because in the
spring of 2020, Americans were desperate to keep themselves
safe from COVID-19 and the demand for hand sanitizer grew, and
sadly, FDA's recall list for harmful hand sanitizers or
sanitizers with failing standards grew as well.
The agency was unable to issue mandatory recalls. Sometimes
it would take weeks or months before these dangerous or faulty
products were taken off the shelves.
Dr. Cavazzoni, while I understand that typically
manufacturers have voluntarily recalled drug products from the
market and that FDA has determined should be removed, what
advantages would the agency experience by having mandatory
recall authority for dangerous drugs?
Dr. Cavazzoni. Thank you, Congresswoman.
I have to say that our inability to mandate recalls for
most drugs is a real gap for us, and the example that you
provided when it comes to hand sanitizers is a very good one.
In that instance, we became aware through our surveillance
that hand sanitizers were contaminated by methanol, which is a
poison that the use of that hand sanitizer led to deaths,
blindness, and other very severe injuries.
And rather than being able to quickly mandate the recalls,
we had to work with each single manufacturer to do so, and some
of them were very responsive, but some of them were not, and to
the point where we had to publish a list of contaminated hand
sanitizers while we were continuing to try to persuade the
manufacturers to recall the contaminated product.
And so we think that, you know, just an ability to mandate
recalls is an outlier even across FDA products, and it is also
an outlier when we look at the authorities of other major
regulatory agencies throughout the world.
Ms. Castor. So what harm could come if we do not grant FDA
this authority?
Dr. Cavazzoni. Well, using the example that I just used,
there may be egregious instances where manufacturers downright
decide not to recall a dangerous product or there may be
instances such as what we have seen with the hand sanitizers
where it may take weeks for us to work, persuade the
manufacturer, and during that time the publics are exposed to
harmful, if not lethal, contaminants in drugs and products.
Ms. Castor. Thank you very much.
Madam Chair, I yield back my time.
Ms. Eshoo. The gentlewoman yields back. She has raised an
excellent point, and the authority for the FDA to have
mandatory recall power is contained in the Competes Act that
was debated and will be up for a vote in the House this week.
The Chair is now pleased to recognize the gentleman from
Virginia, Mr. Griffith, for your 5 minutes of questions.
Mr. Griffith. Madam Chair, in honor of my friend Wiley
Nelson, I yield one minute to Dr. Burgess.
Mr. Burgess. I thank the gentleman for yielding.
Dr. Marks, if we could just go back to the previous
conversation we were having, we have all had acquaintances,
friends, staff members, families where they end up in the ICU,
and there is literally nothing, literally nothing else to
offer.
Again, help us with the ability to evaluate a product that
seems to show some promise. It is not that there is zero
promise. It is in a Phase 3 trial, for crying out loud. So it
obviously got there because of showing some efficacy.
And what we lack at this point is a guard for Right to Try
legislation that was signed into law a couple of years ago that
does deal with some of the liability issues. It does not help
with the cost. The company that is making the product available
is doing so at cost, and that is not a viable business model as
a long-term proposition.
So help us. Help us help people that are stuck in this
situation.
Dr. Marks. So, Congressman, understood, and I think the
best I can say right now is that I think we have been very
committed to trying to use whatever provisions we have at our
disposal to ensure access, be that our standard access
provisions or have conversations about when products were ready
to come in for emergency use authorization.
I think we will look forward to trying to ensure that there
is access to meet needs as quickly as we can.
Mr. Griffith. I thank you. I thank you for your answer, but
we need to move quicker when you have your college roommate
pass away and there might have been something to help him. It
makes you feel like you have got to do something when you sit
on this panel.
All right. That is it. I am aware of at least a couple of
recent REMS, risk evaluation and mitigation strategy rollouts
that have gone poorly, wreaking havoc on the industry, and in
some cases creating a real risk of patient harm.
Dr. Cavazzoni, how does the FDA keep track of lessons
learned from situations like this?
Because you already said you have got input previously from
the doctors when answering Congresswoman Matsui's question.
But the physicians I have been talking to and others
working in the industry believe that you did not get enough
stakeholder input ahead of time.
So how do you learn those lessons?
Dr. Cavazzoni. Well, thank you, Congressman.
The problems that we have with REMS were through the
company that owns the platform that delivered these REMS
deciding to get out of the REMS business, and so the
manufacturers have to find other vendors and other platforms
that could support these REMS, such as the Clozapine REMS, the
iPLEDGE REMS, and so on.
So we knew that this transition was going to happen, and to
that effect we engaged prescribers, pharmacies, and other
stakeholders months before this transition to get----
Mr. Griffith. Well, I appreciate that and hope that the
lessons from this will be learned and we will get more input
sooner.
I have got to move on to other questions. Dr. Marks, last
month the British publication Lancet published a study that
found antimicrobial resistance. AMR is a leading cause of death
around the world, more than HIV or malaria. The study used
2019, meaning the problem could be much larger if, as many
believe, COVID is making resistance worse.
How worrisome is the rising trend of the antimicrobial
resistance? How big a deal is that to you all at the FDA?
And as a subpart of that while you are answering that, are
you looking at Phage Therapies, something I think we ought to
be taking a good look at?
Dr. Marks. So thanks very much for that question.
So obviously the Center for Drugs handles antibiotics, but
we handle Phage Therapy. It is, to stay short, it is a
tremendously important problem because if we run out of
effective antibiotics, we will have tremendous problems,
especially in our hospital and ICU environment.
We have been aggressively working with sponsors developing
Phage therapies. This is a very interesting area because these
are products that are highly targeted. They may have to be
individualized for particular patients. So we are working
through the needed regulatory paradigms, and we will look
forward to continuing working this area.
Mr. Griffith. So let us know how we can help.
That being said, do you believe we have enough drugs in the
pipeline to meet increasing challenges of the antimicrobial
resistance?
Dr. Marks. I am going to defer to Dr. Cavazzoni for the
complete response, but I would probably say the answer----
Mr. Griffith. Well, answer yes or no. Do we have enough or
not?
Dr. Marks. No.
Mr. Griffith. Because I do not have much time left.
Dr. Marks. No.
Mr. Griffith. OK. I got a ``no.'' I appreciate that.
I will tell you another thing that is interesting about the
study was because we have always believed that the
antimicrobial resistance was going to be showing up in areas
where we used it a lot. This study says it is worst in Sub-
Saharan Africa and Southern Asia where they do not use the
antibiotics as much.
Very curious. Do not have an answer; do not expect one. It
is just something to think about.
I yield back. Thank you, Madam Chair.
Ms. Eshoo. Right to the point, Mr. Griffith. Thank you.
The Chair is happy to recognize the gentleman from
Maryland, Mr. Sarbanes, for 5 minutes of his questions.
Mr. Sarbanes. Madam Chair, thanks very much for holding
this hearing.
I want to thank our witnesses for their testimony today.
Obviously, as we all know because we have been focused on
it for years now, the price of prescription drugs has been
increasing. It is an overwhelming burden for so many Americans
out there, including obviously my constituents in Maryland as
well as families across the country.
And one of the agreements that we are talking about today
is the Generic Drug User Fee Amendments, which play a large
role in how generic drugs are reviewed and approved by the FDA.
Once approved, as we know, these generic drugs are often
considerably less expensive than brand name drugs. However, in
fiscal year 2021, the FDA approved only 17 percent of
abbreviated new drug applications, or ANDAs, for generic drugs
during the first review cycle.
This means that companies had to resubmit these drugs for
approval a second time, which of course slows the process down
and means that new generic drugs can take quite a long time to
be approved and to get to the individuals who need them.
Dr. Cavazzoni, can you describe how successful the
implementation of GDUFA II review goals has been over the last
five years and what progress has been made towards reducing the
ANDA review times during this period?
Dr. Cavazzoni. Thank you, Congressman.
So what we have seen over the past four and a half years
under GDUFA II is consistent gains in making each review cycle
efficient and trying to increase the amount or the number of
generics that are approved after one review cycle.
We have made some gains, and the program has met its review
performance metrics consistently over the years.
Now, when we look at GDUFA III, it actually introduces even
more tools for us to be able to maximize the first review
cycle. It introduces ways to extend the goal date depending on
the type of issues that is remaining rather than moving the
application to the next review cycle, which obviously can be
more cumbersome for manufacturers because they have to restart
the submission and so on.
And so we think that the provisions in GDUFA III will
really allow us to continue to build on the progress that we
have made so far to increase the proportion of first cycle
approval for generics, including the complex generics, more
difficult to manufacture.
Mr. Sarbanes. I have got two minutes of time left with you.
Could you give me an example of maybe a specific drug or a
category of drugs of how the GDUFA III toolkit is being
expanded to allow for that first review process to achieve kind
of more success?
Dr. Cavazzoni. I could give you the example of complex
generics. These are generics that are drugs that include, for
instance, the drug-device combination or are a more complex
formulation or route of administration, for instance, eyedrops
or inhaler, inhaled drugs, and so on.
And the GDUFA III agreement has a number of provisions that
we think will really facilitate the speedier development of
these complex generics, including, for instance, new goals for
FDA to issue specific guidances for each product that are a
``how to'' compilation of how the drug should be developed and
how the manufacturer could demonstrate that the drug is
equivalent or bioequivalent to the branded drug.
For those complex generics, the agreement introduced some
new opportunities to meet with the manufacturer. For instance,
after we issue a complete response letter, there is a new
meeting with manufacturers that is introduced in GDUFA III that
would allow us to really explain our thinking and really focus
on the problems and constructively work with the manufacturer
to make the next cycle be the last cycle and really get us to
where we need to go with the application.
Mr. Sarbanes. Well, I am out of time, but I will just
observe that that kind of technical advice and guidance
obviously demands resources and capacity on the part of the
agency, and that is one reason we need these important user
fees in place.
With that, Madam Chair, I will yield back my time. Thank
you.
Ms. Eshoo. Thank you. The gentleman yields back.
The Chair is pleased to recognize the gentleman from
Florida, Mr. Bilirakis, for his 5 minutes of questions.
Mr. Bilirakis. Thank you, Madam Chair. I appreciate it.
First of all I want to wish a good friend or former
colleague here on the Energy and Commerce Committee and now a
United States Senator, Ben Ray Lujan, a speedy and full
recovery.
So, Madam Chair, as the co-chair of the bipartisan Rare
Disease Caucus, I believe FDA can do better to facilitate the
development of rare disease therapies through better
coordination and fewer bureaucratic hurdles. That is why I was
interested to read in the FDA's joint testimony about ideas to
build on the rare disease programs in the PDUFA proposal.
Dr. Cavazzoni, do you agree that we can be doing more to
ensure coordinated efforts within the agency to advance rare
disease drug development?
And can you elaborate on what additional actions FDA is
committed to taking for this community that faces unique
challenges in getting treatments to the patients, the
treatments that the patients deserve?
Dr. Cavazzoni. Thank you for that important question.
And we are very committed to do everything that we can to
find more [audio malfunction] since there are thousands of rare
diseases with a lot of permanent need.
Right now if we look at the new molecular entities that we
have been approving, rare diseases represented half of our new
molecular entities. So we have made significant gains, and we
are continuing in that to make gains thanks to the elements
that are in the PDUFA VII proposals to build upon what we have
in the current cycle.
Some of the elements are that new, a rare disease pilot
that allows us to sit down with manufacturers and identify
anything that could be used to design clinical trials for rare
diseases. [Audio malfunction.]
We also are going to continue the patient-focused drug
development program, which has been very successful with over
50 patient-focused drug development meetings. We will issue
guidance on clinical outcome assessments and take this
multiprong exhaustive approach to continue to accelerate the
delivery of therapies for rare diseases.
Mr. Bilirakis. I do not know. The light keeps coming off,
but anyway you can hear me.
As you know, around 95 percent--Doctor, I know you know
this--95 percent of the 7,000 known rare diseases have no FDA
approval therapy, but affect millions of Americans nationwide.
That is why I introduced H.R. 1730, the Speedy Therapy
Access Today Act, or the STAT Act, with my fellow co-chair of
the Rare Disease Caucus, Representative Butterfield. This
bipartisan legislation seeks to replicate the Center of
Excellence model embraced by the FDA in the oncology space and
thus complement and build upon the existing cross-agency work
focused on rare disease and providing a stronger inter-FDA
organization for rare diseases.
I am hopeful, Doctor, we can get this included, Madam
Chair, in the PDUFA process.
So the next question is, again, for Dr. Cavazzoni.
Considering the small patient populations and difficulties
surrounding clinical trial programs for rare diseases, another
program in the toolkit that can be particularly useful to the
rare disease community is accelerated approval.
Can you explain how this process has helped get drugs to
treat rare diseases to market faster when there is no
alternative treatment available?
Dr. Cavazzoni. Thank you for the question.
So accelerated approval has the larger [audio malfunction]
in anti-infectives and some rare diseases. In order for us to
be able to use accelerated approval, we need to have a
surrogate marker that reasonably predicts the clinical benefit
of the drug so that particularly for diseases that are chronic
and take a long time to progress, we can approve the drug
earlier or we can also use an intermediate clinical endpoint.
The problem with many rare diseases, in fact, the majority
of rare diseases is that we have yet to identify the biological
underpinning of the disease and as a result of that, we have
not identified those surrogate markers that would allow us to
use accelerated approval.
We are making gains and we want to continue obviously to
use accelerated approval and all our expedited pathways, but we
need the science and the biology to also move as it has in
oncology and cancer.
Mr. Bilirakis. Thank you, thank you, Doctor. I appreciate
it.
I yield back, Madam Chair
Ms. Eshoo. The gentleman yields back.
Members, let's all try to stay within our time. We have a
classified briefing at 1:30 this afternoon, and so I hope that
we can conclude our hearing today so that we do not keep the
second panel waiting and we can go off to our classified
briefing and not have to return.
So with that in mind, the Chair is pleased to recognize the
gentleman from Vermont, Mr. Welch, for his 5 minutes of
questions.
Mr. Welch. Thank you very much, Madam Chair.
We are in this pandemic, and it is unique, and it creates
real strains on doing the inspection process. The remote
inspection tool is obviously very, very important, very
difficult, but really essential, and it is focused on mission
critical inspections, and that makes sense.
But it does leave out generics and biosimilars, and the
question I have is for Dr. Cavazzoni. How do we pick up
inspections on the biosimilars and generics so that they can
get to the market?
Because we do have this problem that Mr. Sarbanes just
mentioned, the brutal and unrelenting price increases, and if
we do not have inspections of generics, we do not have
inspections of biosimilars, there is no route for them to the
market. There is no competition, and the pricing pressure
continues.
Dr. Cavazzoni.
Dr. Cavazzoni. Thank you, Congressman.
And as you indicated, during the pandemic we were quite
successful in using these alternative methods to physical
inspection of manufacturing plants, which include a host of
tools, such as exchanging documents, relying on the inspections
of other health authorities, and also doing these remote
assessments through cameras and technological platforms.
These alternative methods can be used in a number of
circumstances.
Mr. Welch. No, but how do we pick it up? I mean, I know
they can be. What I want to know is how do we pick it up so we
can get the biosimilars and the generics to be inspected.
Dr. Cavazzoni. Yes. So we have utilized these approaches
for all the instances among mission critical inspections, which
include the preapproval inspections when the facility lent
itself to that approach.
There are some instances because of the compliance history
of the facility or because the facility has had very serious
inspection findings where we have no choice but to require a
physical inspection of the facility and where these alternative
approaches are really not possible.
And the pandemic----
Mr. Welch. Let me----
Dr. Cavazzoni. Yes.
Mr. Welch. OK. Thank you. Thank you very much.
I just want to ask Dr. Marks about the BsUFA commitment
letter indicates that FDA will communicate its thinking on the
use of remote inspection tools before September 2023, which
really is a long way off, as the prices continue to increase.
Can you tell us anything about how these tools can be used
in the field?
Dr. Marks. So you know, we are still learning how effective
these tools can be by using them, and at least at our center,
we have had some mixed results with using remote inspection
technology.
So we are still sorting through this because at the end of
the day we have to ensure that the products that come out, once
we say they are safe, are truly safe and manufactured with the
quality that Americans have come to expect.
Mr. Welch. So is there a reason why those tools should be
limited to the use of biosimilars?
Dr. Marks. No, not necessarily.
Dr. Cavazzoni. I am happy to take that question.
There is no reason. The applicability of those tools
depends on the state of the facility, and there are some
facilities including biosimilar facilities, but not only those,
where because of past history we feel that we have--we
determine that we have to do a physical inspection and,
therefore, we are not able to use these alternative methods.
So this is not an issue that applies only to biosimilars
but really all of the drugs under review. We really need to
make that decision.
And the stronger the quality history for that facility, the
more likely we are to be able to use these alternative methods.
Mr. Welch. OK. Thank you very much.
Madam Chair, I yield back.
Ms. Eshoo. The gentleman yields back.
The Chair is pleased to recognize the gentleman from
Missouri, Mr. Long, for your 5 minutes of questions.
Mr. Long. Thank you, Madam Chair.
And being an auctioneer, I do not think you have to worry
about me going over my 5 minutes . I can talk pretty fast.
Dr. Marks, as you note in your testimony, almost two-thirds
of the new active substances approved in the world market are
launched first here in the United States. I hope we can advance
policies that encourage innovation here in the United States,
that we do not stifle innovation and make the United States
less attractive for development of new treatments and cures.
One area where we need more innovation and new treatments
is in rare disease space which poses unique challenges for both
the industry and the FDA.
Could you speak to the challenges you see from a regulatory
perspective at the FDA, as well as research and development
challenges for the industry for the development and approval of
rare disease medicines?
Dr. Marks. Thanks very much for that question, Congressman.
I think that we have already touched on some of them, but
the issue here is that for many of the rare diseases we do not
yet have good endpoints in order to facilitate the development.
So there is a lot of work going on at the agency to try to
develop the biomarkers or intermediate endpoints that can help
us understand that a product is effective earlier on so that we
can facilitate the development of these.
The other piece at least for us in the cell and gene
therapy manufacturing area is a place where work needs to be
done, and we are working with colleagues at the National
Institutes of Health and through the foundation of the National
Institutes of Health in a public-private partnership to try to
help facilitate gene therapy manufacturing, to help that
process speed along so that therapies could get to patients
more quickly that way.
So combination of needing better endpoints and increasing
throughput for the manufacturing process at least on the gene
and cell therapy end.
Mr. Long. And I might have missed it in your answer there,
but what makes the endpoint development process particularly
challenging for development of rare disease treatments?
Dr. Marks. It is because you have a small number of
patients, and it is often hard to find any particular marker
that will definitively correlate with the disease outcome.
Particularly in some of the rare diseases where it might take
years for a [audio malfunction] to occur. So we need to be able
to correlate a marker with that outcome, and that is why we
very much are supporting patient advocacy groups that are doing
natural history studies even ahead of drug development so that
they collect the information to help determine those markers in
advance of the drug development programs.
Mr. Long. Thank you.
And I apologize if I went over some plowed ground here, but
I have been here for about 90 percent of the hearing and have
to step out occasionally. So if some of those questions were
asked earlier, I apologize.
And I yield back a world record two minutes and four
seconds.
Ms. Eshoo. Absolutely world record. Thank you.
The gentleman yields back.
Mr. Schrader was here earlier, but I do not see him, and he
evidently is not on Webex. So we will move to and the Chair
recognizes the gentleman from California, Mr. Cardenas, for
your 5 minutes of questions.
Are you there? No?
All right. Well, then we will go over to the Republican
side. The Chair recognizes the gentleman from Indiana, Dr.
Bucshon.
Mr. Bucshon. Thank you, Madam Chairwoman, for that quick
recognition. I appreciate this hearing.
First, I want to talk about why Congress absolutely needs
to reauthorize these user fee agreements. They are key to
helping patients in this country and increasing access to care,
to allow for the continued innovation and the development of
new drugs and treatments, and also this presents us with a
great opportunity to learn from the successes of Operation Warp
Speed on how we can reduce burdensome and unnecessary red tape
to speed up drug development, as we witnessed in the
development of the vaccines for COVID-19.
FDA's PDUFA VII commitments include a chemistry
manufacturing and controls. CMC development and readiness
pilot, a program aimed at expediting CMC readiness so the
patients will have earlier access to important new products.
FDA committed to outlining the eligibility criteria for
this pilot by the end of this year. I want to ask you
specifically about cell and gene therapies, as those are an
important and growing area for patients and, in my opinion, a
key component of the future of personalized medicine.
And as you both know, they have some unique CMC issues.
Dr. Cavazzoni, can the FDA ensure that the eligibility
criteria for CMC development and readiness pilot are broad
enough to encompass a wide range of important products for
patients, including cell and gene therapies?
Dr. Cavazzoni. I can speak to this. I can start us off and
Dr. Marks since cell and gene therapies are in his center.
We are very excited about this new pilot because this new
pilot would allow earlier and more frequent interactions with
the manufacturers and the centers during development when it
comes to the manufacturing aspect of the drugs.
And this will have an impact, among other things, in the
development of rare diseases where there is so much unmet need.
And so we really look forward to this pilot and to the results
that we anticipate it might yield.
I will turn over to Dr. Marks for additional comments.
Dr. Marks. I do not want to waste your time. We totally
agree that we very much think that the chemistry manufacturing
control team is incredibly important in the cell and gene
therapy space and totally support moving ahead and advancing
this area.
Mr. Long. Thank you.
I just urge you to get this program started as soon as
possible once you have approval, and to make sure that some of
the focus for the pilot is on cell and gene therapy. CMC
readiness will help get these important therapies to patients
earlier.
I also now want to talk about the diversity in clinical
trials. As we have seen through the clinical trials for the
COVID vaccines, we need to do better promoting diversity in
clinical trials.
It is difficult to get a diverse population enrolled in
some of these trials. I understand that, but we need to do
better at promoting that, and this is something I have been
advocating for.
As a doctor, I know the importance of the needed diversity
participation in trials to better understand how the drug
treatment and/or vaccine would respond to the different
patients in our country, the different population of people in
our country, just as I know from my medical training that
certain diseases could and would affect certain patients
differently based on factors such as genetics and ethnicity.
As the future of medicine continues to move towards
personalized medicine, this will only continue to become more
important, and my hope is that the FDA and industry continue to
collaborate to find better ways to encourage and promote
participation in clinical trials.
This is why I introduced legislation with my good friend,
Dr. Ruiz, that will help promote clinical trials having
proportionate representation of all communities, as well as
support education outreach and recruitment for future clinical
trials.
Dr. Cavazzoni, the commitment letter includes a section on
enhancing the use of digital health technology to support drug
development and review. The letter suggests the use of DHTs can
support and enable the conduct of decentralized clinical
trials.
Does the FDA believe these enhancements will be impactful
in improving clinical trial diversity?
And does FDA have plans for expanded outreach around the
importance and value of clinical trial participation?
Dr. Cavazzoni. Thank you, Congressman.
We could not agree more about the importance of increasing
diversity in clinical trials. And as you have mentioned, we
have made some real gains in the development of vaccines and
therapeutics, and we should try to maintain those gains.
One of the important tools in facilitating diverse
recruitment is decentralized clinical trials, and decentralized
clinical trials with the use of technologies, such as digital
health technologies, to collect endpoints, our information
during the trial, or also technologies to check the one that we
are using today to make clinical assessments or to obtain
consent from the patient.
[Audio malfunction] having to travel to a clinical
investigation site.
We have really seen an example of these tools, and we look
forward to----
Mr. Long. Thank you. My time has expired.
I just want to say, if you will indulge me, Madam
Chairwoman, for just a second, in the COVID vaccine space, we
have seen some resistance to vaccination in certain subgroups
of our population based on the clinical trials not having
people of a diverse nature in those trials.
So this is really, really important.
Thank you.
Ms. Eshoo. The gentleman yields back, and I would just say
to him thank you for raising the issue of diversity in clinical
trials. I have legislation on it, as do you. I believe that the
bills are complementary to one another and we will continue
working on it.
But thank you for that. It is so important.
The Chair nowrecognizes the gentleman from Oregon, Mr.
Schrader.
He is not here? All right. Then we will go to the gentleman
from California, Mr. Cardenas, for your 5 minutes of questions.
Mr. Cardenas. Thank you very much, Madam Chairwoman and
also Ranking Member, for having this very incredible, important
bipartisan meeting where we are in agreement and we are working
together, and we have been working together for a long time to
bring this about.
Unfortunately, it is not going to be on Fox News, CNN,
MSNBC, or anywhere else. It is probably going to spread out to
the nerds who watch us on television, in our hearing or what
have you, but I do want to say thank you so much to my
colleague, Dr. Bucshon. I agree with everything you just said
over the last 5 minutes -plus, and I just want to say thank
you. It is wonderful to see that we agree on many things.
Unfortunately, the public only thinks that we always disagree.
So I just wanted to point that out that this is an amazing
opportunity for us to demonstrate that we are, in fact, getting
things done on behalf of the American people.
And when it comes to the FDA, when it happened in the
United States, it benefits the rest of the world and is
something we should be proud of.
The user fee process ensures that the FDA has the funds it
needs to evaluate and approve medical innovations and therapies
in a timely manner. I want to talk a bit about patient-focused
drug development, which is a systematic process that would help
to center patient input in the drug evaluation and decision-
making process.
Dr. Cavazzoni, again, thank you so much for your work and
your dedication and your public service.
Can you talk a bit about why this focus on patient-focused
drug development is a growing priority for the FDA?
Dr. Cavazzoni. Thank you, Congressman.
This is one of the top priorities for us. We recognize that
for therapies to be meaningful to patients, they have to be
studied using measures that take into consideration what
matters to patients in the patient experience.
And so we are really looking forward to continue to build
on the major gains that we have made during the current cycle
of PDUFA, to continue the Patient-Focused Drug Development
Program, continue the work that we have been doing to issue
grants for the development of clinical outcome assessments, and
issuing guidance.
Mr. Cardenas. Thank you.
Can you give a quick example of having the patient
perspective incorporated into the process and how it has helped
patients to this date?
Dr. Cavazzoni. Well, for instance, an example of the
patient experience is having information on how the patient
experiences improvement in function when they take a drug, and
that functional improvement is very important and may not
necessarily be seen even if some of the traditional endpoints
show that the drug has an effect on those endpoints.
Mr. Cardenas. Thank you. Thank you so much.
Dr. Marks, also thank you for you dedication and your
expertise that has helped so much advancing what we do here at
FDA.
The Center for Biologics Evaluation and Research will be
using some of the funds to conduct patient-focused drug
development activities in the evaluation of gene therapy
products and regenerative medicine therapies as well. How will
you ensure that the patient's experience is an integral part of
the approval process for these therapies?
Dr. Marks. Thanks very much for that question.
So much the same way as Dr. Cavazzoni has outlined, we hold
patient-focused drug development meetings. We meet with patient
advocacy groups and, indeed, have conversations with patients
which sometimes are very revealing, particularly for rare
diseases where sometimes doctors and patients have different
ideas about what is the most important endpoint in their
disease.
For instance, there is a certain genetic disease where
there is sudden cardiac death, but it turns out that the
patients did not really care about that risk. It turned out
that they really cared about the fact that they were tired and
terribly fatigued all the time, and they wanted that to be the
endpoint sought.
So we are committed to listening to patients in this regard
and then working with sponsors to try to come up with endpoints
that incorporate the different nature of the endpoints into
their clinical development programs.
Mr. Cardenas. What are some of the nuances you will need to
apply in implementing patient-focused drug development for
these therapies as opposed to other types of drug therapies?
Dr. Marks. You know, I think for cell and gene therapies
they will be listening carefully to what the most important
outcomes are in terms of how patients feel, function, or
survive, and then potentially correlating those to intermediate
endpoints or biomarkers so that we can help advance the
development as quickly as possible.
So there is that linkage between what the ultimate outcome
is that patients want and some intermediate endpoint to the
drug development process, and that is hopefully going to help
us bootstrap our way through more----
Ms. Eshoo. The gentleman's time has expired.
Mr. Cardenas. Thank you, Madam Chairwoman.
Yes, my time has expired. I apologize. I yield back.
Ms. Eshoo. The gentleman yields back.
It is my understanding that Mr. Crenshaw is next, followed
by the gentleman from Oregon, Mr. Schrader, and then when we go
back to the Republican side, we will go to Dr. Dunn.
So the gentleman from Texas.
Mr. Crenshaw. Thank you, Madam Chairwoman.
Thank you to the witnesses for being here. Thank you, Dr.
Marks, and it is good to have you back, Dr. Cavazzoni.
It is my first time being part of the User Fee
Authorization Program, and it is exciting to see where we are
at and where we are going to be for the next few years.
One of the most exciting things about the PDUFA commitment
letter is an expansive section of cell and gene therapies.
These therapies are incredibly promising, but they lack the
regulatory certainty needed to take advantage of their full
potential.
One of these therapies, autologous stem cell therapies, has
been met with a significant amount of regulatory uncertainty.
This has led to a backwards result of innovators being unsure
of how to move forward and bad actors taking advantage of
loopholes, namely, the same-day surgery loophole, in the
system.
For Dr. Marks, I know you have spoken at length about this
problem. What can Congress do to support the FDA so that we can
support innovators without flooding the market with bad actors?
Dr. Marks. So thanks very much for that question.
Actually Congress did a wonderful thing for FDA with the
passage of the 21st Century Cures Act and the medicine advanced
therapies which allow us to designate therapies of promise in
this space and help them to move forward as quickly as
possible.
Our goal is to try to get these therapies, which I agree
are potentially transformative, to patients as quickly as
possible.
Mr. Crenshaw. Do you think it is possible to regulate the
safety of autologous stem cell therapies under the current
designation or will these products have to seek a BLA,
biologics designation?
Dr. Marks. So we regulate these on a risk-based approach,
and that is they can be regulated according to the risk that
they may place, depending on how much they are manufactured and
in which manner they are used.
And that risk-based approach is how we have done this, and
I think it does serve patients very well in that products that
have significant manufacturing are regulated under the
biologics license pathway.
Whereas products that undergo minimal manufacturing and are
used in the same way in the recipient as in the donor do not
have to undergo that same pathway.
Mr. Crenshaw. Thank you. I am glad to hear that. I agree
with that statement, of course.
One of the challenges though in regulating these products
has been with the minimally manipulated definition and
broadening this definition to include adipose-derived, say
MSCs--I am not going to try to pronounce Mesenchymal-- which
are easier to extract than stem cells from blood or bone
marrow, easier to process and have high levels of
effectiveness.
Now, including these in the definition might increase the
number of bad actors in the market. How can Congress rewrite
the definition of minimally manipulated to include adipose-
derived MSCs while limiting the risk of bad actors taking
advantage of that designation?
Dr. Marks. So thanks for that.
Right now they are [audio malfunction] by a regulation, and
the issue of minimal manipulation for these cells is one that
minimally manipulated means generally washed or sized or things
like this.
But once one uses enzymes, as one often does, when one
isolates adipose-derived stem cells, or Mesenchymal stem cells,
or once one puts these things into an incubator and has them
grow so that you have more cells, the risk profile does change.
And we know that adverse events can occur with these. We
have seen adverse events, such as when adipose-derived stem
cells were injected into the eye in Florida, for instance, at
CORNEX, there were several cases of blindness because there
were probably residual enzymes in the injection.
So we do have to take a careful approach to these, and that
is the reason for being somewhat conservative in our definition
of minimally manipulated.
That said, the agency continues to always look at making
sure that we are regulating these at an appropriate level to
maximally bring forward effective therapies in a timely manner,
while protecting the public.
Mr. Crenshaw. It just seems that we are stuck in this
process at the moment, that there is a knowledge gap that I
think some of the innovators are not sure how to close.
Are there resources that OTAT would need to close this
knowledge gap and understand the safety of this particular
process?
Dr. Marks. I appreciate that.
They continue to work on regulatory science in this area,
and I think we will continue to work that in this area in
collaboration with academic investigators to see what can
advance the field.
Dr. Marks. I am out of time. I yield back.
Thank you, Madam Chair.
Ms. Eshoo. The gentleman yields back.
It is a pleasure to recognize the gentleman from Oregon,
Mr. Schrader, for your 5 minutes .
Mr. Schrader. Thank you very much, Madam Chairwoman. I
really appreciate it.
Thank you all for being here.
Reducing drug costs remains one of my top priorities. I am
proud of the work I did in Build Back Better Plan to address
these costs. One of the policies that I am the lead on, along
with some of my Republican colleagues, is trying to increase
competition in the use of biosimilars.
You know, if we have competition, price decreases. We are
having trouble, however, getting generic biosimilars into the
marketplace in a competitive manner being taken up. They are
routinely used in Europe, not so much here in this country.
What additional improvements do you guys think we need to
make in the application process to get these products to
market?
Dr. Cavazzoni. Thank you, Congressman.
First, I would like to point out that we have made quite a
lot of inroads when it comes to the number of biosimilars that
have been approved. We have gone from five at the beginning of
the BsUFA II cycle to now 33, including an interchangeable
insulin.
And so we really are looking forward to continuing to build
on this trend and bring more biosimilars to market.
Some of the elements that are important are to make the
review as effective and efficient as possible, and the BsUFA
proposal includes some enhancements around that.
Also, facilitating the new indications for biosimilars, and
the agreement also includes some new elements there.
It is also very important that we really try to spur the
development of interchangeable biosimilars so that those are
the biosimilars that can be interchanged at the pharmacy, and
the BsUFA proposal has some very important enhancements,
including introducing a pilot research program that would allow
us to really evaluate how we can make the development of
biosimilars and even more so, as importantly, interchangeable
biosimilars.
That also includes issuing guidance around----
Mr. Schrader. Can I interrupt just for a second? I
apologize, but limited time.
But on your comment on interchangeability, I guess I am
pleased to hear that. I think that is a huge improvement, but I
think my understanding is that at this point in time, like for
instance, a change in volume of the overall product, is
considered interchangeable but not the active ingredient.
What is the scientific basis for that?
Dr. Cavazzoni. Well, this is where we need to continue to
do research. [Audio malfunction] help us clarify those aspects
and introduce more clarity and hopefully also more flexibility
when it comes to the development of biosimilars.
Mr. Schrader. And I agree. Again, I just urge you to look
at the active ingredients. It seems to be much more important
than the volume of these products.
Now, the Federal Food, Drugs, and Cosmetics Act started in
1938. To get good endpoints, if you will, animal models were
considered the best opportunity out there and probably the only
opportunity to get a real idea of how a particular medication
or pharmaceutical agent would respond in a living body, a
mammal, rather than testing on humans.
But, you know, in the intervening years, there have been
some amazing advances made and preclinical drug screening and
different organs or cell cultures that can mimic human organ
systems and what have you.
Is the FDA allowing use of these new technologies rather
than requiring animal models in all cases?
Dr. Cavazzoni. We recognize the need to decrease our
reliance on animal models, but having said so, animal models
are extremely important in drug development, particularly in
determining whether the drug is safe to be put into humans for
the first time.
We are working with developers, and we also have research
programs internally to evaluate and qualify these alternative
approaches to use of animals, and we are beginning to see some
gains there, and we hope to be able to continue down that path,
understanding that it may not be possible to completely
eliminate our reliance on animals when it comes to drug
development at least.
Mr. Schrader. I appreciate that. I would hope that you
continue to use these alternate routes.
I would enjoy some written information since my time has
run out regarding how COVID in the last four years has affected
your FTE in the agency and your ability to deliver on the
GDUFA, BsUFA, and PDUFA endpoints and goals from the last
reauthorization.
And I yield back. Thank you very much, Madam Chair.
Ms. Eshoo. The gentleman yields back.
I especially appreciate your questions relate to
biosimilars. I was the House author of the legislation to
create that, but there are many questions to be answered, I
think, about the vitality of competition of products in our
country.
The Chair is very pleased to recognize Dr. Dunn, the
gentleman from Florida.
Mr. Dunn. Thank you very much, Madam Chair and Ranking
Member Guthrie, for hosting the hearing today about the
reauthorization of the FDA user fee agreements.
You know, it is my hope that the agreements that we pass
this year will push the FDA to be more efficient and reliable
and transparent in its review process. American biotech is
leading the world in innovation, and the government agencies
should rise to that moment.
I have a few process questions for the FDA panel regarding
appeals in the course of events that take place, you know,
following the issuance of a CRL. So please be brief in your
answers, all the same reasons.
Dr. Marks, it is my understanding that the formal dispute
resolution pathway provides a structured process for sponsors
to resolve a scientific or a medical dispute.
That should be a simple yes/no.
Dr. Marks. Yes.
Mr. Dunn. Yes. OK. Good. Per the agreements, the FDA then
responds to that request within 30 days; is that correct?
Dr. Marks. Yes.
Mr. Dunn. OK. Great. How often does the FDA meet that 30-
day turnaround?
Dr. Marks. I can get back to you on that for the FDA
overall. For our center at least in the past years, we have met
that date pretty reliably.
Mr. Dunn. Thank you. Please get back in writing.
It is my understanding that there are certain circumstances
where the period is extended. How long does it take when a
sponsor appeals a decision at multiple management levels, so
two and three, et cetera?
Dr. Marks. That can all depend because it depends on how
many people are in the chain as it----
Mr. Dunn. Well, I will tell you that in your agency's
information it says it takes an average of 211 days if there
are two levels, and if there are three levels, it is 256 days.
So that begins to become pretty painful.
Next, I want to shift to a few questions regarding the
complete response letter and the FDA review documents that are
attached to that.
It is my understanding that a CRL basically includes a very
brief summary of the deficiencies holding an application back
from approval, often leaving the applicant in the dark
concerning the reasons the application was deemed deficient.
It is also my understanding that there are generally
hundreds of pages of FDA review documents with each CRL, no
doubt many hours of work as well, and that information that
underlies those CRL letters is not provided to the applicant's
sponsor.
Do you think that a sponsor would be better able to resolve
their deficiencies more completely and more efficiently if they
were granted access to the full FDA review in addition to the
simple CRL?
Dr. Marks. No, I do not. I think that could be chilling on
the effect of our reviewers. Most sponsors actually know quite
well what the deficiencies are in their applications before
they receive a complete response letter because they have been
part of a process which is guided by the user fee commitments
in which they have multiple meetings leading up to this, and
most often they have been told either at their midcycle meeting
or their late cycle meeting of the deficiencies that ultimately
lead to their complete response letter.
We could perhaps enhance what we place in the complete----
Mr. Dunn. I will reclaim my time if I may.
They come to our offices, and they tell us just the
opposite. They tell us they do not know why they were denied,
and they have to go back and dig around and find out what the
problem is.
Is it lack of information or is it information that their
drug does not work or----
Dr. Marks. But they are----
Mr. Dunn. We are hearing the exact opposite information
from the people who are, you know, applying for these CRLs and
paying your user fees.
So honestly, it seems to me the transparency surrounding
the FDA review documents makes for a fairer, more efficient
process. It is especially helpful to the small and midsize
biotech companies, you know, who have the most to lose from a
drawn-out process. They cannot survive for a year with no
information from the FDA.
You know, importantly, the American patients lose out when
these innovative companies have to make decisions based on
limited resources, and it chills investors and gives them
concern in those companies.
So I want to be sure the agency is working to help the
American patients and the innovative companies that are coming
before you, both large and small.
Thank you for that.
Madam Chair, I yield back.
Ms. Eshoo. The gentleman yields back.
Thank you for your patience for being here from the very
beginning of the hearing.
The Chair is now pleased to recognize the gentlewoman from
Michigan, Mrs. Dingell.
Mrs. Dingell. Thank you, Madam Chair, and to Ranking Member
Guthrie, for convening today's hearing.
As my colleagues and our witnesses keep reiterating, timely
reauthorization of the FDA User Fee Program is fundamental to
ensuring the agency has the resources needed to effectively
evaluate product applications and remain the gold standard for
the drug approval process worldwide.
Dr. Marks, CBER is responsible for evaluating new and
innovative products like cell and gene therapies. These
therapies hold great promise for future treatments of a wide
variety of diseases and are at the forefront of science.
Dr. Marks, how has the volume of product applications for
cell and gene therapies changed since the last user fee
authorization?
And how will the policies in PDUFA VII ensure the FDA is
able to attract and retain the scientific expertise necessary
to evaluate these applications?
Dr. Marks. Thanks so much for that question.
So over the past five years there has been nearly a
doubling in the number of applications. If you look at the
number of supplements that have come in, those are amendments
to existing investigation of drug applications. They are up
over 100 percent during that time, well over 100 percent.
And so we are now at a place where the workload here is
tremendous. We are very grateful for the additional resources
that the user fee acts have brought to date. This PDUFA VII
commitment letter will bring additional resources that are
desperately needed to expedite the review of those therapies,
and that will be critical to getting these therapies in a
timely manner.
We are also though grateful for part of the 21st Century
Cures Act, which was the pay authority which allows us to
attract outstanding candidates, and that is helping us to move
forward attracting talent that we need.
And so, again, the additional provisions of PDUFA VII that
will allow us to continue to use the funding for that will be
important.
Mrs. Dingell. Thank you, Dr. Marks.
It is also important that FDA evaluators remain objective
and independent while reviewing potential therapies. In fact,
as was recently reported, Biogen, the manufacturer of Aduhelm
engaged in a lengthy, behind-the-scenes campaign that they
researched internally as Project Honest to lobby the FDA for
approval of this drug. This allegedly included off-the-book
meetings between Biogen and FDA regulators, as well as almost
daily working group collaboration between company employees and
agency review staff.
FDA's decision to approve Aduhelm is currently being
investigated by Congress as well as FDA's Office of the
Inspector General, whose report is not due until 2023.
In the interim, Dr. Cavazzoni, what actions has FDA taken
to ensure that its regulators are not inappropriately
influenced by industry?
Dr. Cavazzoni. Thank you, Congresswoman.
The decisions that FDA makes are made independently of
industry's influence, and this includes the decision that was
made on Aduhelm, understanding that there have been allegations
and reports in the news.
We have several levels of review of the data. In the
instance of Aduhelm, the data were very complex and had even
more review within the centers and by experts.
So we agree that it is very important to maintain that
independence, as has been the case in past decisions, and that,
you know, the PDUFA programs are really allowed to be what they
are meant to be, which are ways to have more efficient
processes in place and have more staff available to review more
applications faster, while upholding our independent decision
making and our very high standards.
Mrs. Dingell. So I have got like 26 seconds. You have told
us that you are frustrated here and maybe you can tell us more
about that in writing.
But your perspective is helpful. Can you commit that the
current rules will not be weakened moving forward so that
appropriate guardrails remain with respect to conflicts of
interest?
Dr. Cavazzoni. The guardrails have been in existence and
upheld throughout, and we will continue to maintain our high
standards and the independence in decision making.
Mrs. Dingell. Thank you, Madam Chair. I yield back.
Ms. Eshoo. The gentlewoman yields back.
The gentleman from Georgia, Mr. Carter, is recognized.
Mr. Carter. Thank you, Madam Chair.
And thank all of you for being here today.
Advance manufacturing, which is defined as including both
new manufacturing methods and production of new products
enabled by innovation, extremely important. It has the
potential to dramatically increase efficiency, flexibility, and
the quality of production of medicines in this country, and
that is extremely important.
It is important for us to be competitive. I have got
legislation, Made in America, that we are trying to repatriate
companies back to America.
But the innovation is extremely important, extremely
important to the future. This type of innovation would allow
U.S. manufacturers to be more competitive. It would allow them
to increase the resilience of our supply chain, which we know
is extremely important, particularly after we have been through
this pandemic. And it would, as a result of all of that, ensure
our national security.
So to encourage the development of this new technology, as
I have said, I have got legislation that would create, you
know, a pathway at FDA to assess these manufacturing processes,
a policy that is supported by the National Academies of
Medicine.
Dr. Marks, I will start with you. Do you agree that the
review pathway that is independent of individual drug
applications can help bring new manufacturing technology to
market?
Dr. Marks. So without knowing all of the specifics, all I
can say that I certainly incredibly support advanced
manufacturing technologies, and to the extent that a pathway
that helps foster them forward and helps bring our
manufacturers here in the United States into the use of these
technologies for both drugs and biologics is certainly
something we would support, moving products into use of
advanced manufacturing technologies.
Again, I am sorry I do not know the details to speak to the
exact nature of the review.
Mr. Carter. But you would support that type of legislation?
Dr. Marks. What I can say is I am not in a position to
support----
Mr. Carter. I know you have not seen the legislation.
Dr. Marks [continue]. That we support advanced
manufacturing.
Mr. Carter. OK. Fair enough. Well, it is included in my
bill. You need to get familiar with my legislation because it
is good, and it includes advanced manufacturing.
Dr. Cavazzoni, what about you? Are you familiar with that
as well?
Dr. Cavazzoni. Well, we are very supportive of advancing
technology, and the advanced technologies and expediting the
review of these technologies really needs to go hand in hand
with the review of a specific drug and not dissociated from the
review of the drug because evaluation of the [audio
malfunction] technology is really very much tied to the
manufacturing of a specific drug.
And as Dr. Marks has stated, we are really looking forward
to build on the gains that we have made in advanced
manufacturing, for instance, within CDER. We have approved
over, I think, approximately 11 submissions that use the
continuous manufacturing, and we see this as an area that we
will remain a great focus of ours.
Mr. Carter. OK. Fair enough. Real quick because I have just
a little bit of time left, drug shortages. You know, this is
something that we are dealing with, something that we dealt
with even pre-pandemic, and it is certainly important.
But APIs, APIs, active pharmaceutical ingredients are
extremely important. To what degree does the FDA Office of Drug
Shortages and the agency's Inspection and Compliance staff
coordinate internally?
Do they work together?
And do they work with manufacturers to make sure that a
drug that potentially could be in shortage, to make sure that
we can avoid that?
Dr. Cavazzoni. There is extensive coordination within FDA
across multiple groups, and there is also communication and
coordination with [audio malfunction] centers, and we have
really charged those observations of the supply chain during
the pandemic.
But what is very important to be effective in mitigating
issues is to have as much up-to-date information as possible
for manufacturers as to where these APIs or the finished
products are manufactured and how much each facility makes in
real time or near real time.
Mr. Carter. I am out of time, but please make sure we are
working with the drug manufacturers when we see these potential
drug shortages coming up as well.
Thank you, and I yield back.
Ms. Eshoo. The gentleman yields back, and I appreciate the
questions that he has asked.
In the COMPETES Act that you are going to have the
opportunity to vote on, I do have language in it that deals
with the FDA being able to secure information from
manufacturers as to where their drugs are manufactured, if they
are outside the country, those that use the API from abroad.
All of that information will be approved to the FDA, which
I think is an important step. It does not cure the overall
issue, but it is important information that the FDA can gather.
The Chair nowrecognizes the gentlewoman from California,
Ms. Barragan, for her 5 minutes of question.
Ms. Barragan. Thank you, Chairman Eshoo, for holding this
hearing.
Thank you to our panelists.
It sounds a little controversial, but as somebody whose
mother is 81 with Alzheimer's, I just want to say I was
disturbed by the outcome of the drug only being covered for
those in clinical trials, and I will continue to follow this
issue and want to make sure there is equity for access to this
drug.
And when you have somebody who has Alzheimer's, you want to
be able to have anything available that could possibly help,
and so I just wanted to put that out there myself.
My question, my first question is for Dr. Cavazzoni.
Thank you, Doctor, and Dr. Marks for being with us today.
Your work on these agreements is critical.
In 2020, generic and biosimilar drugs saved the U.S.
healthcare system over $300 billion in drug spending, and
timely approval of the FDA's user fee agreements will ensure
patients continue to benefit from lower prescription drug
costs.
However, under current law, generics can be blocked from
entering the market if safety information on a brand drug's
label is protected under exclusivity, but no other hurdles
remain.
My bill, the Prompt Approval of Safe Generic Drugs Act,
would create a path forward for generic competition in these
instances.
Safety information should be a feature of drug labels, not
an obstacle to competition. Fortunately, FDA recognizes this
problem and the CBO estimates that my bill will save families
nearly $165 million.
Doctor, this is one specific regulatory hurdle that impedes
the generic drug review process. Could you discuss how similar
regulatory hurdles like this can stifle competition and prevent
lower drug prices for consumers?
Dr. Cavazzoni. Thank you, Congresswoman.
Under the current authorities, we are really constantly
looking for ways in which we can facilitate the development of
more generics and, therefore, increase competition and lead to
lower prices.
We would also be very interested in working with Congress
on additional measures that could make us even more efficient,
and to that effect, the department has published a drug pricing
plan that includes some recommendations for Congress in areas
where there could be some legislative changes that would allow
us, for instance, to include more information on the branded
drug in the label, including inactive ingredients and
excipients rather than having the generic manufacturers having
to guess what those are because we are barred from telling
them.
Another really important potential opportunity are some
statutory changes to facilitate the development of hard to make
combination products, drug-device combination products, and
those are also quite expensive products where we see every
opportunity in advancing more generic drugs and creating more
competition.
Ms. Barragan. Thank you.
Dr. Cavazzoni, I am interested in how the agency relies on
the use of real-world evidence when making regulatory
decisions. It is important that the FDA's regulatory decisions
adapt and change as signs change as well.
My understanding is that the prescription drug user fee
agreement includes new proposals to review how real-world
evidence can be used.
Can you describe the new advancing real world evidence
program and what the FDA intends to gain from this kind of
program?
Dr. Cavazzoni. Thank you for that question.
Our ability to utilize the real-world evidence is very much
dependent on the quality and the characteristic of the real-
world data put against the questions that we are trying to ask,
and so we have become very efficient in using real world
evidence, for instance, for safety surveillance.
And during the current cycle we have also had a number of
demonstration projects to use those data for effectiveness, and
so in PDUFA VII we are really looking at additional initiatives
to continue to expand the use of real-world evidence for
safety, but also, for instance, to support our decision when it
comes to new indications for approved products as well as, for
instance, used in the Sentinel System to make the pregnancy
registries more efficient and easier to conduct for
manufacturers.
Ms. Barragan. Well, thank you for that, and I am over my
time. So we probably want to hear about the limitations as
well.
Thank you, Madam Chairwoman, and I yield back.
Ms. Eshoo. The gentlewoman yields back.
It is a pleasure to recognize the gentleman from Utah.
Mr. Curtis. Thank you.
Ms. Eshoo. Mr. Curtis, thank you for your patience. You
have been here from the very beginning of the hearing, and you
have 5 minutes for your questions.
Mr. Curtis. Thank you, Madam Chair and Mr. Ranking Member.
I am here because this is important.
I am actually one of the few members serving on this
committee that has not been through this process before and
does not have a healthcare background.
And I am very well aware how important this is, and I have
spent a considerable amount of time in the last few weeks with
my staff digging in and trying to understand this.
But I also bring a perspective that is different because I
have not been here before. I am far away enough from the forest
to see the trees. I come from a background of business problem
solving and government problem solving.
It is my understanding that this process, as I study this,
is about time, access, safe access to medications for patients.
I am very well aware of the balance between time and safety and
transparent review, and I think Utahans and all Americans
deserve a timely and a safe process.
I am very well aware of a number of Utahans who are in
difficult positions. One that comes to mind is the mother of a
five-year-old whose son is suffering from classic Galactosemia,
and this comes with speech delays. He is five years old. It
comes with speech delays, learning delays, difficulty with fine
motor skills and muscle weakness.
This mother is also aware that there is a drug, AT007, in
the process. Every day that drug is not approved is one more
day that this child falls further and further behind his peers
at a time at five years old when learning is so critical.
And with that in mind, I would like to ask my first
question, and I will ask this to both of you.
I have heard a lot of stories like this five-year-old and
his mother about Americans who are desperate for access to
innovative therapeutics, and then we hear today comments like,
``Well, we will get back to holding in-person meetings when
things get back to normal.''
And you can imagine the frustrations of those waiting for
these cures hearing something like that. There is a strong
sense that government is not doing everything it can to work on
the time aspect of this.
So the both of you I ask: irrespective of this agreement
number VII that is before us, what are we doing to accelerate?
Why do we need an agreement just to accelerate?
Are we doing our best? And are we more focused on the
agreement or on the actual lives that this is impacting?
Dr. Cavazzoni. I am happy to start, Congressman.
These agreements are really in the end their own issues,
and bringing new therapies to patients in areas of unmet
medical needs.
And Galactosemia is a really good example of a disease
where there are tremendous unmet medical needs.
We can all comment on specific programs because the
information is confidential. However, I can tell you that we
really work extensively with manufacturers and sponsors to
guide them and to accelerate the development and review of
these therapies.
And to your point about meetings, in fact, given the
incredible increase in workload during the pandemic, our
ability to have more nimble meetings, such as teleconferences
or video conferences, has allowed us to have more meetings, and
this is something that we want to be able to leverage if needed
going forward.
So the lack of in-person meetings has in no way slowed us
down. If anything, it has allowed us to be more efficient in
the face of all this work.
And despite all of this increased volume of work, we have--
--
Mr. Curtis. I am going to jump in just because we are so
limited on time, and I appreciate your answer.
I think my hope is that with the importance of these
agreements we still do not forget the faces and the people
behind them that we are trying to serve.
Now, in reference to the agreements, I understand that a
lot of our goals related to the FDA review process and
timeliness, but also include initiatives that are part of the
Center for Drug Evaluation Research.
I believe American innovation is extremely important in
what we do. I would like to ask what initiatives are the FDA
intending to prioritize and how will you properly implement
these initiatives?
Dr. Cavazzoni. We could not agree more continuing to
serving the baseline. When we look at a commitment letter,our
intention is to meet all of the new goals and commitments and
as we have done in the past, and we are obviously going to need
some additional resources to do so which is also [audio
malfunction] in your proposal.
Mr. Curtis. I am out of time. Madam Chair, I yield the
balance of my time.
Ms. Eshoo. The gentleman yields back.
Let me just state the following so that members that are
meeting with us virtually as well as those who are in the
hearing room know. We are going to continue on until about 25
after one. I know members on both sides of the aisle want to
attend the classified briefing.
So hopefully we be able to have the second panel give their
testimony, and then we will break for the classified hearing,
and then resume at what, hopefully 2:30.
And then there is an expectation of a series of votes
beginning at either 4:00 or 4:30, but we want to conclude our
work.
So be advised, all of the members.
The Chair is now pleased to recognize the gentlewoman from
Illinois, Ms. Kelly, for her 5 minutes .
Ms. Kelly. Thank you, Madam Chair and Ranking Member
Guthrie, for holding this hearing on the FDA user fee
authorizations.
According to the National Institutes of Health, clinical
trials for cancer treatment funded in fiscal year 2018 had a
median participation of 80 percent White participants, only
five percent Black, and three percent Hispanic participants.
This is one of the many examples underscoring the need for
clinical trials to reflect the disproportionate impact these
conditions have on communities of color.
Given the very low rates of racially and ethnically diverse
participants in clinical trials, I was disappointed to see that
the Prescription Drug User Fee Agreement VII commitment letter
refers to clinical trial diversity only once.
However, I applaud the agency's work in trying to use
digital health tools to improve clinical trial diversity.
Dr. Cavazzoni, how will FDA and industry address some of
the barriers to accessing digital health tools, such as the
lack of digital literacy or lack of English proficiency?
Dr. Cavazzoni. Thank you, Congresswoman.
We could not agree more as to the importance of increasing
diversity in clinical trials. As you mentioned, the commitment
letter includes some enhancements around digital health
technology, and we are doing a lot more beyond that.
We have issued guidance on how to enhance clinical trial
diversity. We are going to continue to track also progress very
closely by issuing periodic reports showing the data on the
clinical trial enrollment and diversity in clinical trials in
the various therapeutic areas.
And we want to continue to work with the sponsors to
encourage them to the full extent of our current authorities to
have diversity in clinical trials.
Understanding that the results were balanced, so we struck
depending on therapeutic areas or the type of clinical trials,
and so we need to also be aware of that and making sure that we
make the clinical trials more diverse while also finding ways
to continue to conduct them in a timely manner.
One of the important elements will be to also have more
access to healthcare for underserved community, which tends to
track also with access to investigative sites and outposts of
clinical trials so that we can enroll diverse populations.
Ms. Kelly. Also on December 2018, FDA released their
framework for FDA's Real World Evidence Program and stated a
commitment to using real world evidence to bolster data in
clinical trials, specifically in populations that were not
studied prior to drug approval.
And I am glad to see FDA's continued commitment to real
world evidence reflected in the user fee agreement.
So I also wanted to ask you what steps is FDA taking to
leverage real world evidence in determining how a drug works in
populations that were not studied prior to approval, such as
racially and ethnically diverse communities.
Dr. Cavazzoni. Thank you for the question.
This is a big part of our program, and we are looking
forward to expanding it in PDUFA VII. Real world evidence can
be used to understand the natural history of disease, to
understand the characteristics of specific populations,
including ethnic and racial minorities.
And it can also be used as an incremental or additional
evidence when it comes to complement clinical trial information
that would arise from clinical trials.
And to that effect the commitment letter includes a number
of enhancements that would allow us to better understand the
quality of real-world data and to hopefully put it to work to
answer more questions, including questions about effectiveness
of drugs.
Ms. Kelly. Thank you so much.
Thank you, Madam Chair, and I yield back.
Ms. Eshoo. The gentlewoman yields back.
It is a pleasure to recognize the gentleman from
Pennsylvania, Dr. Joyce, for your 5 minutes of questions.
Mr. Joyce. Thank you for yielding, Madam Chair Eshoo.
Briefly to touch on the iPLEDGE REMS matter again, on
December 23rd, 2021, the FDA stated that it is ready to
exercise regulatory flexibility on a temporary basis with
regard to certain requirements of the iPLEDGE REMS provided
that Isotretinoin Project Manufacturers Group proposes a
workable solution that ensures the necessary safe use
conditions.
Right now because regulatory flexibility has not been
exercised, many patients have not been able to receive their
Isotretinoin. It is estimated to be in the thousands.
This is a life changing medication. I know that because I
prescribed it for 25 years.
Dr. Cavazzoni or Dr. Marks, would you please describe first
what this regulatory flexibility will look like and, more
important, why has the FDA not exercised this regulatory
flexibility over the past six weeks?
Dr. Cavazzoni. Thank you for that question. I am happy to
address it since the Accutane is regulated by us.
So manufacturers are responsible for the implementation of
grants, and in this situation, the manufacturers had to make a
transition to new platforms to deliver the REMS, which caused
significant challenges for prescribers, pharmacies, and
patients.
And we have been working with those groups since before the
[audio malfunction] and since the transition, and we really
empathize with this [audio malfunction].
We have had conversations with the manufacturers and the
various stakeholder groups, and, yes, we have indicated
openness to make some adjustments, temporary adjustments, to
the REMS to facilitate the transition.
Ultimately, it is up to manufacturers to determine whether
they are willing to make those changes or whether those
adjustments are realistic to make without taking even more time
to solve the problems in the platform.
So we know that this has been a really long road for
prescribers, pharmacists, and patients. The good news is that
we seem to be turning the corner, and if we look at the number
of prescriptions that are currently issued, we are seeing a
return to the historical baseline level of prescriptions before
this transition that took place in December.
Mr. Joyce. Do you feel that the necessary regulatory
flexibility is in place?
Dr. Cavazzoni. As I said, we indicated our willingness to
exercise some flexibility. Ultimately it is up to the sponsors
to take our recommendations or suggestions into consideration
and determine whether it is practically or operationally
feasible to make those temporary adjustments where we would be
able to----
Mr. Joyce. My time is limited. Has the FDA offered those
recommendations?
Dr. Cavazzoni. We have discussed those recommendations and,
as I said, it is up to the sponsor to determine whether they
can be implemented.
Mr. Joyce. Thank you.
I know patients are suffering without access to complete
the 20-week course of Accutane. This ability, as I mentioned,
is lifechanging as far as a medical therapy.
In the brief time that I have remaining, according to FDA
reports from November of 2021 on inspection oversight, there
are 60 applications that are delayed right now due to the
inability to conduct inspections or facility assessments as of
September 30th.
How long will it take to address this backlog, please?
Dr. Cavazzoni. Thank you, Congressman.
While we have authority to use alternative approaches to
inspections to the fullest extent, and while we have intention
to conduct mission critical inspections, there are some
instances where we need to be able to [audio malfunction] with
boots on the ground.
And what has [audio malfunction] us right now are still
some travel challenges, quarantines, and so we will resume
inspections, those inspections, as soon as the overall
conditions will allow us to do so.
Mr. Joyce. With the widespread availability of vaccine,
when do you expect that return to normal operations for
inspections to occur?
Thank you. My time has expired, and I yield.
Ms. Eshoo. I think that that question----
Mr. Joyce. We will submit the question. Thank you.
Ms. Eshoo [continue]. Will be submitted for a written
response. Certainly.
The Chair is pleased to recognize the gentlewoman from New
Hampshire, Ms. Kuster, for her 5 minutes of questions, followed
by, I think, Dr. Schrier unless there are others from the
Republican side, followed by Mrs. Trahan.
Ms. Kuster. Thank you very much, Madam Chair.
Ms. Eshoo. Ms. Kuster of New Hampshire, yes.
Ms. Kuster. Thank you.
And I apologize for losing my turn. We were evacuated from
the Cannon Building.
I want to thank the witnesses from the FDA for being with
us, and I am going to jump right in in the interest of time.
On September 9th last year, the administration released a
report titled ``Comprehensive plan for addressing high drug
prices.'' This report included several administration proposals
on drug pricing, but the issue I want to discuss was related to
accelerating the development and approval of lower cost drugs.
In this report, the administration said Congress should
clarify that it is not an improper disclosure by the FDA to
provide a potential generic drug sponsor with the names and
amounts of inactive ingredients used in the formulation of a
reference listed drug when a generic drug is required to have
the same formulation to obtain approval.
It is my understanding that the limited guidance FDA
currently provides to generic drug applicants and their
proposed drug formulation can significantly delay the approval
of complex lower cost drugs.
As this committee considers opportunities to address
barriers to patient access to affordable therapies, this seems
like a policy worth considering in the user fee package.
Dr. Cavazzoni, does the FDA still consider the type of
feedback they provide to generic applicants a barrier to
generic drug development and patient access to lower cost
medicine?
Dr. Cavazzoni. Thank you, Congresswoman.
The current constraints that we have in our ability to
share information with the generic manufacturers when it comes
to inactive ingredients and excipients is one of the areas that
makes the development of complex generics less efficient than
it should be.
And to that effect, the administration has issued these
suggestions or recommendation to Congress, and we think that
the inclusion of excipient and inactive ingredient information
in the brand label would go a long way in facilitating the
development of complex generics.
Ms. Kuster. Thank you. You anticipated my question, what
legislative policies are that we should consider. So we will
take your response under advisement as we are drafting the
legislation.
I want to go forward now, switching gears, to look for Dr.
Marks, how the FDA is committing to keeping patient
perspectives in mind. I reviewed the FDA's PDUFA VII commitment
letter, and I was pleased to see a public meeting on patient-
focused drug development.
Dr. Marks, when the FDA reviews cell and gene therapies,
for example, for diseases like Type 1 diabetes, how does the
FDA currently evaluate patient perspective data?
And I will just jump right in with the second half. Can you
commit to me that the FDA will make sure the patient
perspectives are a focus area as the agency enhances the cell
and gene therapy program in PDUFA VII?
Dr. Marks. Thanks so much for that question.
Indeed, we are very much involved in trying to get patient
perspective. There are multiple guidances to help develop
patient perspectives, and we are very interested in making sure
that we have an appropriate number of meetings with a variety
of different patient groups on a variety of different topics.
Some of them are larger, more formal. Some of them are
smaller and less formal. They provide invaluable information
about what patients really need from the products that are
being developed in terms of how they feel, function, or
survive.
I can at least commit to the fact that we will certainly
continue to incorporate this, as we move forward and work with
sponsors and consider these approvals ourselves.
Ms. Kuster. Thank you.
And just to wrap up, my focus in this committee is both on
lower cost and access to prescription medication and devices
for patients and the patient perspective. I think those are the
two goals that I think many of my colleagues share.
I will just say my husband picked up my monthly asthma
medication and came home and it was $182, and people are really
struggling, and you are doing an amazing job to bring such
amazing treatments and therapies, but we have got to do our
best to lower the cost and meet the patient's needs.
So thank you, and I yield back, Madam Chair.
Ms. Eshoo. Amen, and the gentlewoman yields back.
The Chair is pleased to recognize the gentlewoman from
Washington, the State of Washington, Dr. Schrier.
Ms. Schrier. Thank you, Madam Chair.
Thank you, Dr. Marks and Dr. Cavazzoni, for taking the time
to be here today, and thank you for your continued hard work to
keep Americans safe and educated during this crisis. So thank
you for your service.
Also, thank you to my colleagues for really interesting
questions to listen to.
As a physician myself and a person with Type 1 diabetes, I
am sure you can imagine how close to home insulin and insulin
pricing and the development of biosimilar insulins really hits
for me.
And I was really honored to work with Representative
DeGette and other members of the Diabetes Caucus in the 116th
Congress to clarify and expedite a biosimilar approval pathway.
And I was really pleased to see the approval of the first
interchangeable biosimilar insulin just last summer. So I am
eager to hear today about some of the regulatory science
enhancements that will be in PDUFA.
And first, Dr. Cavazzoni, just a little timeline here. As
you know, the Biologics Price Competition and Innovation Act
was enacted as part of the Affordable Care Act in 2010, and
yet, as mentioned, the first biosimilar insulin was just
approved this summer. There is an 11-year gap.
And now there are plans in this next authorization to have
a demonstration project to advance interchangeables starting in
fiscal year 2023.
And I am just wondering what you see as a time frame. Why
did it take ten years and what should be expect with these new
projects?
Dr. Cavazzoni. Thank you for the question.
And we agree that the approval of the first interchangeable
insulin was a landmark approval for the program.
The program is relatively new and has had to, you know, get
on its feet in the first cycle, as all programs.
If we look at the achievements for this current program,
they have been truly remarkable. We have gone from five to 33
biosimilars that are approved, and we are talking in the BsUFA
III proposal to have enhancements to facilitate additional
indications for these approved biosimilars.
We also have a very rich pipeline of biosimilars in
development, and so we think that this momentum is going to
continue and that we are going to see faster results.
In particular, thanks to this new pilot program that will
allow us to do applied regulatory research to solve those
problems that have sort of made it more difficult to develop
biosimilars, but even more importantly, to develop
interchangeable biosimilars.
Ms. Schrier. Thank you.
And thank you for pointing out that there have been so
many. As I look at the list and I hear you talk about these 33,
I do not know if the general public knows that some of the most
expensive medications like Humira is on that list as now having
a biosimilar, and that is, you know, theoretically lifechanging
for a lot of people out there.
Kind of on that theme, the generic insulin that I referred
to before is still pretty darn expensive, and when I think of
biosimilars, I think of biosimilars kind of like generics, and
in some cases those generics have met a significant price drop
for the consumer, but that is not always the case.
And so, you know, this generic insulin or biosimilar
insulin is still pretty expensive. I do not know how the
biosimilar Humira is and Neulasta, comparing with price.
I was wondering if you could comment on that. You know, for
the everyday American who is looking forward to having these,
what can they expect in terms of cost and availability?
Dr. Cavazzoni. Congresswoman, it is a top priority to make
lower cost drugs accessible to all Americans, and while FDA
does not have a role in setting prices or negotiating prices,
we do have a role in increasing competition.
And the way in which we can increase competition which has
the potential and as shown with generics to lower prices is to
approve more biosimilars and approve more interchangeable
biosimilars.
And so we think that this program, which we have, thanks to
Congress, has and really shows the wisdom of Congress
establishing this program, will really yield increasing results
for the American public in lowering prices.
Ms. Schrier. Well, thank you very much.
And I yield back.
Ms. Eshoo. The gentlewoman yields back.
The Chair is pleased to recognize the gentlewoman from
Minnesota, Ms. Craig, for her 5 minutes of questions.
Ms. Craig. Well, thank you so much, Chairwoman Eshoo, and
thank you for holding this incredibly important hearing today
for us.
As a member of Congress, one of my top priorities is
expanding my constituents' access to lifesaving prevention,
treatments, and cures at affordable cost.
One of the issues I hear most often from my constituents is
the ever-rising cost of prescription drugs. Policies like
PDUFA, the generic drug user fee agreement, play a critical
role in ensuring that lower cost generic alternatives can reach
more patients more quickly.
Since 2012, GDUFA has provided FDA with the resources it
needs to shorten approval times and clear the backlog of
generic drug applications. GDUFA III builds on ongoing efforts
to increase product-specific guidance and communication between
FDA and industry for the specific benefit of patients.
My questions today focus primarily on complex generics
which have faced unique barriers and carry significant
potential to improve patients' lives.
Dr. Cavazzoni, we know that complex generics like
epinephrine auto injectors or inhalers are more difficult for
manufacturers to develop. They are also more challenging for
FDA to evaluate.
In your experience, why is it so difficult to get complex
generics developed and approved?
Dr. Cavazzoni. Well, there is an inherent, you know,
greater degree of difficulties in these generics because of the
type of formulation or because, to your point, they may include
a device and a drug combination and route of administration,
and so on.
And so it is more complicated to find ways to establish
that those complex generics are bioequivalent to the brand,
which is the standard that we need to use.
And there is also in many instances need to actually study
new methods to determine that bioequivalence. And so one of the
very important elements of GDUFA currently is a very successful
research program that has really focused on how we can find new
analytical methods to establish bioequivalence and spur the
development of complex generics.
I echo also your point about the importance of product-
specific guidances, and the GDUFA proposal includes new
performance goals to issue product-specific guidance for these
complex generic products so that we give clarity to developers
on how to develop them.
Ms. Craig. You actually touched on my second question there
in your answer here. When you talk about product-specific
guidance, can you give us an example or examples of how that
will help developers and enable them to get those products to
patients much more quickly?
Dr. Cavazzoni. Yes. An example, these product-specific
guidances are a bit like a ``how to'' guide and guide
manufacturers on how to establish the parameters that would
allow us to determine that the drug is the same as the brand
drug.
They also clarify our expectations when it comes to those
parameters and the methods to which we would expect them to
conduct those analyses.
And so they are really somewhat of a recipe book, and it is
much easier to have a recipe book than having to do trial and
error when it comes to making anything, including drugs.
Ms. Craig. Well, thank you so much, Dr. Cavazzoni.
I really do look forward to my colleagues and I coming
together in hopefully a bipartisan fashion to support an
expedient and fair user fee reauthorization process.
I know that FDA's ability to make sure that patients can
gain access to safe and effective products absolutely depends
on it.
So thank you so much.
And, Madam Chair, I yield my time.
Ms. Eshoo. The gentlewoman yields back.
The Chair is pleased to recognize the gentleman from
California, Dr. Ruiz, for his 5 minutes of questions.
Mr. Ruiz. Thank you, and thank you all for being here to
testify today.
As we all know, there is a severe lack of appropriate
diversity in clinical trials, which leads to under-sampling of
large populations and incomplete data. That means that we might
not know how effective a drug is on certain patient
populations, and patients that are underrepresented in clinical
trials may be taking medications that are not effective for
them, potentially leading to worse health outcomes.
As a doctor who both grew up and served in a community that
is very extremely underserved, I know firsthand the many
barriers that exist for individuals who may want to participate
in a clinical trial. Those barriers include traveling long
distances, the lack of transportation, inflexibility of work
schedules, and inflexible work schedules and limited financial
resources needed to participate, just to name a few.
So it occurs that the prescription drug user fee agreement
commitment letter includes expanding the use of decentralized
clinical trials, which is an important step to addressing some
of those barriers.
Ultimately, this will help increase trial participation by
allowing patients to get some of their care virtually.
Dr. Cavazzoni, is there a plan on how the FDA will expand
the use of decentralized clinical trials?
And if so, can you share that plan?
Dr. Cavazzoni. Thank you, Congressman.
It is very much our intention to continue to promote and
expand the use of decentralized trials. We have really learned
a lot about decentralized trials during the pandemic. We have
actually issued guidance clarifying for manufacturers that they
should really try to adopt those approaches to the fullest
extent possible.
And we are going to take what we have learned during the
pandemic and use it to develop guidance, go-forward guidance,
not tied to the public health emergency, to continue to make
those trials easier to conduct, when appropriate.
Mr. Ruiz. Thank you.
While decentralized trials can broaden access, we also know
that not everyone may have the necessary equipment for such
visits. So I introduced the DIVERSE Trials Act, which creates
safe harbors for sponsors to supply patients and trials with
tech-like tablets that they would need to do remote care, for
example.
We also know that the reality for many clinical trials like
cancer treatment is that a patient will still have to
physically come into the office for procedures like surgery or
chemo infusion.
So that puts us back into the access issue for folks who
live further from academic centers or have limited means or
flexibility.
So the DIVERSE Trials Act will ensure that clinical trial
sponsors can provide financial assistance to patients to cover
nonmedical costs like travel or lodging related to a trial
visit.
So while I realize that these provisions are outside of the
FDA's jurisdiction, I do want to raise the issue that there are
additional barriers to address to create greater access and
diversity and participation.
So given that, Dr. Cavazzoni, in addition to decentralized
clinical trials, what additional concrete steps can the FDA
take to help further the use of alternatives to standard
clinical trials and effectively get lifesaving drugs into the
hands of patients more quickly, safely, and equitably?
Dr. Cavazzoni. We have a number of tools at our disposal.
First, we strive to work with manufacturers and sponsors to
make sure that clinical trials do not have sort of a whole
bunch of added things that are not really essential and just
make everyone's life more complicated, including the patient's,
because they usually entail more visits, and so on. So trying
to make trials efficient is very important.
The use of digital health technologies is really important,
and access to those technologies, to your point, is very
important because they can really make taking a consent from a
patient much easier and save a visit and just do it like we are
doing it today, individual conference.
What we also want to promote as far as decentralized
clinical trials is the trial going to the patient. So the
nurse, for instance, going to the patient to administer the
drug or to take a measure, and so on, recognizing that in order
to have more diversity in clinical trials we need to make it
easier for patients to be able to participate.
And not all patients have the luxury of being able to trek
across town three times a week to be able to participate in a
clinical trial.
Mr. Ruiz. Thank you very much.
I yield back my time.
Ms. Eshoo. The gentleman yields back.
The Chair recognizes the gentlewoman from Massachusetts,
Mrs. Trahan, for your 5 minutes of questions.
Mrs. Trahan. Thank you, Madam Chair.
And thank you to the witnesses here today to discuss FDA
user fees with our subcommittee.
FDA's mission is to protect and promote the public health
in the country, and FDA user fees are essential to these
efforts.
In FDA's testimony, the agency says that over the past two
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 meet critical public health needs.
Through COVID-19, FDA has been critical in the approval of
vaccines and therapeutics to see our Nation through this
crisis. The infrastructure and capacity to review applications
so rapidly is due in large part to the funding from these user
fees.
So, Dr. Marks, how does PDUFA VII reflect the lessons
learned through the COVID-19 pandemic?
And if you could, also touch on any pandemic preparedness
measures in PDUFA VII.
Dr. Marks. Thanks. Thanks very much.
I think one of the key pieces that is essentially put in
place here are some of the enhancements to meetings. Again, I
know it sounds very boring, but that early input that sponsors
can get, the interact meetings provisions that are now put into
the commitment letter will help sponsors get early, relatively
informal regulatory advice that will hopefully set them on the
right track towards the development of their product.
If they do not make mistakes and waste time and money early
on in development, they are able to move forward more quickly.
It also sets them up and establishes them with a
relationship with the agency early on in their development
program to interact with our reviewers.
So I think that is just one example. There is also the Type
C meeting, which is a very specific type of meeting around one
or two issues that will hopefully allow people to get
resolution more quickly in this.
So those, I think, will be very helpful moving forward as
we go ahead. I think those also will help us, for that matter,
in terms of pandemic preparedness because we have had any
number of very innovative products come in early on looking to
try to address potential hazards in the future.
Mrs. Trahan. Great. I appreciate that. It is not boring to
us. So thank you for that.
So prescription drug user fees were first passed due to
lessons learned from the HIV/AIDS epidemic. As the agency and
this subcommittee are fully aware, another epidemic the Nation
continues to grapple with is the ongoing opioid and overdose
crisis.
From April 2020 to April 2021, we lost over 100,000
Americans to an overdose, and that is just a staggering number.
Dr. Marks, I am wondering how does PDUFA VII reflect these
unprecedented deaths in this ongoing crisis, and will PDUFA VII
allow for expedited review of OUD treatments and opioid
antagonist medications that are in the pipeline?
Dr. Marks. So I really appreciate the question, which I am
going to turn over to Dr. Cavazzoni because her center handles
that.
We have a few very creative and innovative treatments, such
as vaccines, for opioid addiction that are in the pipelines,
but I will turn it over to her.
Dr. Cavazzoni. Yes, thank you, Congresswoman, and we
recognize the tragedies of the opioid epidemic, and within our
center we are looking at all the aspects of our authorities
right now to see whether we can do more and where we can sort
of double down.
When it comes to development of treatments for opioid use
disorder or medication assistant treatments, the answer is,
yes, absolutely. All of the expedited pathways that we
currently have in PDUFA and all of the enhancements that we are
or many of the enhancements that we have in PDUFA VII will
apply also to accelerating the development of opioid use
disorder treatment.
And I would add to that also hopefully the development of
nonaddictive pain medications that may be able to replace or
decrease the use of opioids for pain conditions.
Mrs. Trahan. Great. I appreciate your thorough answers.
I have one more question, but given the time, I am going to
submit it for the record, and thanks again for being here and
lending your expertise at this important hearing.
Thank you.
Ms. Eshoo. The lovely gentlewoman has completed.
We have Representative Schakowsky, a member of the full
committee but not ours, and so she is waiving on. I recognize
her for 5 minutes .
And I should say that on the heels of Ms. Schakowsky
questioning, we will recess so that the next panel of witnesses
can get some lunch and the members of our committee are able to
attend the classified briefing, which is important to all of
us, and we will resume at 2:30.
So, Ms. Schakowsky, you are recognized for 5 minutes .
Ms. Schakowsky. Well, thank you once again, Madam Chair,
for allowing me to waive onto this important committee.
You know, I am happy to meet with the Food and Drug
Administration, which really does have a mission to make sure
that the drugs, including biologics, are safe and effective.
But I am very, very concerned that recently we have seen a
wavering of that commitment to do that, and I am talking about
what happened recently with the Biogen's Alzheimer's drug,
Aduhelm, and I just feel like this has been very scandalous.
This is a drug that at first, initially, you said that
would not be approved at all and now it has been on accelerated
approval. And this drug was only tested on people with mild
Alzheimer's and dementia, but yet the FDA approved the first
label to be for all Alzheimer's patients, holding on the hope
that this was good for all of them.
And, you know, there have been reports from the limited
trial that was done of severe harms, including brain bleeding
and other serious harm, and actually there were people, I
understand, that even died, and it excluded in that limited
trial that was done before the accelerated approval; it
eliminated people who had other diseases.
I am sorry. If you have Alzheimer's disease, many people of
that age have many other complicating diseases. But those
people were excluded.
And all [audio malfunction] independent advisory group.
These are the experts that you had in the field who said that
this should have been approved. Ten of them actually said, no,
this drug should not be approved. One of them did not vote or,
you know, abstained.
And it is just outrageous. Three of those advisors actually
resigned from the committee.
So Dr.--I am sorry--Dr. Cavazzoni, and, Dr. Marks, if you
want to respond at all, how did this happen?
You know, this is also a drug that they said the price was
going to be $56,000 per person per year. I know that that price
is unlimited, and I know that CMS is looking at other ways, but
I want to really understand how such a thing has happened.
Dr. Cavazzoni. Thank you, Congresswoman.
There are a lot of aspects to your question, and I will try
to address as much as I can in the very limited time we have,
and we will be happy to follow up with your staff to address
the rest.
What I can say is that the data for this application was
very complex. We brought it to the Advisory Committee. We heard
very loud and clear from the Advisory Committee that they
believed that the data did not support a traditional approval.
We took that to heart. We went back and did more analysis
of the data and----
Ms. Schakowsky. Excuse me. You say you took it to heart.
All of the members, none of them said that they supported it.
Ten said no. Three resigned as a result. One said this was the
worst thing he had ever seen. So do not tell me that you took
it to heart.
I do not understand what you are saying.
Dr. Cavazzoni. Well, in fact, we did because we agreed with
the Advisory Committee that the data did not support
traditional approval.
We did conclude after looking at the data even more
extensively that it supported using accelerated approval based
on a surrogate biomarker, an amyloid decrease reasonably
predicting the clinical benefit of the drug.
So in fact, we did----
Ms. Schakowsky. Who approved----
Dr. Cavazzoni [continue]. Agree with the Advisory Committee
on----
Ms. Schakowsky. My time has expired, but you know, I simply
want to say to you that I think this----
Ms. Eshoo. The gentlewoman's time has expired. The
gentlewoman's time has expired, and I believe you can----
Ms. Schakowsky. Let me just say----
Ms. Eshoo. [continue]. And I believe that you can----
Ms. Schakowsky [continue]. Look in this committee----
Ms. Eshoo. You can submit----
Ms. Schakowsky [continue]. Accelerated approval. You need
to look at accelerated approval and how that works.
Thank you.
Ms. Eshoo. All right. Well, the gentlewoman's time has
expired.
The Chair is now going to call a recess.
We want to thank both of our witnesses, Dr. Marks and Dr.
Cavazzoni. It has been a long hearing for you, but we want to
thank you for your testimony, for answering the questions, and
for the questions that will be submitted to you in writing.
So on behalf of all of the committee, we thank you. We
thank you.
To the second panel, we will resume at 2:30.
So we are now in recess.
[Recess.]
Ms. Eshoo. The Subcommittee on Health will now come back to
order.
I want to welcome our witnesses that are part of this
second panel, each one distinguished in their own way.
Dr. Lucy--now, let me see if I can get your name right and
pronounce it correctly--Vereshchagina; is that correct? Is it
correct?
Dr. Vereshchagina. You bet.
Ms. Eshoo. Oh, good. She is the Vice President of Science
and Regulatory Advocacy at PhRMA, the Pharmaceutical Research
and Manufacturers. Welcome and thank you, especially for your
patience today.
Dr. Cartier Esham; is that correct? A little bit beginning
of my name. So I got the first syllable correct.
She is the Chief Scientific Officer and Executive Vice
President of Emerging Companies at the Biotechnology Innovation
Organization and our abbreviation of that, of course, is BIO.
Welcome to you and thank you.
To Juliana Reed. How is Juliana----
Ms. Reed. I am here. I am here, Chairwoman. I am virtual
today.
Ms. Eshoo. OK. Well, welcome to you, Juliana.
Juliana is the Executive Director of the Biosimilars Forum.
So thank you for joining us and being willing to be a witness.
And David Gaugh. He is the--welcome--the Senior Vice
President of Science and Regulatory Affairs at the Association
for Accessible Medicines, AAM.
And Dr. Reshma Ramachandran, correct? Thank you.
And she is a Physician-Fellow at the Yale National
Clinician Scholars Program, and the Chair of the FDA Task Force
at Doctors for America.
Thank you for joining us and for being willing to be a
witness at this important hearing.
So we will begin with Dr. Vereshchagina for 5 minutes of
your testimony.
STATEMENT OF LUCY VERESHCHAGINA, Ph.D., VICE PRESIDENT, SCIENCE
AND REGULATORY ADVOCACY, PHARMACEUTICAL RESEARCH AND
MANUFACTURERS OF AMERICA; CARTIER ESHAM, Ph.D., CHIEF
SCIENTIFIC OFFICER, EXECUTIVE VICE PRESIDENT, EMERGING
COMPANIES, BIOTECHNOLOGY INNOVATION ORGANIZATION; JULIANA M.
REED, EXECUTIVE DIRECTOR, BIOSIMILARS FORUM; DAVID GAUGH,
SENIOR VICE PRESIDENT, SCIENCE AND REGULATORY AFFAIRS,
ASSOCIATION FOR ACCESSIBLE MEDICINES; AND RESHMA RAMACHANDRAN,
M.D., PHYSICIAN-FELLOW, YALE NATIONAL CLINICIAN SCHOLARS
PROGRAM CHAIR, DOCTORS FOR AMERICA FDA TASK FORCE
STATEMENT OF LUCY VERESHCHAGINA, Ph.D.
Dr. Vereshchagina. Good afternoon, Chairwoman Eshoo,
Ranking Member Guthrie, and the members of the subcommittee.
My name is Lucy Vereshchagina, Vice President, Science and
Regulatory Advocacy at the Pharmaceutical Research and
Manufacturers of America, or PhRMA.
PhRMA represents the country's leading innovative
biopharmaceutical research company which is devoted to
discovering and developing----
Ms. Eshoo. I think, Doctor, if you could bring your
microphone even closer. You have a soft voice, and we do not
want to miss anything you are saying.
Dr. Vereshchagina [continue]. That enable patients to live
longer, healthier, and more productive lives.
I am pleased to appear before you to provide PhRMA's
perspective on the importance of the Prescription Drug User Fee
Act, PDUFA, and the Biosimilars User Fee Act, BsUFA, and their
timely reauthorization.
Today I will briefly speak to PhRMA's perspective on the
success of the two user fee programs and key elements of each
agreement.
For nearly 30 years, PDUFA has helped the FDA fulfill is
central mission, to help protect and promoted public health by
allowing the agency to keep pace with ever-evolving science and
have the resources to review innovative drugs and biologics.
In large part, because of PDUFA and the biopharmaceutical
system, the United States now leads the world in the
introduction of new medicines, and FDA's human drug review
program is the global gold standard for regulatory review and
approval.
The PDUFA program has produced five different tangible
results that matter to patients. Since 1992 when the program
was first enacted, PDUFA has provided timely patient access to
more than 1,700 new drugs and biologics.
The uncertainties of COVID-19 have highlighted the
importance of the economic competitiveness of our Nation and
the need for continued advancement of the innovation-based
industries.
PDUFA VII efforts built on the program's past successes and
are aimed at modernizing the FDA's regulatory and drug
development paradigms, stressing as they increased co-
capabilities and improving issues in drug review.
Increased regulatory predictability encourages continued
significant investment in research and development made by
pharmaceutical companies in the United States. The continued
number of approvals occurring despite COVID-19 pandemic is a
testament to the agency's ongoing commitment to the public
health and dedication of biopharmaceutical companies to drive
medical advancement.
PDUFA VII also addresses new areas such as advancing
digital health technologies, supporting a new wave of advanced
biological therapies, such as cell and gene therapies, and
enhancing innovation in manufacturing and product [inaudible]
areas.
PDUFA VII will advance new and powerful tools, including
new clinical trial design, digital health technologies, and
real-world evidence that will harness scientific advances,
expedite drug development, and ultimately increase patient
access to new therapies.
PDUFA VII will also enhance patient-centric drug review
with the use of patient preference information and enhancement
to monitoring, including for pregnant women.
PDUFA VII also includes commitment that advanced COVID-19
lessons learned and enhance our future preparedness in the
ability to keep pace with scientific advancements, including
the broader use of these technologies during a pandemic that
has enormous positive impact on the conduct of clinical trials.
Digital health technologies including artificial
intelligence enable conduct of remote or distant [inaudible]
clinical trials that can enable more diverse patient
populations to participate.
PDUFA VII will also ensure FDA's backing resourcing in the
infrastructure and be able to support increasing drug review
and approval, modernize the basic infrastructure, including
adapting cloud-based technologies and enhance pf the financial
and staff resource management by promoting contribution
transparency.
So with these targeted improvements, PDUFA VII will have a
lasting and meaningful impact on the biopharmaceutical industry
and basically developing [inaudible] safe and effective
medicines for patients in a timely manner.
I will now briefly turn to BsUFA. Biosimilars are playing
an increasingly critical role in bringing new options to
patients. And BsUFA has been essential for FDA's ability to
review biosimilar products and has resulted in 33 approved
biosimilar products to date, including two interchangeable
products.
And BsUFA III will build on the program's success and
enhance the development and review of both biosimilar and
interchangeable biosimilar products while ensuring stability
and continued maturation of the program.
In conclusion, it is imperative that there be the ability
to help us deliver new treatments and cures to meet patients'
medical needs. PDUFA VII and BsUFA III will help ensure that
patients have timely access to vaccines and medicines while
maintaining the United States global leadership in
biopharmaceutical innovation.
PhRMA and its member companies strongly support PDUFA VII
and BsUFA III and are committed to working closely with FDA and
all stakeholders to ensure the continued success of these
programs.
And PhRMA, therefore, urges Congress to reauthorize PDUFA
and BsUFA in a timely manner to protect against any disruption
to this critical program.
And we look forward to continuing to work with the
committee, members of Congress, and other stakeholders on these
important issues.
Thank you for the opportunity to provide this testimony,
and I will be happy to address any questions.
[The prepared statement of Dr. Vereshchagina follows:]
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Ms. Eshoo. Thank you very much, Doctor.
Now the Chair recognizes Dr. Esham.
You are recognized for 5 minutes , and thank you again for
being with us today to testify on these important programs.
STATEMENT OF CARTIER ESHAM, Ph.D.
Dr. Esham. Thank you.
Good afternoon, Chairwoman Eshoo, Ranking Member Guthrie,
and members of the committee.
My name is Cartier Esham, and I am the Chief Scientific
Officer at the Biotechnology Innovation Organization, or BIO.
BIO appreciates the opportunity to speak with you today
about the benefits of and vital need for the timely
reauthorization of PDUFA VII and BsUFA III.
BIO is the world's largest trade association representing
biotechnology companies, academic institutions, and related
organizations across the United States and more than 30 other
nations.
While our membership includes most of the large
international biopharmaceutical companies, the majority of our
members are small pre-revenue companies working on cutting edge
biomedical innovations.
Since 1992, the user fee agreements have collectively
worked to ensure effective and timely reviews, improve safety
management, enable the agency to keep pace with medical and
scientific advancements, and continue to improve processes that
allow for early issue identification and resolution where
possible.
Those commitments continue to build on those successes with
a focus on strengthening review fundamentals and ensuring the
agency has the necessary resources and capabilities to meet
current and projected needs to advance the development and
availability of next generation medicines and biosimilars.
Today we will highlight a few of those provisions that
serve to meet those goals, starting with the PDUFA commitment.
First, there are numerous commitments in PDUFA that will
advance the utilization of patient-centric drug development and
review processes. These include but are not limited to
continued support for the utilization and review of patient
perspective data and innovative clinical trial designs;
expanding the ability to utilize real world evidence; advancing
knowledge about how to develop acceptable endpoints for rare
disease drug development; and strengthening the FDA's safety
monitoring capabilities.
Additionally, PDUFA VII will provide much needed resources
to ensure the FDA is able to take advantage of the digital age
by improving the agency's analytic capabilities and supporting
the use of digital technologies which have the potential to
reduce patient burdens and more effectively capture information
about clinical outcomes.
Second, it is critically important that CBER has the
resources necessary to meet the demands of a vastly growing and
exciting pipeline of cell and gene therapies. A 2020 analysis
by BIO found that there were 231 gene therapy programs under
development compared to 93 in 2015, a trend that is expected to
grow in the coming years.
To ensure that new and innovative cell and gene therapy
products can be effectively developed, reviewed, and available
to patients in a timely manner, the commitment letter provides
CBER with resources not just to increase personnel to meet
growing workload, but also provides support for training needs
and the ability to modernize data analytic capabilities.
The totality of the commitment to PDUFA will ensure the
center's best position to keep pace with scientific
advancements and more effectively community learnings and
expectations to the entire research and development community.
Third, the ability to engage in a timely and effective
scientific dialogue is fundamental to ensuring early issue
identification and resolution, as well as creating clear
pathways for the utilization of modern approaches to drug
development.
The PDUFA agreement creates a new meeting opportunity that
will allow FDA and sponsors to have focused conversations about
unique challenges or innovative approaches.
There is an expansion of the ability to have early stage
planning discussions prior to the submission of an IND to
better enable alignment of expectations and minimize delays to
clinics for medicines that have complex issues or lack clearly
understood precedence.
And lastly, the PDUFA agreement will serve to improve
review processes through more timely discussions and processes
relating to post market commitment, CMC and manufacturing
issues, and there is the ability and there is an expansion of
tools and approaches the FDA can utilize to better manage
inspection workloads.
Like the PDUFA agreement, the BsUFA agreement also works to
ensure timely and productive scientific dialogue and advance
the regulatory science in key areas.
Both agreements share a common goal, ensuring effective,
efficient, and patient-centric drug development and review
processes for the next generation of medicines. They both work
to ensure the FDA has the ability to recruit and retain world
class personnel and effectively manage resources.
BIO urges Congress to act swiftly and support timely
enactment of these vital reauthorizations so that the FDA is
best able to meet its mission of protecting and promoting the
public health and that there will be clear pathways for
approved availability of medicines that will improve the lives
of patients and their families.
And before I close, I would also like to say that BIO is
committed to enhancing and approving clinical trial diversity
as part of our BIO's quality agenda.
We look forward to working with all of you on proposals
that will help build a sustainable, more inclusive clinical
development ecosystem.
Thank you.
[The prepared statement of Dr. Esham follows:]
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Ms. Eshoo. Thank you.
It is now my pleasure to recognize Ms. Reed. You have 5
minutes for your opening statement.
STATEMENT OF JULIANA M. REED
Ms. Reed. Thank you, Chairwoman Eshoo, and thank you,
Ranking Member Guthrie and members of the committee.
My name is Juliana Reed, and I am the Executive Director of
the Biosimilars Forum. On behalf of the Forum members, I would
like to thank you for inviting me to participate in the hearing
today.
This is an especially significant hearing for me not only
to represent the biosimilars industry in the United States, but
like you, Chairwoman Eshoo, I have been committed to advancing
patient access to lower cost biosimilar medicines since we
worked on this together to pass the BPCIA years ago.
It is exciting to think we are on our third user fees, but
as we know, even more needs to be done to advance biosimilars.
The Forum is a nonprofit trade association representing the
companies with the most significant U.S. biosimilars
development portfolios. Our members include Biogen, Boehringer,
Engelheim, Coherus Biosciences, Organon, Pfizer, Samsung
Bioepis, Sando, Teva, and Viatris.
My remarks today represent the views of our members, all of
whom manufacture or market biosimilar products in the U.S., as
well as other parts of the world.
Biosimilars have the potential to provide very significant
healthcare savings in the U.S. Without robust competition,
innovator biologics will continue to represent approximately 40
percent of the total prescription drug spending, while they
represent only four percent of the medicines prescribed to
patients.
Biosimilars provide competition to allow Americans access
to lower cost medicines, and their timely licensure launch is
vital to ensuring patient access to lower cost biologic
medicines.
The Biosimilars Forum is supportive of the negotiated BsUFA
III agreement, and we believe it represents important progress
in facilitating timely access to safe and effective biosimilar
medicines for patients.
We are pleased the commitment letter codifies review
timelines for labeling supplements, provides meeting management
enhancements, and promotes best practices of communication
between FDA and sponsors.
The Forum is particularly pleased the BsUFA III program
will include a regulatory science program that can help bring
more biosimilars to market faster.
Since the BPCIA was enacted over a decade ago, there have
been many advances in the science of developing biologic drugs.
The regulatory sciences program will provide FDA and industry
the ability to incorporate the latest scientific innovations
into biosimilar development and regulations.
Although we are very satisfied with the progress
represented in BsUFA III, we want to stress that the pandemic
has impacted biosimilars and patient access disproportionately
hard for almost two years. COVID-19 has stalled on-site
inspections for biosimilars, delaying their approvals.
While biosimilar inspections have been delayed for the past
two years, on-time actions for the GDUFA and PDUFA programs
have averaged over 90 percent, and the BsUFA program plunged to
75 percent during the fourth quarter of 2020 and further
dropped to 67 percent in 2021 where it remains today.
Per the agency's May 2021 roadmap for FDA inspection
oversight, biosimilars' actions are not considered mission
critical and thus they are not prioritized.
This has the ultimate outcome of slowing timely approval
for biosimilars. We would like to ask the FDA for clarity to
sponsors and the public as to the estimated timelines the FDA
believes it will take to address this backlog.
For the BsUFA III commitment letter to be a success, the
inspection backlog for biosimilars must be addressed, and
remote inspections be implemented consistently across all
programs. Biosimilars cannot remain a low priority for the
agency.
The Forum is encouraged by the FDA's commitment to hire and
retain sufficient numbers and types of technical experts to
efficiently conduct review and applauds the agency's efforts to
improve its use of data and technology.
We will work with the FDA to determine how we can allocate
reviewers specifically for BsUFA goals. Industry understands
FDA staff works on numerous types of applications. A small
cadre of focused biosimilar staff could help expedite the
assessment in the inspection process for biosimilars.
As we head into BsUFA III, we look forward to working with
the agency and Congress to implement the commitment letter to
the mutual benefit of biosimilar sponsors and the FDA.
We are committed to developing a robust biosimilar industry
in the U.S. and to help the BsUFA program to further develop
over the next five years.
We are at a critical inflection point in the biosimilars
industry, and we believe that enhancing the process for
biosimilar review is a critically important component to
sustaining and cementing the biosimilar pathway.
But as you all know, more needs to be done outside of the
BsUFA to help us all achieve our goal of lowering the cost of
medicines and improving patient access to biosimilars.
To conclude, thank you for the opportunity to speak. Thank
you.
[The prepared statement of Ms. Reed follows:]
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Ms. Eshoo. Thank you.
Next, I would like to recognize Mr. David Gough. He is the
Senior Vice President of Science and Regulatory Affairs at, as
I said earlier, the Association for Accessible Medicines.
Welcome to you, and you have 5 minutes for your testimony,
sir.
STATEMENT OF DAVID GAUGH
Mr. Gough. Thank you.
Chairman Eshoo, Ranking Member Guthrie, and members of the
subcommittee, thank you for the opportunity to testify.
Ms. Eshoo. Move the microphone a little closer. You have a
soft voice, and we want to hear everything.
Mr. Gough. Is that better?
Ms. Eshoo. Much better.
Mr. Gough. Thank you.
Thank you for the opportunity about the critical role BsUFA
and GDUFA hold in increasing patient access to more affordable
generic and biosimilar medicines.
My name is David Gough, Senior Vice President for Science
and Regulatory Affairs at the Association for Accessible
Medicines.
I am a licensed pharmacist with many years of experience in
both generic and biosimilar drug industries, and I represented
the industry in the initial development and in both subsequent
renewals of generic and biosimilar user fee agreements.
AM and the Biosimilar Council strongly support
congressional authorization of GDUFA and BsUFA as negotiated
and without changes.
Timely approval of the FDA user fee agreements ensures
patients will continue to benefit from new, more affordable
generic and biosimilar medicines
Over the last ten years, GDUFA and BsUFA significantly
increased the resources available to the FDA for these timely
reviews of applications. The benefit of this partnership
between FDA and industry is clear. A record number of generic
drugs were approved in 2017, again in 2018, and again in 2019,
and a total of 33 biosimilars have been licensed.
A direct result of licensed competition is lowering
prescription drug costs for America's patients. Since 2012,
patients in the U.S. healthcare system have saved more than $2
trillion, including $469 billion from new generic and more than
$12 billion from biosimilars.
GDUFA III and BsUFA III build upon these successes. The
user fee agreements incorporate lessons learned, including
enhancements to ensure the timely review of applications and
provides FDA with sufficient resources over the next five
years.
GDUFA III and BsUFA III are the culmination of months of
negotiation, have been subject to public review and comments,
and represent a careful balance between stakeholders.
My written statement details many improvements negotiated
in GDUFA III and BsUFA III, but let me highlight just a couple.
Complex generics. These are generic versions of brand-named
drugs that have complex active ingredients or drug-device
combinations, for example. These drugs are more difficult to
develop due in part to the lack of FDA product-specific
guidances.
GDUFA III includes commitments to facilitate the
development and publication of these product-specific guidances
for complex generics. These commitments will increase
transparency and developers' understanding of FDA's
expectations to allow for a more predictable review process.
Inspections. Generic and biosimilar developers support
FDA's inspection program. In fact, one of the original purposes
of GDUFA was to provide resources for FDA to conduct risk-based
facility inspections.
GDUFA enhances the efficiencies of the inspection process
by helping ensure reinspection occurs within a specified time
frame.
In addition, in BsUFA III, FDA commits to issuing guidances
on its use of alternate tools to request records and other
documentation in lieu of inspection.
Suitability petitions. These are required to submit to the
FDA when a generic drug manufacturer intends to seek approval
for a drug that differs from the reference brand product.
Current law requires FDA to grant or deny suitability petitions
within 90 days from submission. That deadline, however, is
rarely met today.
GDUFA III will enhance FDA's ability to conduct timely
review of these suitability petitions with additional
resources.
BLA supplements. Biosimilar developers can submit
supplements to modify and approve BLA, for example, updating
labeling with new safety information of changes to indications.
Under BsUFA III, FDA commits to accelerate supplement
reviews for safety labels, for extrapolation for label carve-
in/carveouts, and for new data.
And finally, interchangeability. As of 2022, FDA has
licensed two interchangeable biosimilars. BsUFA III will help
manufacturers to develop more interchangeable biosimilars to
the regulatory science and demonstration projects. These
demonstration projects will also evaluate mechanisms to
streamline overall biosimilar development.
In closing, we strongly support timely reauthorization of
GDUFA and BsUFA, and we look forward to working with members on
both sides of the party to accomplish this goal.
Thank you, again, for this opportunity. I look forward to
questions.
[The prepared statement of Mr. Gaugh follows:]
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Ms. Eshoo. Thank you very much, Mr. Gaugh.
And last but not least, Dr. Ramachandran, your 5 minutes of
testimony.
STATEMENT OF RESHMA RAMACHANDRAN, M.D.
Dr. Ramachandran. Chairwoman Eshoo, Ranking Member Guthrie,
and distinguished members of the subcommittee, thank you for
the invitation to testify today.
My name is Reshma Ramachandran. I am a physician and a
researcher in the National Clinician Scholars Program at Yale
School of Medicine. I also lead the Doctors for America FDA
Task Force, which is an independent group of physicians working
together to support and strengthen the FDA to ensure medical
products meaningfully improve clinical outcomes for our
patients.
I am honored to testify before you today. My remarks
reflect my own views and not that of my employer nor the
organizations I work with.
Taking care of patients amid an ongoing devastating
pandemic has reinforced the critical role of the FDA in
protecting our patients and our Nation's public health. The
agency has not only enabled the availability of multiple proven
vaccines, drugs, and diagnostics, but has also been
continuously evaluating rapidly emerging evidence to make
scientifically driven regulatory decisions that ensure their
appropriate use.
While COVID-19 has certainly highlighted the need for the
FDA and its strengths, other recent events, including the
controversial approval of the Alzheimer's disease drug
Aducanumab, have exposed how the agency has faltered,
especially when putting industry and insurance before that of
patients.
The proposed user fee agreements reflect this tension. On
one hand, as a clinician I do want to make sure that the FDA
regulatory review process is as efficient as possible so that
my patients have timely access to new treatments and vaccines.
This means ensuring adequate funding for hiring and
retaining staff to review the growing number of drug and
biologic applications submitted to the FDA for approval and for
the agency to be nimble in shifting personnel and resources
when confronted with a public health emergency, a key priority
that is included within the proposed user fee legislation.
Conversely, the FDA has been increasingly approving new
medications more quickly and based on lesser best evidence.
This has left our patients and us as prescribers with greater
uncertainty around whether these approved products are truly
clinically beneficial and safe.
With accelerated approval, the expedited review pathway by
which Aducanumab was approved, FDA struck a bargain with
industry sponsors, in allowing for approval to be expedited
through smaller, shorter clinical trials that used surrogate
endpoints that are hypothesized to be associated with
clinically meaningful outcomes.
In exchange, industry sponsors are required to conduct
trials after approval that confirm clinical benefits. However,
industry has not upheld their end of the bargain. Since
accelerated approval was introduced in 1992, almost half of the
drugs approved through this pathway have not yet been confirmed
to be clinically beneficial for patients as of 2020.
Of these, one-fifth have remained available for patients to
use for more than five years. Even when the completed post-
approval trials have failed to confirm the drug's clinical
benefit, the FDA has either delayed withdrawing or not
withdrawn these approvals.
Both this prolonged uncertainty of these drugs' clinical
benefit as well as the FDA allowing them to be prescribed even
after they failed confirmatory trials harms patients both
medically and financially.
As in Europe and other countries, the FDA should require
manufacturers to renew accelerated approval on a yearly basis
and submit interim reports on their progress in completing
mandated confirmatory trials. If they fail to do so, the
approval should expire.
Additionally, should a confirmatory trial show negative
results, the indication approvals should be automatically
withdrawn.
Moreover, the FDA should also require sponsors receiving
accelerated approval to finalize their confirmatory trial
protocols with agency officials, preventing any delays in
initiating such trials.
The FDA must also improve the quality of these trials by
requiring them to use clinical endpoints, not surrogate
endpoints, especially those that are unvalidated or were used
as the basis of the initial approval.
Moreover, one study found that none of the 50 confirmatory
trials mandated by the FDA for recent accelerated approvals
could be feasibly emulated using real world data, making real
world data currently an unlikely source of reliable evidence to
replace post-approval confirmatory trial requirements, as has
been proposed in other legislation.
Additionally, the user fee agreements include several
agency review metrics that the FDA will be reporting on
regarding their success in expediting approvals.
However, the FDA should develop and publicly report other
more meaningful clinical metrics for patients and clinicians.
For instance, how many new drugs and biologic medicines were
approved even though the primary clinical trial endpoint was
not met, as with Aducanumab?
Our preliminary findings suggest that this might be as high
as ten percent in recent years.
Another example, for how many accelerated approvals were
benefits confirmed post approval?
If such metrics are not included, the FDA will continue to
focus its efforts towards reaching industry-driven benchmarks
instead of those that are patient centered.
In my written testimony, I have outlined other
opportunities through the proposed user fee legislation to
ensure a strong, independent FDA that will also instill public
trust in its important work.
I am happy to answer any other questions you might have.
Thank you, again, for this opportunity.
[The prepared statement of Dr. Ramachandran follows:]
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Ms. Eshoo. Thank you.
We now will move to member questions, and I recognize
myself for 5 minutes to do so.
Right back to you, Doctor. In what you just presented to us
in the accelerated trials, can you give us examples of outcomes
that hurt patients?
And was this raised, what you just testified to? Did you
raise this during the negotiations?
Dr. Ramachandran. I thank you so much, Congresswoman, for
the question.
So just some relevant examples, particularly with cancer
drugs that have been approved through this pathway, we have
found that a number of the trials use the same surrogate
endpoint in the post-approval trials as the pre-approval.
Ms. Eshoo. Wait a minute. Slow down a little bit so I catch
every word.
Dr. Ramachandran. Sure.
Ms. Eshoo. Say that again.
Dr. Ramachandran. Sure. We found for cancer drugs that were
approved through the accelerated approval pathway, their
confirmatory trials used the same surrogate endpoints in their
confirmatory trials, which are meant to show clinical benefit,
as the pre-approval trials.
So the clinical endpoints that were surrogate endpoints did
not correlate or were not associated in many cases with
clinical and meaningful outcomes, such as, you know, patient
survival, whether there was mortality and morbidity, patient
function.
And so those we see as harms in the sense that accelerated
approval is this idea that we should be able to confirm whether
or not these drugs are truly clinically beneficial after they
are approved and also to make sure that patients, when they are
taking these drugs know for a fact that when they make these
financial decisions to be able to take these drugs, that they
know for certain that it is actually clinically effective and
safe.
A number of my colleagues, including physicians and others,
did raise this in the PDUFA meetings, but they wanted to make
sure that the accelerated approval pathway did mandate that
confirmatory trials----
Ms. Eshoo. Well, let's just get to another point. In terms
of this discussion in the negotiations, what is changing?
Dr. Ramachandran. And so right now at least in response to
the public stakeholder comments, when we put forward these
different types of metrics that we wanted the FDA to look at,
they are more patient centered.
Unfortunately, the FDA responded that they would not be
making these changes. So that has not been included into the
negotiations.
Ms. Eshoo. OK. Let me go to Ms. Reed.
I think that we have known each other for a long time, and
I am proud to have been the House sponsor of the Pathway for
Biosimilars Act in 2008. It was folded into the ACA, and it was
first granted the FDA or, you know, it was a first, a first.
Today the biosimilar market is expanding. I have to say
that I have been frustrated along the way even though it is
said that it is set to double in size by the year 2025, except
I do not think the market has really taken off since Congress
put the legislation into law.
Can you just give us a brief profile of what is to come out
of biosimilars?
I know that the FDA did testify this morning as to how many
have been approved, and that is encouraging. Do you have more
to add to that?
Ms. Reed. Thank you, Chairwoman, and thank you. This has
been a wonderful adventure for me to partner with you on this
commitment.
Yes, I can definitely do that, and I think, first of all,
to the agency's commitment and our commitment to the agency's
program is significant, and that is a very good thing, and that
is why we support the BsUFA III.
But as you know and said, more can be done for the uptake
and the access of biosimilars, and that is something the Forum
is committed to.
We need to change the way biosimilars are incentivized for
it to get to patients. Biosimilars are a cost saving solution
on the shelf ready to go. If we were to see that patients had
access to 90 percent of the time to a biosimilar, this country
will save the billions of dollars that we predict will be
available and have an incredible cost savings for consumers,
patients, and the government.
There are a number of ways we can do that. We can
incentivize. We can continue to combat missed information. We
can look at----
Ms. Eshoo. My time is running out.
Ms. Reed. Thank you.
Ms. Eshoo. Did you raise all of this during negotiations?
And if so, what is the----
Ms. Reed. Yes.
Ms. Eshoo. Are any of these things that you are raising
being addressed?
Ms. Reed. Thank you, Congresswoman and Chairwoman.
These things need to be addressed outside the user fee
programs. So we have a commitment to accelerate and streamline
development of biosimilars with the agency, but we would love
the opportunity to work with you and the committee and look
at----
Ms. Eshoo. My time is--I do not want to set a bad example
for my colleagues. My time has expired, but we can continue
this conversation with follow-up written questions to our
witnesses.
It is a pleasure to yield to our distinguished ranking
member of the subcommittee, Congressman Guthrie.
Mr. Guthrie. Thank you. Thank you, Madam Chair.
You know, some of the biggest influencers on Capitol Hill
are families and people who have diseases. They come to see our
offices. I think, as the Chair would say, we have quite a few
people that visit it and make a big impact because they tell
their stories and they tell their lives.
And so what we try to do and what we try to push in public
policy is to get these miracle cures, if they are miracle
cures, and drugs and pharmaceuticals to the patient as quickly
as possible, accelerated if possible, but it also needs to be
safe and effective.
And so that is where we try to balance what we do and have
a lot of faith in what the FDA does moving forward, but I do
not know. I know you have every year this. We had a hearing
where they all left. I think that had a big impact on a bill
that moved forward with the patient that came here from
Chicago.
And so, Dr. Esham, you know, I voiced my concerns with CMS
early on their Aduhelm, the way they had limited circumstances
offering in addition to the process they took.
Could you use that as an example of how or do you believe
that this decision will impact future investments in these
potential lifesaving drugs?
And just talk about what are the issues that you take with
that process CMS went forward with.
Dr. Esham. Certainly. I would say that the decision it
finalized will have a chilling effect not just on the future of
investment in the research and development for innovative
Alzheimer's treatments, but for other treatments to treat
difficult disease.
As you know, producing a novel therapeutic is one of the
riskiest business ventures an entrepreneur can take, and
importantly, most of the science and research being conducting
today has been conducted by small companies that are reliant on
venture capital.
And those significant investments that are necessary to
advance this work are predicated in large part on a stable and
understood pathway from approval to access, where FDA makes
determinations on safety and effectiveness, and CMS makes a
determination of reasonable and necessary, where coverage is
provided for treatments to be used as indicated on FDA-approved
labels.
Further, the assertions to and impact on an entire class of
drugs as proposed under this NCD proposal are really untenable
from an investment standpoint.
Mr. Guthrie. OK. Thank you.
And Dr. Vereshchagina--I am sorry--some work on
legislation. So here is another thing that we have. We have, I
think, what Dr. Ramachandran talked about.
You know, it is not just investment that goes in from the
company putting forward. Once it comes out, it is the
investment that the individual and the patient puts into buying
the pharmaceutical either through their health insurance or out
of their pocket or however they move forward.
And so we want to make sure that they are available, and
some of these can be expensive because a lot of research goes
into it.
And so I have worked with Congressman Schrader. The
information--well, that was not with him. I am sorry--the
Information Exchange Act of 2017, and what that is it allows
during the Phase 3 trials for there to be discussion between
payers and pharmaceutical companies to determine what, because
the idea would be if there is a breakthrough drug that comes
out on day one, day two they can make a coverage determination,
and obviously a payer has to have the financial information to
know how to put it in their formulary, and so forth.
You know, there has been some resistance here to say, well,
that is marketing a drug before it has been approved, but the
thing is then you wait a year, and understand the issues that
are raised with that.
And I think we can deal with it and make sure we have a
pharmaceutical. You hear migraine. They come out quite often,
and I know people with migraines. ``I do not think I can get
this drug.'' And it takes them a while to get a coverage
determination.
Could you talk to how if we could have discussions
particularly in Phase 3 where we know there has to be some
success with the drug or it would not be in Phase 3 and with
payers and how that would benefit the marketplace?
Dr. Esham. Certainly. So you mentioned the Pharmaceutical
Information Exchange Act in 2017. So my understanding is FDA
issued the final guidance to help implement provisions in this
act, and from what we hear, the guidance helped to facilitate
productive communications between FDA, sponsors, and payers.
So while we cannot comment on any specific proposal, PhRMA
will welcome an opportunity to work with you and your office to
make sure that any further legislative proposals accurately
reflect the final guidance, and they really help to facilitate
those productive discussions and conversations with payers.
Mr. Guthrie. What if we just codified the final guidance so
there is not a new proposal? Just the final guidance comes and
we codify it.
Because the problem you hear is not just in pharmaceutical,
but in almost every deal that we deal with, is people say,
``Well, we do not know.'' The uncertainty of the regulatory
environment and things that Congress can put into law makes
certainty better.
And so that is my question, if we codified the guidance
that came out.
Dr. Esham. So I am not a lawyer. I would definitely defer
to a lawyers and legislative experts whether codifying the
guidance would make a meaningful impact.
But PhRMA does agree that the final guidance was helpful in
promoting such productive communications with payers.
Mr. Guthrie. OK. What we hope to do is have, if drugs are
going it make a big impact on people's lives, approved as soon
as possible they are safe and effective and approved as soon as
possible by payers to make sure that people have access to
these cures.
And as I said, and I will close with this. I have gotten to
know families and I have seen families. I have been to funerals
of families who have been here and talked to us and advocated,
and people are in desperate situations, and the American
pharmaceutical industry addresses it, but it also is expensive,
and we have to have a way to pay for it and make sure people
have access to it.
We appreciate the investment, and we certainly appreciate
the cures. But we want to make sure we get coverage.
So thank you, and I yield back.
Ms. Eshoo. The gentleman yields back.
It is a pleasure to recognize my colleague fromCalifornia,
the gentlewoman from California, Congresswoman Matsui, for your
5 minutes of questions.
Ms. Matsui. Thank you, Madam Chair.
And I want to thank our second panel of witnesses for being
here today.
I want to follow up on some discussion on biosimilars. The
biosimilars competition is key to lower drug prices, and I am
concerned that existing inspection backlog will stifle
opportunities.
Now, we heard today how the pandemic has disproportionately
impacted inspections and review timelines for biosimilars in
comparison to the other user fee programs.
Additionally, with more than 30 approved biosimilar
products today, industry is expected to submit more
supplemental applications to FDA over the next five years.
Ms. Reed, the third biosimilar agreement includes new pre-
market review processes for certain applications. Can you
expand on how these processes will accommodate incoming
supplements from sponsors, and why this is important to
advancing a robust biosimilars program?
Ms. Reed?
Ms. Reed. Thank you, Congresswoman, for that question.
So these enhancements, especially in the BsUFA III, are
very important because they reflect the evolution of the
science and technology for biologics and biosimilars.
So those enhancements will shorten the time frame for
responses and communications between sponsors, as well as the
agency; require less data from sponsors, which is very
important because the streamline will lower the cost.
Ms. Matsui. OK. Good. Is it Dr. Gaugh? Is that how you
pronounce your name, Gaugh?
Mr. Gough. Yes.
Ms. Matsui. In your testimony, you discuss the challenges
of developing complex generics. As we heard from the first
panel, the BsUFA III agreement includes a new midcycle review
meeting commitment between industry and regulators for a
complex generic drug application.
In your view, what information can industry learn from
these new opportunities that were missing in the current review
cycle practice?
Mr. Gough. Thank you for the question.
Yes, so in GDUFA II we started building a complex generic
structure that would allow and would somewhat mimic the new
drug development process, and by that I mean allowing the
companies to have a pre-development meeting with the FDA, a
pre-filing meeting with the FDA, a midcycle meeting, and then
an end meeting with them.
We were not able to gain all of those accesses in GDUFA II,
and we also asked for the product-specific guidances to be
enhanced in GDUFA II, which, again, that was not able to
happen.
In GDUFA III, however, we have continued down that path. So
we now have those pre-development meeting capabilities that we
can asked for with the FDA. They do not necessarily have to
grant them, but we can ask and hopefully will get those.
We also have the midcycle review meetings, and then we have
the more robust product specific guidance structure setup.
Thank you.
Ms. Matsui. Thank you.
Now, I would like to follow up on the discussion we had
with the FDA earlier. There was a lot of work to advance the
development of therapies and cures for rare diseases. Because
drug development for rare diseases typically focuses on novel
areas that affect few patients, the critical trial populations
are often inherently small, and there is a lack of regulatory
precedence for drug development.
Dr. Esham, from your perspective, how would a rare disease
endpoint advancement pilot program help industry better design
clinical trials for rare disease and treatments?
And how would that impact the rare disease drug development
process overall?
Dr. Esham. Thank you for that question.
I just want to make sure. Are you questioning about the
provision in the PDUFA agreement about the rare disease
endpoint pilot, correct?
Ms. Matsui. Right, right.
Dr. Esham. We do think it will be highly valuable, as Dr.
Marks said in his earlier testimony. The ability to have
stronger engagements that will allow for scientific dialogue
about how best to approach the development, solve and support
for utilization of an endpoint in rare diseases, which does
have its own unique challenges, will be highly beneficial.
And it is beneficial these kinds of pilots are built to be
beneficial beyond, not only those that are in the pilot
program, but it is set up to ensure that the learning and best
practices are shared to the entire research and development
community.
So we really do think that this pilot program offers true
value and will be broadly applicable to help researchers
understand what needs to be done to develop and support
utilization of endpoints for rare diseases.
Ms. Matsui. So you believe that the lessons learned from
this pilot program and other initiatives for rare diseases
throughout the review process can help the review program
practice for other programs?
Dr. Esham. Yes, absolutely. The key provisions in those
user fee agreements are the ability for the FDA to share
information from the applications that were part of the pilot
program so that they can share them more broadly with the
entire research and development community. That is right.
Ms. Eshoo. The gentlewoman's time has expired.
The Chair is pleased to recognize the gentleman from
Georgia, Mr. Carter, for your 5 minutes of questions.
Mr. Carter. Thank you, Madam Chair.
And thank you all for being here.
Very quickly, as a pharmacist, drug shortages are extremely
important, and for me personally, and it is something that I
have been working very diligently on and I continue to.
Also moving pharmaceutical manufacturing back to America,
that is one thing. You know, I often say there is a difference
in knowing something and realizing something. We knew we were
too dependent on other countries for our pharmaceutical needs
pre-pandemic. We realized it during the pandemic.
We have to do this, and I have got legislation that will do
just that, but one of the things is innovative manufacturing
technologies. This could help. It could help solve the drug
shortage problem as well as to help incentivize pharmaceutical
manufacturers to move their production back here to America.
But it seems the FDA review process for these technologies
is slowing this innovative manufacturing, and I just wanted to
ask you Dr. V. I ask you first. Can you speak to the importance
of approving innovative advanced manufacturing technologies and
their benefit for manufacturers and, most importantly, for
patients?
Dr. Vereshchagina. Absolutely. So industry and FDA
recognize that it is a critical issue, and this is why PDUFA
VII, actually the first time in the history of user fees,
includes manufacturing provisions, and advanced manufacturing
Section 08 [inaudible] manufacturing and risk-based inspections
are all included in PDUFA VII.
So we do hope that it will help expedite all the things
that you just mentioned.
Mr. Carter. OK. Well, I am going to hold you to that, and I
hope it does because we need this. This is essential.
And, Dr. Esham, do you want to add to that? Is there
anything you can add to it?
Dr. Esham. No, I will underscore that we believe the
ability of these technologies due to the promises that they
offer, optimization of efficiency, scalability, reducing
variability, and increasing product quality assurances, all of
which are good for patients in ensuring expedited availability
of high-quality medicines.
Mr. Carter. Good. Thank you both for that.
Mr. Gaugh, I want to ask you. One of the things in my many
years of practice in pharmacy, I often say that I have seen
nothing short of miracles through research and development, and
I have not.
I use the example quite often, and I think it is a good
example of Hepatitis C. I remember when I started practicing
pharmacy back in 1980, that if you were diagnosed with
Hepatitis C, you were going to die. I mean, we did not have
anything to treat it.
Now we can cure it with a pill. That is phenomenal, but if
you cannot afford that pill, it does you no good whatsoever.
That is something that is extremely concerning to me. I
know that GDUFA III is supposed to improve FDA's review and
approval of complex generics because generic drugs, and it
baffles me and frustrates me to no end that it takes so long
for a generic to get to the market.
I always thought that, quite honestly, before I became
familiar with the process, I always thought working as a
pharmacist that, OK, they get seven years and then on day seven
year and one, then the generic comes out.
But I have learned since I became a member of Congress and
a member of this committee particularly that is not the case at
all. It may be years and years after that.
GDUFA III, is that going to improve that at all?
Mr. Gough. Yes, we believe it is going to improve. So a
couple of things.
One, I talked a minute ago about the complex generic pieces
that we have built into GDUFA III which will help move that
along.
The second thing is first cycle approvals instead of, to
your point, several years. We have a ten-month goal in the
approval process, but what we found was that at the end or not
the end, but at nine-ish months that review cycle may not be
close enough or close but just not there yet to get an
approval. And so we get a complete response letter instead of
approval.
So we built in an imminent approval piece that adds an
additional 60 days to that to allow the FDA and the company to
work together to meet that deadline.
Mr. Carter. Is there any way we can get that process
started earlier?
They know in seven years the patent is expiring. Can they
not get it started like two years before then or in year five
or whatever?
Mr. Gough. Well, in many cases we do. We file----
Mr. Carter. And it still takes that long to get a generic
to market?
Mr. Gough. Depending on the product and the product
category, yes. But many products are tentatively approved by
the FDA, and to your point, ready to launch the day after the
expire date or the day of the expire date.
Mr. Carter. I think we see that happen seldom. I think it
is the other way around. I think it is years later more often
than it is the day after.
Mr. Gough. It can be, but it is both actually.
Mr. Carter. Well, is there anything we can do in Congress
to accelerate that?
Mr. Gough. Approve this User Fee Act and that will help a
lot, yes.
Mr. Carter. OK. Thank you all.
Mr. Gough. Thank you.
Ms. Eshoo. The gentleman's time has expired.
The Chair now recognizes the gentleman from Maryland, Mr.
Sarbanes, for your 5 minutes of questions.
And I would also like to add that I have one other from our
side that is waiting to question, and that will be it, and
then--09
Mr. Guthrie. We are letting our people know.
Ms. Eshoo. Good. OK. So, Mr. Sarbanes, you are on.
Mr. Sarbanes. Yes, thank you. Thank you much, Madam Chair.
And I want to thank the panel.
We certainly know that R&D investments of pharmaceutical
companies are absolutely critical to advancing new therapies,
but too often, I think, industry claims that we must make a
false tradeoff between promoting innovation, on the one hand,
and the affordability of increasingly expensive prescription
drugs millions of Americans rely on, on the other hand.
Dr. Ramachandran, can you speak to whether this tradeoff
really exists and the role that legislation being discussed in
Congress, including the GDUFA proposal before us today, can
play in impacting the affordability of prescription drugs?
Dr. Ramachandran. Thank you, Congressman, for your
question.
This tradeoff does not really exist that we are seeing, and
unfortunately, our patients are the ones that are hearing
things, kind of the bad end of a bad bargain from that
tradeoff.
Just to kind of reiterate one of the points that has been
made earlier, you know, in relation to Aducanumab, the drug
that was recently approved by the FDA based on a surrogate
endpoint that two dozen clinical trials found no association
with a clinically meaningful outcome for patient, you know, a
number of people had concerns about this. They had three
resignations that came through after that approval went through
by the FDA.
And it has actually sent a signal of bad innovation to the
industry instead of, you know, truly incentivizing innovation
that is going to be clinically meaningful to patients.
Instead a number of other manufacturers came in to want to
make similar drugs with the same mechanism of action that is
unproven, and so who is going to lose in that situation? Our
patients. Our patients are going to be flooded with, you know,
a number of drugs that are not going to be very good or
beneficial for them both medically and financially.
The GDUFA agreement and BsUFA agreement, I am grateful for
the fact that there are mechanisms within that to make the
process more efficient for biosimilars and generics to be
produced, to be, you know, reviewed much more quickly, and also
to get out to patients because I have seen the impact of those
generic and biosimilars on my own patients, particularly
generics.
You know, a number of my patients, especially my older
adult patients who take multiple medications, have significant
cost savings as a result of the availability of generics and
biosimilars.
Woodcock had sent a letter to the Patent Office last year
and had talked to them specifically about collaboration through
additional barriers that are impeding biosimilar access and
generic access, in particular.
And I am hoping that these agreements will actually include
metrics on FDA's collaboration with the PTO or there might be
legislation to kind of ask about this a little bit further to
see if those questions that are being asked to the PTO are
going to be realized through regulatory action.
Thank you.
Mr. Sarbanes. Thank you.
Let me ask you a little bit about the source of dollars to
support these reviews. It is certainly clear that you are going
to need adequate resources to take on the wide [audio
malfunction] work of keeping Americans safe.
I have some concerns that a large portion of FDA's budget
is attributable to user fees from the industries that are being
regulated. For example, in fiscal year 2020, FDA spent about
$400 million from congressional appropriations on the PDUFA
program compared to almost $1.1 billion from user fees.
[Audio malfunction] have confidence in scientists and other
[audio malfunction] at the FDA, but, Dr. Ramachandran, in your
testimony you described some of the challenges the FDA faces in
the public trust given its close ties to the industry.
Can you briefly outline some of the points that you raise
on this topic?
Dr. Ramachandran. Thank you, Congressman, for that
question.
You know, like a number of my colleagues, especially my
other fellow physicians and patients, we do have concerns that
FDA's increasing reliance on industry user fees has led to
faster approvals, but also faster approvals where we have more
uncertainty on clinical benefit and safety.
So you know, short of not having enough congressional
appropriated funding to ensure the independence of the FDA, I
am hoping the user fee agreements will include a number of
provisions that are safeguards to protect patients and to
instill that public trust.
And one of those that I have mentioned in my testimony,
both written and today, was around these metrics that are more
patient centered and not just on industry benchmarks.
Thank you.
Mr. Sarbanes. Thank you very much.
I yield back.
Ms. Eshoo. The gentleman yields back.
The Chair now recognizes the ranking member of the full
committee, Representative McMorris Rodgers, for your 5 minutes
of questions.
Mrs. McMorris Rodgers. Thank you. Thank you, Madam Chair.
I had a couple of questions for Dr. Vereshchagina and Dr.
Esham.
When we discuss the importance of including diverse
populations in clinical trials, we cannot forget those with
disabilities, especially those with developmental disabilities.
How can we improve representation of those with disabilities in
the clinical trials?
Dr. Vereshchagina. I can start and, Dr. Esham, I will pass
to you.
This is why we are excited about digital health technology
provisions in PDUFA VII, which are intended to enable what we
call remote or decentralized clinical trials.
And in such trials, it is possible to collect data
remotely. As we heard this morning perhaps patients do not have
to travel to clinical trial sites that are far from their home.
They can see a doctor hopefully in their community.
Maybe some data can be collected through wearables. So we
believe digital health technologies have great potential for
the future of clinical trials.
Mrs. McMorris Rodgers. Yes, I agree.
Dr. Esham. And I concur with my colleague and her
statements.
I will add a few additional thoughts, and that is we concur
that inclusivity needs to be all-encompassing. We at BIO have
developed a detailed proposal outlining key steps and
activities for the FDA and cross-agency activities we think
will enable a more inclusive clinical development ecosystem.
And among those are discussions relating to inclusion and
exclusion criteria, which under current practices may be
prohibiting participation from specific segments of the patient
community, including those with disability.
So we would be happy to share with you and discuss in more
detail if you would find that beneficial.
Mrs. McMorris Rodgers. Yes. I am quite dismayed by the
recent coverage determination by CMS with respect to the
coverage for all FDA approved drugs targeting Amyloid for the
treatment of Alzheimer's. It appears to be entirely excluding
Americans with Down's Syndrome from any form of coverage while
trials are ongoing to meet the coverage with evidence
development requirements.
I am very concerned about the precedent that this is
setting. Could the exclusion of individuals with Down's
Syndrome from the CMS-covered trials disincentivize the
recruitment of clinical trial participants from this population
in the future study for drugs targeting Amyloid?
Yes. I was going to ask the two of you again.
Dr. Esham. Do you want me to go first this time?
Mrs. McMorris Rodgers. Or if others want to speak to it.
Dr. Esham. Well, as I stated earlier, we have many concerns
about the proposed national coverage determination. Not only
could it negatively impact the future of AZ research, but the
uncertainty it creates for all future approvals of innovative
medicines.
It is imperative that the mandates and distinct mandates of
CMS and FDA are maintained.
But more directly to your question, the provisions, the
additional provisions in the coverage that may, in fact,
compound or delay medicines for patients with disabilities is
equally troubling.
Mrs. McMorris Rodgers. And have you ever seen this before?
Dr. Esham. I believe ``unprecedented'' is a term that leaps
to mind.
Mrs. McMorris Rodgers. OK.
Dr. Vereshchagina. And I would echo what Dr. Esham just
said. PhRMA is concerned about the proposal and especially
about potential negative impacts that it may have on access for
patients, especially since it affects a broad class of drugs,
including some of those that are still in development that have
not even been approved yet.
Mrs. McMorris Rodgers. Yes. Does anyone else care to speak
to this question?
Dr. Ramachandran. Yes, I can definitely speak to this.
Mrs. McMorris Rodgers. That would be great.
Dr. Ramachandran. The national coverage determination is
not as unprecedented as one might think. There has been other
coverage with evidence development determinations where they
have required a greater amount of controlled trials, and I am
happy to share that information with the Congresswoman, you
know, after the hearing.
The one thing I will say is that as a physician and someone
who has reviewed the clinical trial evidence from Aducanumab
where that surrogate endpoint that you have mentioned, there
has not been an association with a clinical meaningful outcome.
So I am grateful that the CMS is actually allowing for
further evidence to be generated so that patients are not
paying $28,000 per year for a drug that might not work and that
might cause harmful side effects, such as brain swelling and
brain bleeds.
Mrs. McMorris Rodgers. Why was that not raised with FDA?
Dr. Ramachandran. It was raised with the FDA. The Advisory
Committee, and this is actually a quote from the FDA official,
that they were not going to consider Amyloid as a surrogate
endpoint. They did not feel that it was sufficient to actually
determine efficacy.
But then later after conversations with the manufacturer,
which was found in multiple reports, and when they did not
reconvene the Advisory Committee, they went ahead with the
accelerated approval.
Mrs. McMorris Rodgers. Have you ever seen a class of drugs
limited for people with disabilities?
Dr. Ramachandran. So in the number of clinical trials the
way that enrollment works what a number of manufacturers do
unfortunately is that they exclude oftentimes sick patients in
which they are concerned that they will not see a positive
benefit from the drug.
So I am grateful that the FDA and the Congresswoman are
paying attention to the fact that these trials' enrollments
need to be adjusted to also include patients with other
comorbidities, including developmental disabilities.
Mrs. McMorris Rodgers. OK. Thank you.
I will yield back.
Ms. Eshoo. The gentlewoman yields back. And we all
appreciate your staying on this issue of the disabled, and I do
not think really very much is going to change unless and until
we have real diversification in clinical trials. That is a
must, and many of us have legislation drafted and have offered
it on that.
We really should come together and make up our minds and
get a really solid bill through.
Now, we have Mr. Cardenas, the gentleman from California
who is next, followed by Mr. Curtis, and I do not have any
others, but votes are going to be called pretty soon. So we
want to conclude.
So, Mr. Cardenas, you are recognized for your 5 minutes of
questions.
Mr. Cardenas. Thank you very much, Madam Chairwoman and
Ranking Member, for this opportunity for us to have these
amazing panels to help educate not only ourselves but the
public on what we are doing here in Congress to make sure that
we can still have the best process in the world when it comes
to approving safe solutions to people's health. So thank you so
much.
And also to the witnesses, I appreciate your expertise and
your thoughtfulness and your insightfulness in being with us
today.
Dr. Ramachandran, thank you for being here, and thank you
for the critical work that you do.
I am especially interested in your recommendation for more
patient-centered performance measures when reviewing
applications. Obviously, the most critical aim of the review
process is to ensure that any approved therapies are safe and
effective.
Why are patient-centered metrics important to include?
And how do we best balance a patient-centered perspective
while maintaining a reasonable timeliness?
If you can be brief because I have another question for
you.
Dr. Ramachandran. Yes. Thank you, Congressman, for the
question.
You know, patient-centered metrics, the way that I view
them is that it will help actually incentivize truly clinically
meaningful innovation. FDA sets regulatory standards, and it
oftentimes becomes the bar by which other companies follow in
terms of how they develop new drugs.
So the hope is that including patient-centered metrics
where we know for certain how often these approvals are
actually clinically beneficial and safe, how often they are
actually requiring post-marketing trials for accelerated
approvals that show clinical benefit. All of those will lead to
manufacturers being incentivized to do better innovation that
truly matters to our patients.
Mr. Cardenas. Thank you.
And based on your experience as a practicing clinician, how
have some of your patients benefitted from increased access to
safe and effective, yet lower cost generics and biosimilars?
Dr. Ramachandran. This has just been paramount for my
patients. I will tell you I see a number of patients who take
multiple medications for multiple chronic conditions, and the
things that they have to take for the rest of their lives. And
when they are not able to access those medicines, they
oftentimes will end up in the hospital or are much more sick.
It has been devastating to watch.
When generics have been available for a number of
medications, a lot of combination medications, for instance,
for heart disease, for high blood pressure, cholesterol and
whatnot, these have been incredibly beneficial for my patients
because that means that they do not have to make a decision of
food and access to drugs or they do not have to make a decision
of, you know, having to abandon the medicines at the pharmacy
counter and facing some downstream consequences.
So the availability of generics and biosimilars has just
been paramount for them to be able to continue to live healthy
lives, and it gives me full reassurance that when I prescribe
medicine, they are able to access them.
Mr. Cardenas. OK. Thank you so much for that insight.
I would like to continue this focus on biosimilars and some
of the promise they show in expanding access to affordable
drugs. Biosimilars have proven remarkably effective at driving
prices down by introducing lower cost competition in the
biologic drug market.
This is especially critical for low-income folks with
health conditions who often have to make impossible decisions
between affording their medications and putting food on the
table.
Today over 30 biosimilars have been approved by the FDA,
with many more still in the review process. I want to see the
FDA continue its trajectory of increasing approvals for safe
and effective lower cost biosimilar drugs, as well as
interchangeable biosimilars.
So my question to Ms. Reed, thank you for your work in this
area. Based on your testimony, it is clear that you have
extensive experience in spreading awareness of what biosimilars
can do and how to expand access to them.
What does the evidence say about their effectiveness and
what are some of the conditions that they are used for?
Ms. Reed. Thank you so much, Congressman, and thank you for
your ongoing championship championing the biosimilars and lower
cost medicine.
So we have 33 biosimilars approved. And we have a number of
other biosimilars approved around the world. We have seen that
they are as safe and efficacious and provide the same clinical
results of their referenced biologics. So that is very key.
And we continue with the agency with this BsUFA III
commitment letter to see that we are advancing the technologies
and the commitments and streamlining the development of
biosimilars.
What is really key for us though, and this is key if we
talk about innovative medicines and access to innovative
medicines. We need the funds to provide, to be able to get the
access to those.
So biosimilars, lower cost biosimilars are key.
Biosimilars need to be a priority at the agency, and we
would like to see that.
Mr. Cardenas. Thank you.
And, Madam Chairwoman, I would be remiss if I did not
mention how amazing it is to see so many awesome women
testifying today and people from all over the country that look
like America with names that are hard to pronounce, but thank
you all for all of your amazing, amazing work.
Thank you very much, Madam Chairwoman. I yield back.
Ms. Eshoo. Well, thank you for that wonderful observation.
Typical of California thinking as well.
It is a pleasure to recognize the gentleman from Utah, Mr.
Curtis, for his 5 minutes of questions, and it looks like you
will be the last questioner, and we can wrap up.
Mr. Curtis. Madam Chairman, it seems like you and I share a
theme that just as you want to go vote, it is my turn to ask
question.
[Laughter.]
Ms. Eshoo. I know.
Mr. Curtis. So I appreciate a few minutes and our witnesses
this morning.
You know, this morning I mentioned that I am in a unique
situation. I have not been on the committee as we have done
this process before, and I do not have a healthcare background.
But I also believe that lets me see a little bit of the
forest and the trees in the forest from a distance and a
different perspective and bringing kind of a problem solving,
businessman mentality to this as well.
This morning I also shared a story about a Utahan, a woman
who has a son. He is five years old, and he has classic
Galactosemia, and this mother is desperate for access to AT007,
a central nervous system penetrant inhibitor used to treat this
disease.
This drug can change her son's educational trajectory at a
time when his mind is developing very quickly and a unique
period in his life, what will make a difference to help him be
a self-sufficient adult.
I know that this panel may not be able to speak to the
specific drug, but I have heard multiple stories about
Americans and Utahans like this that I referenced this morning
and who are desperate for access to these innovative therapies.
Dr. Vereshchagina and Dr. Gaugh or Mr. Gaugh, how would
these agreements being considered before us today help
accelerate the approval process for these medical products and
give these people hope?
Doctor, we will start with you please.
Dr. Vereshchagina. This is an ultimate goal of both PDUFA
and BsUFA programs, to make sure that the drug development
process is efficient as possible and that FDA's review as
expeditious as possible, and the system in place is predictable
for sponsors and for patients because they can be sure that the
process is moving in a timely manner, and they will have access
to device and medications as soon as they can make that
benefit-risk determination.
Mr. Curtis. Thank you.
Mr. Gaugh?
Mr. Gough. Thank you for the question.
So as we talked earlier, Mr. Carter asked that question
about getting generics to market, and of course, the innovator
has to come to market first, and then we have to get through
all the patents and the patent tickets to happen with those
products.
Once that happens, we have now built into GDUFA III and
specifically the product you are talking about would be in
complex generics that would allow it to move through that
process more quickly.
Mr. Curtis. Thank you.
I mentioned this morning it is my hope we can put names and
faces behind these people, and that might help us motivate to
go quicker.
We had a biomedical innovation hearing in December in this
very room right here, and I shared that ALS is a diagnosis that
hits very close to me, as it did for many people in that room
that day. I have lost too many good friends to this disease.
And so the times that we do not give patients enough
flexibility to access and try therapies, despite urgency of a
degenerative disease.
Dr. Ramachandran, you mentioned concerns over accelerated
approval pathways. Let me just ask this. Keeping in mind that
very personal nature of these diseases, if patients are made
aware of the adverse risks, if they consent, if we acknowledge
somewhat of a death sentence that they have been given, do you
believe that they should be given the opportunity to access
these treatments?
Dr. Ramachandran. Thank you, Congressman, for the question.
I definitely appreciate that viewpoint, having taken care
of patients in which I am left kind of flustered in the exam
room or in the hospital, not being sure what I can give them
because there is really no option.
You know, to your point, you know, I understand that, you
know, when patients are willing to accept the risk, there are
pathways in which they can get access, and that is through an
expanded access or through clinical trials.
And the reason why I think that pathway is important in
order for them to get access is because we should be able to
study whether or not the drug is actually working for them,
whether it is, you know, clinically beneficial for them or they
are actually feeling better.
And that way it can help inform a whole population of
patients to see whether or not it would also be beneficial for
them as well.
Mr. Curtis. Thank you.
I do not deny the logic of what you are saying, but the
sheer numbers of people who would like to try and do not have
access to what you have just described, I just want to leave a
marker that is something that we ought to be thoughtful about.
I firmly believe in the importance of our ingenuity and
innovation here in America, and we need to do all we can to
foster it.
Ms. Reed and Dr. Esham, how can we clearly or more
frequently engage with the agencies that show through
interactive meetings or RDA pilots for rare disease help bring
novel treatment to the market?
Ms. Reed. So I think from a biosimilars perspective, we are
working with the BsUFA III, but also have started working with
the agency on a best practice for communications. So I think
that is a great opportunity for industry.
But for members of the Congress, I, you know, encourage you
to continue dialogues with the agency and follow up to say how
is it going. Let's not wait every five years to find out how
user fee programs are going. Let's ask----
I apologize because my time has expired and, Doctor, thank
you for letting us pass on this. I am simply out of time.
And, Madam Chair, I yield my time.
Ms. Eshoo. OK. The gentleman yields back.
Boy, you sure made it under the wire.
[Laughter.]
Ms. Eshoo. Mr. Joyce, you are recognized for 5 minutes ,
and if we can do it in less time, it would be wonderful because
we have votes on.
Mr. Joyce. Thank you, Madam Chair.
And thank you to our distinguished panel for appearing here
today.
This is an incredibly important issue, the safe,
consistent, and prompt approval of pharmaceuticals, biologics,
generics, biosimilars is critical to our health of our
constituents.
I think I am going to go straight to the questions. What
has been the general experience with the FDA's use of remote
oversight tools?
Have these tools been effective? Do they facilitate
adequate review and approval?
Mr. Gaugh, I will ask you to start.
Ms. Reed. Yes, I will take that for biosimilars.
The FDA needs to improve its inspections of biosimilars. In
my testimony I mentioned that biosimilar inspections are not a
priority and not mission critical for the agency.
We have biosimilar applications and approvals that are
delayed for over a year because of COVID. We need to see the
agency prioritize biosimilars, use these remote tools, and use
their staff that are on site in developing or different
countries. They have people outside the U.S. that could help
facilitate the use of the remote tools and the remote
inspections. [Audio malfunction.]
Mr. Joyce. In my whole State of Pennsylvania, I have heard
from one company in particular, Nabriva Therapeutics, which has
faced these delays, and they are seeking to bring to market in
the United States a novel, first class therapeutic for the
treatment of complicated urinary tract infections.
And unfortunately, due to these delays the drug is not
approved in the United States.
Do you believe that there are steps that we can take to
improve this process, especially taking into consideration what
we have learned in COVID-19?
I will ask Dr. Esham.
Dr. Esham. OK. Happy to answer that question.
And I would say that, you know, we have long supported the
increased use of expanded tools in the toolbox to meet the
growing demands and complications of inspection activities.
The pandemic offered the opportunity of necessity to
collect a lot of learning about how we could more effectively
utilize more collaborations with foreign regulators, use of
digital tools, and record of use, again, to mitigate against
disruptions we were seeing during the pandemic.
I will note that it may be of interest in early 2021, BIO,
PhRMA, AM, and PBOA met with the FDA to share its collective
thinking about how we could utilize risk-based approaches for
inspections and things, record requests.
And in the PDUFA agreement there are steps being taken,
including the publication of guidance that we think will be
very beneficial in advancing that thinking and expanding that
toolbox.
Mr. Joyce. And, Doctor Esham, in conclusion in the face of
the time, that collaborative effort has to be so important.
Americans expect the innovation that we look for to treat our
patients.
I thank you, and I thank you, Madam Chair. I think we are
going to all make it in time to vote.
Ms. Eshoo. And the gentleman yields back.
So that concludes our second panel. To each one of the
witnesses, thank you. Thank you for your testimony. Thank you
for the work that you have done, as it all related to the
negotiations with the FDA to our purposes for us to move this
legislation forward, and we will.
And we thank you, again, for your participation today.
So we have documents to submit for the record. So I request
a unanimous consent to enter the documents into the record.
Mr. Guthrie. No objection.
Ms. Eshoo. No objections. That is wonderful.
Let's see. Without objection, so ordered.
[The information appears at the conclusion of the hearing.]
Ms. Eshoo. And I should remind members if anyone is paying
attention that they have ten business days to submit additional
questions for the record to the witnesses.
Please respond promptly to any questions that you receive
from members.
And at this time the subcommittee is adjourned.
[Whereupon, at 3:55 p.m., the subcommittee was adjourned.]
[Material submitted for inclusion in the record follows:]
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