[Senate Hearing 116-490]
[From the U.S. Government Publishing Office]
S. Hrg. 116-490
COVID 19 AND BEYOND:
OVERSIGHT OF THE FDA'S FOREIGN DRUG MANUFACTURING INSPECTION PROCESS
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HEARING
BEFORE THE
COMMITTEE ON FINANCE
UNITED STATES SENATE
ONE HUNDRED SIXTEENTH CONGRESS
SECOND SESSION
__________
JUNE 2, 2020
__________
[GRAPHIC NOT AVAILABLE IN TIFF FORMAT]
Printed for the use of the Committee on Finance
__________
U.S. GOVERNMENT PUBLISHING OFFICE
45-640 PDF WASHINGTON : 2021
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COMMITTEE ON FINANCE
CHUCK GRASSLEY, Iowa, Chairman
MIKE CRAPO, Idaho RON WYDEN, Oregon
PAT ROBERTS, Kansas DEBBIE STABENOW, Michigan
MICHAEL B. ENZI, Wyoming MARIA CANTWELL, Washington
JOHN CORNYN, Texas ROBERT MENENDEZ, New Jersey
JOHN THUNE, South Dakota THOMAS R. CARPER, Delaware
RICHARD BURR, North Carolina BENJAMIN L. CARDIN, Maryland
ROB PORTMAN, Ohio SHERROD BROWN, Ohio
PATRICK J. TOOMEY, Pennsylvania MICHAEL F. BENNET, Colorado
TIM SCOTT, South Carolina ROBERT P. CASEY, Jr., Pennsylvania
BILL CASSIDY, Louisiana MARK R. WARNER, Virginia
JAMES LANKFORD, Oklahoma SHELDON WHITEHOUSE, Rhode Island
STEVE DAINES, Montana MAGGIE HASSAN, New Hampshire
TODD YOUNG, Indiana CATHERINE CORTEZ MASTO, Nevada
BEN SASSE, Nebraska
Kolan Davis, Staff Director and Chief Counsel
Joshua Sheinkman, Democratic Staff Director
(ii)
C O N T E N T S
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OPENING STATEMENTS
Page
Grassley, Hon. Chuck, a U.S. Senator from Iowa, chairman,
Committee on Finance........................................... 1
Wyden, Hon. Ron, a U.S. Senator from Oregon...................... 3
ADMINISTRATION WITNESSES
Abdoo, Mark, Associate Commissioner for Global Policy and
Strategy, Food and Drug Administration, Department of Health
and Human Services, Silver Spring, MD.......................... 7
McMeekin, Judith, Pharm.D., Associate Commissioner for Regulatory
Affairs, Food and Drug Administration, Department of Health and
Human Services, Silver Spring, MD.............................. 8
Denigan-Macauley, Mary, Ph.D., Director, Health Care, Government
Accountability Office, Washington, DC.......................... 9
Throckmorton, Douglas C., M.D., Deputy Director for Regulatory
Programs, Center for Drug Evaluation and Research, Food and
Drug Administration, Department of Health and Human Services,
Silver Spring, MD.............................................. 11
ADDITIONAL WITNESSES
Light, David, founder and CEO, Valisure, New Haven, CT........... 40
VanTrieste, Martin, RPh, president and CEO, Civica, Inc., Lehi,
UT............................................................. 42
ALPHABETICAL LISTING AND APPENDIX MATERIAL
Abdoo, Mark:
Testimony.................................................... 7
Prepared statement........................................... 49
Responses to questions from committee members................ 62
Denigan-Macauley, Mary, Ph.D.:
Testimony.................................................... 9
Prepared statement........................................... 97
Responses to questions from committee members................ 114
Grassley, Hon. Chuck:
Opening statement............................................ 1
Prepared statement with attachments.......................... 120
Lever, Harry, M.D.:
Prepared statement........................................... 131
Light, David:
Testimony.................................................... 40
Prepared statement........................................... 132
Responses to questions from committee members................ 155
McMeekin, Judith, Pharm.D.:
Testimony.................................................... 8
Prepared statement........................................... 49
Responses to questions from committee members................ 62
Throckmorton, Douglas C., M.D.:
Testimony.................................................... 11
Prepared statement........................................... 49
Responses to questions from committee members................ 62
VanTrieste, Martin, RPh:
Testimony.................................................... 42
Prepared statement........................................... 162
Responses to questions from committee members................ 168
Wyden, Hon. Ron:
Opening statement............................................ 3
Prepared statement with attachments.......................... 172
Communications
Association for Accessible Medicines............................. 197
Kolchinsky, Peter, Ph.D.......................................... 208
Natural Products Association..................................... 214
Ohio State University, Fisher College of Business................ 216
TruTag Technologies, Inc......................................... 218
U.S. Pharmacopeia................................................ 219
COVID-19 AND BEYOND:
OVERSIGHT OF THE FDA'S FOREIGN DRUG
MANUFACTURING INSPECTION PROCESS
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TUESDAY, JUNE 2, 2020
U.S. Senate,
Committee on Finance,
Washington, DC.
The WebEx hearing was convened, pursuant to notice, at 2:30
p.m., in Room SD-106, Dirksen Senate Office Building, Hon.
Chuck Grassley (chairman of the committee) presiding.
Present: Senators Cornyn, Thune, Toomey, Cassidy, Daines,
Wyden, Stabenow, Menendez, Carper, Cardin, Brown, Whitehouse,
Bennet, Casey, Warner, Hassan, and Cortez Masto.
Also present: Republican staff: Joshua Flynn-Brown, Deputy
Chief Investigative Counsel; and Charles Pankenier, Detailee.
Democratic staff: David Berick, Chief Investigator; Peter
Gartrell, Investigator; and Joshua Sheinkman, Staff Director.
OPENING STATEMENT OF HON. CHUCK GRASSLEY, A U.S. SENATOR FROM
IOWA, CHAIRMAN, COMMITTEE ON FINANCE
The Chairman. Good afternoon, everybody. I want to welcome
everyone to the Finance Committee oversight hearing on Food and
Drug Administration's foreign drug manufacturing inspection
process. This committee has an obligation to ensure drugs paid
for by the taxpayers, whether it is Medicare or Medicaid,
satisfy quality standards and are safe and effective for
patients.
Second, besides taxpayer concerns, this committee has
jurisdiction over trade, and we have responsibilities to
guarantee only quality pharmaceuticals enter the United States.
That responsibility, both of Congress and the FDA, is
heightened now that we are living through the COVID pandemic.
Whether we are in the midst of a pandemic or not, these supply
chain issues must be shored up and solved.
Starting in June of last year, I began oversight activities
on this issue. I wrote letters at that time to Secretary Azar
and Acting FDA Commissioner Dr. Sharpless. I asked a series of
questions relating to manufacturing facilities overseas that
manufacture final dosages for drugs and active pharmaceutical
ingredients. And I am going to refer to ``active pharmaceutical
ingredients'' throughout the day as APIs. I also asked how the
Food and Drug Administration manages its foreign inspection
regime.
The Government Accountability Office has said that the FDA
does conduct some unannounced inspections overseas, but they do
not have data on the frequency. However, the Government
Accountability Office noted in 2019 that the FDA estimated that
they generally provided 12 weeks of notice before the
inspection.
So, simply said, FDA then is undermining the ability of
field inspectors to do their job. Twelve weeks, common sense
tells me, is plenty of time to doctor up a facility to make
sure that it passes inspection. Yet incredibly, some facilities
still get caught. That is how bad it is, and we have to do
something about it. The result is that the consumer is put at
risk.
According to the most recent FDA data, the United States
has 46 percent of finished dosage form facilities. That is
where API are turned into final form such as tablets. That
means over 50 percent of the sites manufacturing finished drugs
are located outside the United States. But that is just part of
the story.
What we really need to know is, where did the API come
from? According to the most recent FDA data, 13 percent comes
from China, 19 percent from India. Combined, that is more than
any other country. And overall then, more than 70 percent of
facilities that make APIs are located overseas.
These figures, coupled with the COVID pandemic, have
garnered a lot of attention, including what might need to be
done from a national security standpoint. But the figures do
not make clear what needs to be done from a drug safety
perspective.
We need to have a robust and aggressive foreign inspection
program. Now, with respect to China and India, both those
countries have had serious quality control problems. We all
remember the valsartan recall, where that drug was found to
contain contaminants used in rocket fuel. Facilities in China
and India produce that drug. We also should not forget Heparin,
and that is a scandal all by itself. In that case, patients
undergoing dialysis began to have severe and life-threatening
side effects because the manufacturing plant in China
introduced a toxin into the production chain.
Hundreds of people died, and hundreds were sickened. And
then we have Ranbaxy, an Indian manufacturer. Ranbaxy's
production chain exposed drugs to potential cross-contamination
by penicillin and used APIs from facilities that were not
approved by the FDA. That company also manufactured Lipitor and
was shut down because it could not explain why some of those
tablets had pieces of glass in them.
I fear these examples are just the tip of iceberg. They
show why the FDA must maintain an aggressive inspection machine
to ensure drug quality, but at the same time also impose a
strong enforcement regime on bad actors.
In February of this year, FDA Commissioner Hahn told me
that in Fiscal Year 2018 the Center for Drug Evaluation and
Research issued almost five times as many warning letters for
human drug manufacturers as compared to 2015. He said that is a
sign that FDA is better able to use its resources for
identifying problems.
Now that is very good: stay aggressive and do not hesitate
to be more aggressive. On the front end, though, that process
should include unannounced inspections overseas. After all, why
would we give manufacturers time to prepare their facilities
for inspection? They ought to be looking over their shoulder
every day. That would keep them honest.
During the Obama administration, we had what was called the
India Pilot Program. It allowed for no-warning inspections, or
a couple of days' worth of warning. Under it, the FDA issued a
60-percent increase in what are termed ``official action
indicated'' findings. In 2015, the Obama administration shut
the pilot program down, and I believe that there was no
explanation of why.
It sounds like the program was a victim of its own success.
Now, this issue is a very bipartisan issue. Republican and
Democrat administrations have come up short. The Government
Accountability Office has a body of work from multiple
administrations that proves that this is bipartisan. For
example, both the Obama and Trump administrations have
struggled to fill vacancies in foreign offices. So that brings
us to today, as what I have just said is what we found out from
over a year or more of investigations without a hearing.
Today we have witnesses from the FDA. They can speak to all
these issues and how the pandemic has impacted their work. On
the first panel we have FDA witnesses and a Government
Accountability witness. On the second panel, we have private-
sector companies.
So I thank all of you for being here. It is important to
note that I plan to follow up with another hearing soon
examining another problematic aspect for the medical supply
chain, specifically, the increase in trade of fake and faulty
personal protective equipment. That is separate from what we
will discuss today.
In closing, I want to say two things. First, thank you to
FDA officials who work tirelessly to inspect facilities
overseas. Second, regardless of party, we must have an honest
discussion of the government's shortcomings so that we can
better understand what we as Congress can do to ensure drug
safety for the taxpayers. After all, we work for them and must
always answer to them.
One thing before I introduce Ranking Member Wyden, and that
is simply to say that we have one more vote in a series that
started at 2:15. We will continue to go through that vote, and
we also have a vote at 4:30, and we will continue to go through
that vote.
[The prepared statement of Chairman Grassley appears in the
appendix.]
So, Senator Wyden, are you ready?
Senator Wyden. I am, Mr. Chairman. Would you like me to
proceed now?
The Chairman. Please do.
OPENING STATEMENT OF HON. RON WYDEN,
A U.S. SENATOR FROM OREGON
Senator Wyden. This afternoon, the Finance Committee is
holding its first meeting since March, focusing on the FDA's
failure to adequately inspect foreign drug manufacturers for
safety. In my view, the head of the FDA ought to be at this
hearing to face tough questions on this issue, but FDA
Commissioner Hahn is not with us today for one reason, and that
is because the Trump administration blocked his testimony. The
Trump administration did this to prevent the committee from
holding the point person for the FDA accountable.
I also asked for the committee to invite the journalist
Katherine Eban to testify, because she has literally written
the book on this issue. That also, unfortunately, has not
happened.
In lieu of that, I would ask unanimous consent to enter
into the record testimony and articles from Ms. Eban on this
subject.
The Chairman. Without objection, so ordered.
[The documents appear in the appendix beginning on p. 174.]
Senator Wyden. Thank you, Mr. Chairman.
While the committee meets for this hearing, COVID-19 is
ripping through nursing homes and killing thousands of
Americans each week. Unemployment is at near-Depression levels.
The kindling laid down over the centuries of racial injustice
was reignited by the murder of George Floyd. The President is
agitating for more violence and more escalation as our Nation
suffers.
The injustice driving peaceful protesters to the streets
over the last few days is woven throughout society. Since the
committee is dealing with health care in this hearing, I am
going to start my remarks with an immediate piece of urgently
needed health-care reform. COVID-19 has hit the African
American community harder than virtually any other group of
Americans. I would note, the recent analysis that was described
in The Washington Post showed that counties that are majority
black had three times the rate of infections and almost six
times the rate of deaths as counties where white residents are
in the majority.
The racial injustice status quo is simply immoral, with the
long terrible history of our health-care system working against
black people in America, from simply not listening when
symptoms are reported, up to performing cruel experiments on
black human beings. That is part of why COVID-19 is having such
an out-sized impact on the African American community. There is
a risk, for example, that when a COVID-19 vaccine becomes
available, vaccination rates in the African American community
may be lower because many in the community, for understandable
reasons, do not believe that American health care is really
looking out for them and is really going to give them a fair
shake.
So I want to make something very clear right now. This
committee has real muscle when it comes to Federal health-care
spending and doing something about what I just described. Two
trillion dollars in spending over flagship programs like
Medicare and Medicaid, the Affordable Care Act, and more are
inside the jurisdiction of the Finance Committee.
So today, in the beginning, I am calling on this committee
to come together and use all of that power and authority to
right the wrongs of the past that I have described this
afternoon. On our watch, colleagues, this just has to get done.
Now, as to the subject of today's hearing, I want to focus
on one specific example of the FDA and the President teaming up
to put Americans in danger. I want to talk about
hydroxychloroquine. Back in March, with the pandemic exploding
nationwide, far-right media began talking about using this old
malaria drug to treat COVID-19. The President seized on the
report, without any valid evidence, and spent weeks declaring
it to be the ultimate game changer in the fight against this
horrible pandemic. The FDA, in my view, bowed to pressure and
issued what's called an emergency use authorization for the
drug. Doing so throws open the doors to tens of millions of
pills, including some directly related to this hearing,
manufactured inside facilities in Pakistan and India that have
either failed FDA inspection or never been inspected by the FDA
at all.
Studies have now shown that the drug has no benefit for
COVID patients. In fact, it is actually linked to higher rates
of COVID-19 mortality. On April 24th, the Food and Drug
Administration warned against using the drug in COVID
treatment, and they said there were serious, I quote here,
``serious and potentially life-threatening heart rhythm
problems,'' unquote. The FDA says it still can be imported from
unapproved manufacturing facilities.
A recent article in The New England Journal of Medicine
said the episode posed, and I quote, ``fundamental threats to
the U.S. drug evaluation process.'' Mr. Chairman, without
objection, I would like to have that article from The New
England Journal of Medicine put into the record at this point.
The Chairman. Without objection, so ordered.
[The article appears in the appendix on p. 194.]
Senator Wyden. The fact is, lots of Americans take this
medication to treat other diseases, including lupus and
rheumatoid arthritis. It is prescribed by their doctors as part
of a valid treatment. They are counting on having a safe supply
of their medication, and it seems Donald Trump has pretty much
taken that away from them. He repeated a bunch of far-right
pundits touting junk science. Now the U.S. market is polluted
with tens of millions of hydroxychloroquine doses that may or
may not be safe. It is not clear that there is a system in
place to distinguish them from other stockpiles that came from
unapproved sources.
So if you are talking about FDA failures leading to greater
risk for Americans, hydroxychloroquine is the case in point.
There is also the botched roll-out of COVID-19 antibody tests.
There is the emergency use authorization for faulty K-95 masks
that pose a danger to health-care workers and first responders.
There is the fact that the number of FDA inspections for
foreign drug manufacturing facilities was already down under
the Trump administration.
Now on this committee, we know that there is bipartisan
interest in seeing improvements at the FDA. It makes sense for
us to build our drug manufacturing capacity in America.
However, the Trump administration just handed a big contract
for COVID-19 drug manufacturing to a company with no experience
in manufacturing drugs and no facilities in which to
manufacture them. That is not good enough in my view, Mr.
Chairman and colleagues. It is not a good enough plan to help
COVID patients who are suffering right now.
It also raises questions about how this administration
would handle a COVID-19 vaccine if and when a vaccine becomes
available. There is much to account for on this issue. The
Trump administration's continuing efforts to stonewall our
oversight by blocking Commissioner Hahn from answering our
questions today is preventing real, actual accountability.
Still, I want to make it clear to our witnesses who are
here with us, we thank them for doing so, and I look forward to
their testimony.
Thank you, Mr. Chairman.
[The prepared statement of Senator Wyden appears in the
appendix.]
The Chairman. One clarification. The Trump administration
did allow Commissioner Hahn to show, but we decided for the
purpose of the issues of this hearing, which deal with the
importation of some less-than-quality products from foreign
countries, that having additional FDA witnesses would fill a
very important gap in knowledge for our committee.
I am going to introduce Mark Abdoo, Associate Commissioner
for Global Policy and Strategy, providing executive oversight,
strategic leadership, and policy direction to FDA's global
operations, trade and diplomacy activity, and engagement with
international stakeholders. He leads the Office of Global
Policy and Strategy, which is comprised of the Office of
Diplomacy and Partnership, the Office of Global Operations, and
the Office of Trade, Mutual Recognition, and International
Arrangements--which are collectively dedicated to expanding the
reach of FDA's global agenda in sustainable and measurable
ways.
Judith McMeekin is Associate Commissioner for Regulatory
Affairs and has responsibility for 5,000 staff and operations
within the Office of Regulatory Affairs. The Office of
Regulatory Affairs is FDA's field force supporting FDA's
product center through responsibilities including inspections
and investigations, criminal investigations, compliance with
enforcement, import operations, regulatory science, and field
laboratory operations.
Dr. Douglas Throckmorton is Deputy Director of Regulatory
Programs at the Office of Drug Evaluation and Research. Dr.
Throckmorton is a board-certified physician. He carries the
responsibility for overseeing the regulation of research
development; manufacturing; marketing of prescription, over-
the-counter, and generic drugs in the United States; and
ensuring that the benefits of approved drugs outweigh their
known risks.
Dr. Mary Denigan-Macauley oversees the U.S. Government
Accountability Office's portfolio of audits on public health,
private health, and the markets associated with them, including
opioid issues. Mary joined GAO in 2001, managing a diverse
portfolio related to science, agricultural production, and
defense on GAO's Natural Resource and Environment team. This
work covered cross-cutting topics such as antibiotic
resistance, food safety, and emergency preparation.
As the witnesses know, we are under time restrictions at
the moment. And accordingly, the three FDA witnesses will try
to keep their opening statements to a combined 7\1/2\ minutes.
And then GAO will have the equal 7\1/2\ minutes.
We will begin with Mr. Abdoo.
Senator Wyden. Mr. Chairman?
The Chairman. Yes; go ahead.
Senator Wyden. If I could, just for a minute, with respect.
We still feel, for real accountability over all the issues we
are discussing today, you have got to have Dr. Hahn. And in
fact, all of the employees that you just described, we
certainly recognize their role at the FDA. They all report to
Dr. Hahn.
So, respectfully, we have a difference of opinion. I think
it is very unfortunate that he is not with us today, because he
is the person who is really accountable for the entire array of
issues we are discussing today, and I appreciate the chance to
respond briefly.
The Chairman. The only thing I would give back to you is
that these witnesses are the experts and cover the bases that
we are interested in for this hearing.
Mr. Abdoo, would you proceed, please?
STATEMENT OF MARK ABDOO, ASSOCIATE COMMISSIONER FOR GLOBAL
POLICY AND STRATEGY, FOOD AND DRUG ADMINISTRATION, DEPARTMENT
OF HEALTH AND HUMAN SERVICES, SILVER SPRING, MD
Mr. Abdoo. Chairman Grassley, Ranking Member Wyden, members
of the committee, I am Mark Abdoo, Associate Commissioner for
Global Policy and Strategy. As Chairman Grassley noted, I lead
the FDA's Office of Global Policy and Strategy by oversight,
leadership, and policy direction to our global operations in
trade, and diplomacy activities and engagement with
international stakeholders.
Thank you for the opportunity to discuss FDA's
international pharmaceutical oversight today. Over the past 30
years, pharmaceutical manufacturing has become increasingly a
global enterprise. Beginning in the 1970s, industry moved away
from the mainland United States, first to Puerto Rico in
response to tax incentives and then to Europe and nations that
were developing at the time such as China and India, which
offer significantly lower labor, energy, and transportation
costs.
Globalization presented substantial challenges to
regulatory oversight. FDA has responded with a comprehensive
strategy to facilitate greater coordination and oversight of
medical products. In addition to increasing foreign
inspections, our efforts have included the following:
developing new enforcement and regulatory tools; increasing
collaboration with foreign regulators and other stakeholders;
developing internationally harmonized standards and standard
convergence; educating foreign industry about FDA requirements;
and increasing transparency and accountability in the supply
chain.
Responsibility for addressing these global challenges is
distributed across the agency. My office serves as a focal
point for FDA-wide coordination and information-sharing and a
point of access to multilateral organizations, addresses issues
related to international trade of regulated products,
negotiates mutual recognition agreements, enters into
arrangements that facilitate foreign inspections and the
sharing of information with global regulatory counterparts, and
manages FDA's foreign offices around the world.
We have made progress in recent years in developing the
foreign base inspectorate; staffing at the foreign offices is
at historically high levels. Our foreign offices conduct
inspections, particularly unannounced for-cause inspections.
They also work with regulatory counterparts in-country, engage
in outreach education and training with industry associations,
promote good manufacturing practices including data integrity
and quality, and provide boots-on-the-ground data and analysis
to inform decision-making at FDA headquarters.
In recent years, we also completed the historic Mutual
Recognition Agreement between FDA and the European Union, which
is now beginning to yield benefits. The MRA enables FDA and EU
regulatory authorities to rely on information from routine drug
inspections conducted within each other's borders.
As implementation continues and more information is
exchanged, the MRA will help to further minimize duplication of
drug inspections, lower inspection costs, and permit us to
devote more resources to other parts of the world where there
may be greater risks.
We are deeply committed to leveraging all of our resources
to protect the reliability and availability of the drugs to
treat Americans.
Thank you again for the opportunity to be here today.
[The prepared statement of Mr. Abdoo appears in the
appendix.]
The Chairman. Dr. McMeekin?
STATEMENT OF JUDITH McMEEKIN, Pharm.D., ASSOCIATE COMMISSIONER
FOR REGULATORY AFFAIRS, FOOD AND DRUG ADMINISTRATION,
DEPARTMENT OF HEALTH AND HUMAN SERVICES, SILVER SPRING, MD
Dr. McMeekin. Chairman Grassley, Ranking Member Wyden, and
members of the committee, I am Judith McMeekin, Associate
Commissioner for Regulatory Affairs at the Food and Drug
Administration. Thank you for the opportunity to discuss FDA's
foreign drug inspection program.
Protecting public health is the FDA mission, and it is the
foundation of all of our work. Americans can be confident in
the quality of FDA-regulated products. Whether a drug or food
is produced in the United States or overseas, products must
undergo the same rigorous process, and the information must be
fully reviewed by our highly trained scientific staff.
The FDA inspects manufacturing facilities around the world.
As the products we regulate globalize, it is important for us
to modernize our policies and processes to ensure that
companies, regardless of where they are located, meet the FDA's
strict standards.
The FDA's drug inspection program shifted from one focused
heavily on the U.S.-based facilities through the early 2000s to
programs that, since 2015, have conducted more foreign than
domestic drug inspections. Consistent with domestic oversight,
the FDA's strategy for overseeing the safety of imported
products is to maximize the agency's public health impact by
aligning resource allocations to risk levels and tailoring the
use of regulatory tools accordingly.
In the foreign arena, the FDA does not draw upon the same
enforcement mechanisms or have a comparable level of
infrastructure. For example, if a domestic firm refuses
inspection, we are able to seek an inspection warrant. But we
do not have the same capacity in foreign countries. To
supplement our foreign oversight, the agency utilizes
additional tools to ensure the safety and efficacy of products,
including but not limited to import targeting systems; border
surveillance including import alerts, import certification, and
enhanced import screening to identify products for sampling;
and conducting foreign inspections.
The FDA optimizes our oversight of foreign manufacturers by
leveraging the work of partners with strong regulatory systems
and responsible parties in the supply chain. During the COVID-
19 pandemic, the FDA continues to utilize and implement
alternative inspection tools and approaches while postponing
foreign and domestic routine surveillance facility inspections.
This approach will continue, as conditions warrant, with
the exception of certain mission-critical inspections,
including preapproval and for-cause assignments. Importantly,
during this interim period, we are evaluating additional ways
to conduct our inspection work that would not jeopardize public
safety and protects both the firms and the FDA staff.
FDA is utilizing all available tools to oversee the safety
and quality of FDA-regulated products for all Americans.
Foreign inspections present the agency with unique challenges,
including the hiring and retention of qualified investigators.
I am committed to taking an assessment of our inspection
process and identifying opportunities for improvement, ways to
optimize and streamline processes using technology and
innovation, to be more efficient, and modernize our approach.
I welcome continued discussion with the committee and
others. Thank you again for the opportunity to be here today,
and I look forward to answering your questions.
[The prepared statement of Dr. McMeekin appears in the
appendix.]
The Chairman. Thank you very much. Now we call on Dr. Mary
Denigan-Macauley.
STATEMENT OF MARY DENIGAN-MACAULEY, Ph.D., DIRECTOR, HEALTH
CARE, GOVERNMENT ACCOUNTABILITY OFFICE, WASHINGTON, DC
Dr. Denigan-Macauley. Thank you, Chairman Grassley, Ranking
Member Wyden, and members of the committee, for the opportunity
to discuss our work on FDA's foreign drug inspection program.
The COVID-19 pandemic has called greater attention to the
United States' reliance on foreign drug manufacturers and
highlights the importance of a secure pharmaceutical supply
chain.
Like most drugs manufactured for the U.S. market, many that
are important for treating COVID-19 are manufactured overseas.
This includes antibiotics for secondary respiratory infections
and sedatives for ventilating patients. Today, the majority of
establishments manufacturing drugs are overseas. Americans must
have access to safe but effective drugs. However, we have had
longstanding concerns about FDA's ability to oversee the
increasingly global supply chain.
In 1998, we reported that FDA had significant problems
managing its foreign inspection data and conducted infrequent
inspections of foreign establishments compared to what they did
domestically. Since then, we have returned to the topic
multiple times and found that problems persist. In 2008 for
example, we determined that FDA data were not sufficient to
know how many foreign drug establishments were subject to
inspection. In addition, FDA continued to inspect relatively
few foreign establishments, and when it did, investigators
faced challenges that influenced how the inspections were
conducted.
For example, unlike in the U.S., where an establishment has
no notice that an investigator is coming, FDA routinely gave
foreign manufacturers significant notice. And FDA investigators
relied on English-speaking employees of the establishment that
they were inspecting to translate key documents, including
those demonstrating compliance with good manufacturing
practices.
In 2010, we found that while FDA was conducting more
inspections overseas, many establishments still had never been
inspected. We also identified shortcomings in the operations of
foreign offices FDA opened to provide the agency with in-
country information and inspection capability. In 2010 and
2016, we found that these offices faced persistently high
vacancy rates, raising questions about their effectiveness. As
a result of these and other challenges, we added FDA's
oversight of medical products to GAO's high-risk list.
Last December, we reported that from 2012 to 2016 FDA
increased the number of foreign inspections it conducted. And
in 2015, FDA had, for the first time, conducted more foreign
inspections than domestic. A growing percentage of these were
in China and India, which have the largest number of
establishments manufacturing drugs for the United States.
However, as Senator Grassley noted, we also found that FDA
still provided up to a 3-month advance notice for most foreign
inspections, which could give establishments a chance to fix
the problems before an investigator even arrives.
Investigators also continued to face persistent challenges
when they traveled overseas. As we learned on our site visits
to India and China, and in conversation with investigators, a
single investigator often had to inspect manufacturing campuses
covering hundreds of acres of land in rural areas. Most have
little flexibility to extend their time at a facility. Travel
schedules required back-to-back inspections.
FDA also continued to send inspectors into establishments
without translators. We were told this was particularly
difficult in Japan and China. Investigators also had to rely on
translators provided by the same drug manufacturer that they
were inspecting, raising questions about the accuracy of the
information. One investigator told us they had to resort to a
translation app on their phone. We also found that from 2016 to
2018 both foreign and domestic inspections had decreased. FDA
attributed the decline in part to continued vacancies among
investigators available to conduct these investigations.
While FDA has made progress over the years, these
persistent challenges raise questions about its ability to
conduct inspections overseas that are equivalent to those done
here in the United States. The pandemic has further complicated
the playing field. In March, as has already been noted, the
agency announced it had postponed nearly all inspections of
foreign manufacturing establishments. While FDA notes that it
has other tools to ensure the safety of the U.S. drug supply,
the lack of foreign inspections removes a critical source of
information about the quality of the drugs that are
manufactured for our U.S. market.
Further, it is unclear the effect COVID will have on FDA's
ability to fill those persistent vacancies, both in foreign
offices and among the U.S.-based inspectors who conduct most of
the inspections overseas. And it is unclear what the effect
will be on FDA's ability to gather that critical in-country
information to help determine, for example, which
establishments are at highest risk.
Thank you, Chairman Grassley, Ranking Member Wyden, and
members of the committee, for holding this hearing. This
concludes my prepared remarks. I am happy to respond to any
questions you may have.
[The prepared statement of Dr. Denigan-Macauley appears in
the appendix.]
Senator Cornyn [presiding]. Thank you for your testimony. I
see one of your credentials, Mary, is having taught at Sam
Houston State University, so it's good to have you as a witness
here today.
Dr. Denigan-Macauley. Thank you.
Senator Cornyn. Dr. Throckmorton will be the next witness.
He is the Deputy Director for Regulatory Programs, Center for
Drug Evaluation and Research, Food and Drug Administration. Dr.
Throckmorton?
STATEMENT OF DOUGLAS C. THROCKMORTON, M.D., DEPUTY DIRECTOR FOR
REGULATORY PROGRAMS, CENTER FOR DRUG EVALUATION AND RESEARCH,
FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES, SILVER SPRING, MD
Dr. Throckmorton. Chairman Grassley, Ranking Member Wyden,
and members of the committee, I am Dr. Douglas Throckmorton,
Deputy Director for Regulatory Programs at the Center for Drug
Evaluation and Research in the FDA. Thank you for inviting me
to participate in this important discussion. Protecting the
safety, quality, and availability for Americans is at the heart
of everything we do at the FDA. To accomplish this, we use
several tools.
Today's hearing is focused on inspections, which are one
important part of a robust, multipronged approach to overseeing
the safety and quality of FDA-regulated products. While
important, inspections are not the only impetus for drug
quality. First and foremost, the firms manufacturing these
products have the primary responsibility to reliably produce
quality products. Sponsors are required to comply with good
manufacturing practices to assure the identity, strength, and
purity of their products and to provide routine quality
testing.
CDER and FDA support this work by providing guidance to
them about best manufacturing practices, critically assessing
adverse events to spot manufacturing issues, actively
surveilling drug quality, and applying post-marketing study
requirements to identify and evaluate emerging drug safety
signals.
The goal of all of these efforts is to protect the public
health. We also partner with the FDA's ORA to maximize the
values of those inspections. Additionally, other safety
initiatives include proactive testing by FDA of selected
pharmaceutical ingredients and finished dosage-form drugs in
our state-of-the-art laboratories.
Only a small percentage, about 1 percent of drugs, that are
tested fail to meet the established quality specifications.
Additionally, the manufactured quality problems we do identify
are similar for both U.S. and foreign facilities. We also
collect data about safety and quality of the drugs once they
are on the market. And just this week, CDER released our fifth
annual report entitled ``Drug Safety Priorities: 2019''
detailing our key safety programs and activities, and
highlighting the depth and versatility of our drug safety
initiatives across CDER.
All these checks and rechecks are needed because much of
pharmaceutical manufacturing still operates with decades-old
approaches and technologies. CDER's vision is to spur the
industry to modernize so the quality can be consistently and
reliably built into each tablet or vial they produce. This
includes initiatives to encourage advanced manufacturing
technologies and quality management maturity. While time does
not permit me to go into detail, I would welcome the
opportunity to discuss these proactive strategies. CDER
believes they would yield important benefits for both quality
and safety.
Importantly, these advanced manufacturing techniques
provide a safer and more secure drug supply chain and may
promote a shift to more U.S. domestic pharmaceutical
manufacturing. I look forward to working with the committee to
protect the reliability and availability of drugs to treat
Americans, and to strengthen investments in modern
manufacturing technology.
Thank you, very much.
[The prepared statement of Dr. Throckmorton appears in the
appendix.]
Senator Cornyn. Thank you, Dr. Throckmorton. We will now go
to rounds of questioning. The chairman has gone to vote, so he
has asked me to chair in his absence.
I would like to change the topic just slightly, but it
seems to me if there is one thing that COVID-19 has taught us,
it is that we cannot rely on supply chains coming from outside
of our country. We have long become accustomed to being able to
buy cheaper products because they are manufactured in other
countries with the lower overhead, labor, and other costs, but
obviously this pandemic has demonstrated, at least to me, the
importance of on-
shoring a lot of our most basic functions--things like medical
equipment, things like drugs.
And I would just like to get the reaction of the witnesses.
Am I wrong? Do you think we are stuck with this dispersed
global supply chain that can be disrupted in the next pandemic?
Or do you think there are steps, as a matter of sound public
policy, that the Congress ought to consider in terms of
bringing that capacity for manufacturing back onshore?
So, Dr. McMeekin, would you care to take a stab at that?
Dr. McMeekin. Sure; thank you. American consumers should
know that the U.S. drug supply is safe and supply chains are
secure. The U.S. drug supply is among the safest in the world.
FDA thoroughly reviews drug applications to ensure that
medications are safe and effective before they reach the market
and oversees drug quality post-approval.
Senator Cornyn. Excuse me just a second. Did you say our
supply chains are secure?
Dr. McMeekin. Yes.
Senator Cornyn. How much of our active pharmaceutical
ingredients for our drugs in America depend on China?
Dr. McMeekin. I am going to refer to Doug. Doug, can you
add to the----
Senator Cornyn. And how much do we depend on India? Pardon
me. Dr. Throckmorton, go ahead.
Dr. Throckmorton. For active pharmaceutical ingredients,
the U.S. provides about 28 percent; China, about 13 percent;
and India, 18 percent.
Senator Cornyn. So I mean they are as secure as the supply
from China and from India is, at least for the percentage that
they contribute, but I seem to remember that there was at least
one instance during the pandemic where hydroxychloroquine was
being hoarded by one of the countries that ordinarily is a
source for that drug. Do I remember that incorrectly? Or do you
recall that?
Dr. McMeekin. We do have imports of products, and the FDA
uses additional tools to help complement our inspections,
including remote assessments of foreign manufacturing firms.
Senator Cornyn. I am sorry. I am not talking about
inspections now. I am sorry if I was not clear. I am just
talking about, in the midst of the next pandemic, what
percentage of the pharmaceuticals, the active pharmaceutical
ingredients that we depend upon in the United States, are
vulnerable, or are in jeopardy because that supply comes from a
country--let us say in this instance, where China obviously has
been the main source of personal protective equipment, but
after the virus broke out they obviously delayed notifying the
World Health Organization and other countries around the world
why they had hoarded personal protective equipment.
It seems to me the same thing could happen to our drug
supply. Am I wrong?
Dr. McMeekin. The foreign establishments and the domestic
establishments are held to the same standards. The standards
are the same, whether you are foreign or you are domestic. We
follow the same process to inspect them. We have the same
standards to inspect them, and they are held to the same high
standards of FDA requirements.
Senator Cornyn. So the percentage of the active
pharmaceutical ingredients that we get from China--if for some
reason China is either unwilling or unable to continue
supplying that, does that not strike you as a vulnerability for
the United States and our public health?
Dr. McMeekin. It would be good to have redundant systems.
Senator Cornyn. Do any of you care to venture what it is
that the U.S. Congress might do as a matter of sound public
policy to encourage more manufacturing of active pharmaceutical
ingredients here in the United States, as opposed to depending
on these supply chains overseas?
Dr. Throckmorton. Senator, I might take a stab at that one.
I will just echo what you said. We do need a robust, reliable
supply source for all of our drugs for the American public. No
question at all.
We do believe that there are things that we can do as a
country that would encourage additional on-shoring. As I
mentioned in my testimony, we believe that the advanced
manufacturing practices that U.S. firms currently employ put us
ahead of what is seen in the rest of the world. And to the
extent we could encourage and support the adoption of those, it
would reduce costs. We believe it would reduce environmental
impact by reducing the size of factories. It could potentially
improve the security by reducing the length of the supply
chain. And we believe there would be a good business case
potentially for drug firms to make to on-shore those factories
and bring them back to the U.S., with the net result that we
would see the additional redundancy and increased security that
you are rightly asking how to incentivize.
Senator Cornyn. Thank you, Dr. Throckmorton. This is beyond
the scope of really what this hearing is, but I could not pass
the opportunity to ask you those questions. I appreciate your
answer, and I trust that at some point the Finance Committee
and the Senate and the Congress as a whole will take up how to
reduce our vulnerability to the supply chains that we have seen
is a risk to our public health and our ability to deal with
risks like this pandemic, for the benefit of the American
people.
Thank you, Mr. Chairman. I will kick it back to you.
The Chairman. Thank you very much for taking over while I
voted.
I am going to start with Dr. McMeekin. The Government
Accountability Office has noted that almost all domestic
inspections are unannounced. However, the FDA often
preannounces foreign inspections. In some cases, FDA has
provided 12 weeks of notice before a foreign inspection.
Question number one: by providing advance warning, does it
not give bad actors time to hide the true nature of the
problems at their facilities?
Dr. McMeekin. So in general, domestic surveillance
inspections are almost always unannounced, whereas in foreign
establishments, generally we give notice of surveillance
inspections.
Given the importance of avoiding a potential refusal and
waste of ORA resources, most foreign inspections are
preannounced. And this preannouncement is intended to verify
that the facility is indeed a drug manufacturer with the
jurisdiction under the FDA. To facilitate the inspection
process and ensure appropriate reference, the personnel will be
made available.
We also announce foreign inspections due to the
jurisdictional differences between domestic and foreign firms.
The preannouncement process documents the foreign firm's
agreement to allow FDA to inspect.
When a foreign firm refuses an inspection, FDA takes a
different course of action than with a domestic refusal. In the
domestic arena, FDA can seek an inspection warrant to enter the
facility. However, in the foreign arena, due to the
jurisdictional differences, FDA can refuse products at the
border or not grant an approval. But FDA does not have the
authority to compel the firm to allow FDA to enter and inspect.
In mid-2019, we did initiate a change to our IT system to
actually record data of whether an inspection was announced or
unannounced. Efforts are underway to include a data field in
our inspectional database in the next version, scheduled for
this June, to accurately record whether an inspection is
announced or unannounced.
Having this accurate data will enable a critical evaluation
of the outcome of inspections. Although typically domestic
sites are not announced and foreign are typically preannounced,
we do conduct for-cause inspections in the foreign arena.
The Chairman. I want all three people to answer this. Do
any of you know why the Obama administration shut down the
India Pilot Program?
Mr. Abdoo. Thank you, Senator Grassley, for that question.
The India Pilot was not a true pilot. It was rolled out only in
one country. It had no metrics by which we could evaluate
whether it was a success or not. And it was collecting data
with inherent bias, in that we perform unannounced inspections
abroad on a for-cause basis, meaning that FDA had already
determined that those firms had significant problems.
We did, however, implement some best practices that we
determined were useful from the pilot program. First, we
stopped having firms issue letters so that we could get visas
for our investigators. Second, we stopped having firms make our
hotel selections for us. And third, and probably most
importantly, we began a program whereby the investigator going
out on the inspection received a preapproval briefing from his
colleagues or her colleagues at the ORA headquarters to improve
the efficiency and effectiveness of the inspection.
The Chairman. I asked all three of you to respond to that,
but because of time I want to ask Dr. Denigan-Macauley, would
unannounced foreign inspections improve FDA's ability to
oversee the drug supply chain? And if not, why not?
Dr. Denigan-Macauley. We do feel that unannounced
inspections are very important and, as was noted, some are
done, but they are very few, and it does raise questions about
the equivalency to what we do here in the United States.
The Chairman. And also to you, should FDA gain visibility
into the active pharmaceutical suppliers for final dosage form
facilities? Would that better help FDA oversee the supply
chain? And if not, why not?
Dr. Denigan-Macauley. So understanding the supply chain for
the active pharmaceutical ingredients is very important. It is
challenging. It is quite complex. Ingredients can come from
many different sources. And being able to enhance that
oversight and visibility into that supply chain would be
something that would be very valuable to understanding the
safety of the drug.
The Chairman. My time is up, so, Senator Wyden?
Senator Wyden. Let me start with you, Dr. Denigan-Macauley.
On March 28th of this year--so this is on the Trump
administration's watch--the FDA issued an emergency use
authorization allowing the acceptance and use of two malaria
drugs for the treatment of COVID-19 through the stockpile. One
source for these drugs which the FDA specifically allowed into
the United States was manufacturing plants in Pakistan. Rick
Bright, the HHS whistleblower, reported these plants had never
been inspected by the FDA.
Another source of the malaria drugs specifically allowed
into the United States by the FDA was an Indian company which
is on the FDA import alert list, and which has been prohibited
by the FDA from bringing these exact drugs into the United
States since 2015.
These are drugs that have long been known to carry cardiac
health risks. There was not any solid medical evidence that
they were effective in the treatment of COVID-19.
My first question to you, Dr. Denigan-Macauley, is, is it
dangerous to America to import and distribute drugs from India
that, up until a few days ago, could not come into our country
because they were on the import alert list? I hope we could get
a ``yes'' or ``no'' answer to that question.
Dr. Denigan-Macauley. Yes; we would have concerns and hope
that it is a science-based decision.
Senator Wyden. Is it dangerous to Americans to import and
distribute drugs from facilities in Pakistan that have never
been inspected? A ``yes'' or ``no,'' please.
Dr. Denigan-Macauley. Yes; dangerous from any country not
inspected.
Senator Wyden. Dr. Rick Bright, the former head of BARDA,
is now a whistleblower and has said that the FDA process for
approving the drugs was not based on science, it was based on
politics.
So let me ask you--because we are not going to get you into
politics here--is that how the process is supposed to work?
What I have described, is that the way things are supposed to
traditionally play out so as to protect the public interest?
Dr. Denigan-Macauley. It should be based on science.
Senator Wyden. No, but I just described to you the process.
Is the process that I described the way things are supposed to
work?
Dr. Denigan-Macauley. We have not looked extensively into
that, and we have ongoing work looking at emergency use
authorizations, and we would be happy to address that issue
once we have looked carefully to ensure that that was the
process used.
Senator Wyden. So you are going to look at whether this
process I have described sounds like the traditional process
that is based on science? Because Rick Bright, the
whistleblower, has said this does not resemble science, and I
just asked you about whether the processes were dangerous, and
you told me ``yes.'' So it is kind of hard to see how something
that is dangerous by your words is somehow in line with the
process, but we will wait and see about your follow-up inquiry.
Now one of the problems created by efforts by the President
to talk up the dubious nature of these malaria drugs is that it
has created shortages of the drug for Americans who rely on
them for illnesses unrelated to COVID-19. How can those
Americans be sure that the drugs they depend on are safe, when
drugs that we know are not inspected by the FDA are coming into
the country?
Dr. Denigan-Macauley. So there is no country-of-origin
labeling. So as a consumer, you would not know if that came
from Pakistan or from an uninspected or inspected facility.
Senator Wyden. Okay, so that is yet another factor in
raising concern about how all these practices that we are
talking about from March and the following weeks--on the Trump
administration's watch--represent real danger, and I appreciate
your laying that out. And that is why I have, frankly, already
gone through it with the chairman. If you want to get stuff
changed, you have to have the person here who can actually
change matters. And that is why we felt so strongly about it.
One last question, if I might, for you, Dr. Denigan-
Macauley. The U.S. has found itself horribly short of medical
supplies. A search for N-95 respirators and PPE has been a
nightmare for my State for weeks. After Oregon bought
respirators that the FDA had authorized for import from China,
under an emergency use authorization, the FDA then removed them
from the approved list. At the same time, companies that Oregon
had been trying to get EUA approval for to make respirators had
been unable to do so.
How does it make sense that manufacturers of substandard
equipment from China get an FDA emergency okay to ship to
America, and manufacturers in the United States and my State
that want to make those same products get put on hold? How does
that make sense?
Dr. Denigan-Macauley. I do not have an answer for you. FDA
does have oversight over these medical devices. It is a
decision that FDA alone makes with that authority, and in
coordination with the task force, so FEMA and DoD in support of
FDA.
Senator Wyden. I just hope we can get that changed. Because
to me, it defies common sense that respirator manufacturers in
China can get an emergency authorization and manufacturers in
the United States cannot get a call returned. That means
something is really out of whack. Again, the person who is
accountable at the agency for changing the kinds of problems we
have is not here. And that is why I felt so strongly about
making it clear that we think we are not going to get to the
bottom of it until we hear from him.
Thank you again, Mr. Chairman.
The Chairman. Thank you. The next person on a first-come-
first-served basis would be Mr. Toomey. I will wait a couple of
seconds.
Senator Toomey. Mr. Chairman, can you hear me?
The Chairman. Yes, I can hear you. Go ahead.
Senator Toomey. Thank you very much.
I want to go back to the line of questioning that Senator
Cornyn was pursuing. Dr. Throckmorton, back in March the FDA
Commissioner identified 20 drugs out of the over 20,000 drugs
that are available in the United States--20 he identified as
being solely made in China or containing an API that was solely
sourced from China. Further, I believe that in this report it
was determined that none of these drugs were considered
critical drugs. And I think the criteria for being ``critical''
is a drug for which there is no available substitute.
So first of all, is that your understanding of the extent
of dependence on China as a source of drugs and API? Because
certainly that makes it sound as though there is not a great
deal of reliance on Chinese sources for critical drugs. Is that
your understanding?
Dr. Throckmorton. Senator, let me answer your question by
going back to where we found ourselves in March and the
situation we needed to respond to.
So, as we typically respond to an increase in need for a
drug, we see drug shortages occur. When drug shortages occur, I
have a staff whose sole job, 24/7, is to reach out to
manufacturers, look at API manufacturers, identify possible
sources for those products.
So when go back to March, what we found ourselves in was a
situation where we were looking to identify the products that
were essential, and which products were not as essential for
the immediate response to COVID. That drug shortage team, along
with other offices, went to work looking at the available
products. Where were they made? What products were available?
And the shortest answer to your question is, yes, you are
right. China had a small footprint as far as the creation of
manufacturing of those drugs. Having----
Senator Toomey. Well, can I just get a clarification here,
Doctor? Are you saying that this report, these 20 drugs that
were identified, these are just within the universe of drugs
that are for the purpose of treating COVID-19, or is it broader
than that?
Dr. Throckmorton. A great question, and I apologize if I
was not clear. Definitely broader than that. And again, it
starts with where we found ourselves in March. We knew less
than we do now about the impact of COVID, much less than we
know now about the specific drugs that are needed. And so our
focus was on products that we knew were historically in
shortage, products that we anticipated were likely to be needed
in hospitals.
As we learned more, we responded in----
Senator Toomey. Yes; my question is focusing much more
broadly than just on COVID-19. I want to understand. The
American public has an understandable concern about whether or
not, and to what extent, we could be reliant on any one
country, and most of all an adversarial country, for something
as important as life-
saving medicines. But it sounds to me like, from this March
report, the FDA's conclusion is that there are no drugs that
are considered critical drugs--in other words, drugs for which
there is no substitute--on which we rely on China, and less
than one-tenth of 1 percent of all drugs are sole-sourced from
China or contain an API that is solely sourced from China.
Do I have the basic facts correct?
Dr. Throckmorton. I will have to get back to you about the
basic facts. I do not want to mislead you about that. But I do
want to agree with your focus on the larger issue of total
availability. Whether a product comes from a specific country
or not, it is important--I am not minimizing that. But it is
more important for me as a U.S. Federal drug official to make
sure the drug is available from somewhere to meet the needs of
the American public.
So if it is China, or it is France, or it is whatever, is
of interest, but I am even more interested in knowing the total
available market. Can it meet the needs of the U.S. or not? If
it can, and it is done to high quality, then that is the piece
that I am going to want to stay focused on.
Senator Toomey. So we have, certainly in my State of
Pennsylvania, we have heard from health-care providers,
hospitals, and pharmacies about shortages of drugs that they
wanted to be able to administer, and much of which were related
to COVID treatment. It was pain medicine. It was antibiotics.
It was inhalers. It was a variety of medicines. And there were
shortages.
So could you characterize the source? Is it just because
there was a sudden spike in demand, because suddenly we had a
lot of people with COVID-19? Or were there other factors
contributing to these shortages?
Dr. Throckmorton. That is a terrific question. The short
answer is, we do not know all of the factors that led to that,
whether it was distribution challenges with particular
hospitals, or whether it was solely related to isolated demand
in particular areas. There were different factors that drove
spot shortages that were extremely serious.
So where I started before was to say, we focused on the
larger market. And that has been our short goal. With COVID, we
had to start worrying about your hospitals in Pennsylvania----
Senator Toomey. And just as my last--I am probably out of
time--just a last quick, final question. Are you aware of any
case where a source of these medicines from overseas, the
country or the manufacturer overseas, decided for whatever
reason not to distribute to the United States medicines that
they normally would have? Was there a conscious decision to
withhold medicines that American consumers needed?
Dr. Throckmorton. I am not aware of any case where the
country carried through on that--that threat to withhold
medicines; no.
Senator Toomey. Okay; thank you very much, Mr. Chairman.
The Chairman. You bet. Senator Stabenow?
Senator Stabenow. Yes; thank you very much. Thank you, Mr.
Chairman and Ranking Member Wyden. And I certainly agree that
the FDA should increase inspections to make sure that drugs we
rely on are safe and effective.
I do think it is important to note that the current budget,
that is the Trump administration budget for 2021, actually
froze the number of field staff for human drug and biologic
safety programs, which is of great concern to the public. And
they actually called for budget cuts. So we certainly need to
make sure we are not doing that.
This is obviously an important topic. At the moment,
though, we are looking at over 100,000 people having lost their
lives in the United States because of COVID-19, over 5,000
people in Michigan alone. And we have an urgent, urgent need to
address this major health-care pandemic, and be very much
focused on it. And now, on top of everything else, we have
another huge urgent issue, which is what is happening in terms
of African Americans in this country. And not only racial
disparities on display because of COVID-19, but also what we
are seeing now as a result of the horrific murder of George
Floyd.
The violence to African Americans has gone on too often and
for way, way too long. And it is all interconnected. The
reality is that racism is a human rights issue, but it is also
a health issue. And I think that is playing out in COVID-19,
where 14 percent of Michiganders are African American, yet over
40 percent of the deaths are African Americans, because of
health disparities. So this is a huge issue. So we have all got
to come together and bring accountability and change to the
country, and I hope we will do that.
My colleagues have talked a couple of times about what we
need to do in terms of bringing pharmaceutical drugs, bringing
the needed medicine back to the United States. I could not
agree more that we need to do that. I do want to point out,
though, that in the legislation that was passed by Republicans
in 2017, there were trillions of dollars in cuts and billions
of dollars to the pharmaceutical industry, but nothing to
incentivize or require the companies either to lower the cost
of prescription drugs or to bring the jobs back and the
medicines back to the United States.
In fact, the structure of the global minimum tax, the GILTI
tax provision, exempts the first 10 percent of income from
physical assets, factories and so on, in foreign countries,
which creates an incentive to off-shore assets to increase the
exemptions. So we could start by getting rid of that and then
focus on what we need to do here in the United States.
Let me ask a question related to specifically the FDA,
where I have great concern, and the people in Michigan do,
about the politics that have been projected to the FDA.
We need the FDA to be based on science and to be making
decisions that are in the best interest of all of us, our
safety, and the right thing to do based on science. We all know
now about the President's talking and now saying he took
hydroxychloroquine. And in fact the FDA provided emergency use
authorization for the drug on March 28th, and now on your
website you indicate that there is no evidence the drug treats
COVID-19 and in fact could actually cause loss of life. But the
emergency use authorization waived the Current Good
Manufacturing Practices, or they talked about today allowing
the drug to be imported from uninspected foreign manufacturing
facilities.
Is that correct? Just ``yes'' or ``no''?
Dr. Throckmorton. I cannot answer that. I will ask my
colleague, Dr. McMeekin.
Dr. McMeekin. FDA has inspected manufacturers of
hydroxychloroquine, and as recently as April 2020, an
inspection of an alternative manufacturer was actually
conducted by our local office.
Senator Stabenow. Do you share these concerns about Rick
Bright, who was talking about the safety issues around this,
you and your colleagues--you know, the whole question of the
safety around this particular drug?
The Chairman. Can you give a short answer to that so we can
go on to the next member?
Dr. McMeekin. I have not had those discussions. Dr.
Throckmorton?
[Pause.]
Senator Stabenow. Thank you, Mr. Chairman. I am out of
time, but I would just say that people are deeply, deeply
concerned. We want to be able to trust the integrity of the
FDA, and with the politics and things that have been happening,
it is deeply concerning.
The Chairman. Thank you. Senator Sasse is next.
[No response.]
The Chairman. Okay, then Senator Cantwell.
[No response.]
The Chairman. Okay, then Senator Menendez.
Senator Menendez. Thank you, Mr. Chairman.
The Chairman. Go ahead, Senator Menendez.
Senator Menendez. Thank you, Mr. Chairman.
President Trump announced last Friday that the United
States would terminate its relationship with the World Health
Organization, terminating our relationship with the world
premier global health organization. The administration is
abdicating, in my view, the U.S.'s long-held leadership role on
health on the world stage, a role that China will be eager to
fill. This decision also undermines the safety of Americans. We
know that if we do not work in partnership with the WHO and the
international community to combat COVID-19 everywhere, all
Americans will remain at risk.
So, Mr. Abdoo, beyond its urgent work on COVID-19, WHO is
also the central entity to the fight against other major health
threats that matter to Americans. The bulk of U.S. funds to WHO
helps saves lives, gives hope to populations around the world
facing diseases like polio, malaria, measles, tuberculosis,
HIV/AIDs, including in humanitarian hot spots like Yemen, the
Democratic Republic of Congo, where agencies and NGOs are
unwilling to work.
How does the administration intend to address these needs?
What is the plan?
Mr. Abdoo. Thank you for that question, Senator Menendez. I
am not familiar with those discussions and would refer you to
the National Security Council or the presidential spokesperson.
Senator Menendez. So you have no idea on these issues
relating to the World Health Organization?
Mr. Abdoo. As I said, I have not been privy to those
conversations.
Senator Menendez. Pretty amazing.
Dr. Throckmorton, on April 8th I sent a letter with
Representative Pascrell to Dr. Hahn to express concerns about
the FDA's emergency use authorization approval process during
the ongoing COVID-19 pandemic, and in particular the fast-
tracking of approvals for potential treatments promoted by
various administration officials, including the President.
The FDA is the gold standard worldwide for drug and device
approval, and I believe it is important to ensure that nothing,
especially pressure from the White House, erodes that public
trust in the FDA.
Can you confirm for the committee that the FDA did not
change its protocols for EUA approvals during this pandemic, in
specific to approvals for hydroxychloroquine or chloroquine?
Dr. Throckmorton. Senator, I was not privy to all of the
discussions that led up to the EUA authorizations. I can tell
you I am aware of no instance of political influence on any of
the decision-making.
Senator Menendez. But the question is, did the FDA--can you
confirm that the FDA did not change its protocols for EUA
approvals during the pandemic?
Dr. Throckmorton. The approach, as far as I am aware, was
the same as the approach that we have taken in past emergency
use authorizations.
Senator Menendez. Well then, explain to the committee how
is it that the FDA issued emergency approval of
hydroxychloroquine and chloroquine to treat COVID-19, despite
the fact that there was no adequate and well-controlled trial
demonstrating safety and efficacy for COVID-19 patients?
Dr. Throckmorton. I think what I would rather do is refer
you to the materials that are available on our website that lay
out, in general ways, the types of information that we had at
the time that we approved the emergency use authorization.
There were data available, and a decision was made at that
period of time in support of the emergency use authorization. I
should say, we continue to collect additional information,
continue to reevaluate as additional data become available.
That led to the drug safety communication----
Senator Menendez. If you want to refer me to documents, I
do not need to have a hearing. I have you at a hearing. At the
end of the day, there were former FDA officials who questioned
the EUA, noting the lack of scientific evidence; and sure
enough, researchers are raising concerns about
hydroxychloroquine. Just this week, the WHO halted its trial of
hydroxychloroquine due to harmful side effects, including heart
problems.
So you know, we should have Commissioner Hahn, then, come
to explain this discrepancy.
Dr. Denigan-Macauley, given that we are likely to see
additional global spikes in cases during the pandemic, what
specific steps should the FDA take to ensure continued
oversight of foreign manufacturers, and also to ensure the
safety of their inspectors?
Dr. Denigan-Macauley. Thank you; yes, it is important that
the inspectors have their safety taken into consideration. So I
can certainly understand what FDA is doing on that end.
It is important, though, that the decisions be made on
science, and that they continue to get the critical information
that they need to know what establishments may be at risk. And
so, for example, with the EUA, the emergency use authorization,
we do have work beginning that is going to look at that, to
look at the decision-making, and look to see if any criteria
had changed. We have previously reported that you need to
maintain criteria when you take a drastic step like that,
allowing an importer who is banned to be able to have a drug
like hydroxychloroquine come into the United States.
So they need to be diligent. And while we are in an
emergency, they still need to be very careful in moving quickly
during this unprecedented time, to ensure that they follow the
steps they have put in place for the safety of our drugs.
The Chairman. Is Senator Sasse ready?
[No response.]
The Chairman. Is Senator Cantwell ready?
[No response.]
The Chairman. Okay, Senator Carper.
Senator Carper. Senator Carper is ready.
The Chairman. Go ahead.
Senator Carper. Mr. Chairman, thank you for the hearing,
you and Senator Wyden, our ranking member. Thank you to our
witnesses, especially the one who I think was an undergraduate
at the University of Delaware in animal science a few years
ago. We are happy to welcome especially Mary Denigan-Macauley,
and we ask you guys at GAO to pass on our sincere appreciation
for the work that you do every day for our country.
Dr. Denigan-Macauley. Thank you.
Senator Carper. You are welcome, and we thank you.
Before I ask a question or two of our witnesses, I want to
make some brief comments. Racial disparities in this country of
ours are rampant, and the COVID-19 pandemic is only
exacerbating some of those issues, as we know.
People of color are less likely to work at jobs that would
allow them to work from home. In addition to having increased
exposure to the virus, people of color have lower access to
health insurance, healthy foods, thus increasing the likelihood
of a pre-existing health condition. These issues, paired with
many others such as economic inequities, make people of color
disproportionately more likely to contract COVID-19 and die
from it. Nearly 23 percent of the 100,000 COVID-19 deaths in
the U.S. are African Americans, while they only make up about
13 percent of the American population. Hispanics and Latinos
make up 4 percent of the U.S. population, but make up 11
percent of cases.
With the recent killing of George Floyd at the hands of
police officers, we are seeing yet again another form of
devastating effects on communities of color, and particularly
black Americans. Americans across the country are feeling deep
pain and devastation, and they are grieving the loss of loved
ones to COVID-19, and the loss of George Floyd. We can do
better than this. We must do better than this.
The first question I have is for Mary, and I would expect
the GAO--it is kind of a two-part question. Does GAO have any
work examining racial and ethnic disparities in health care
that would speak to important issues to consider in light of
the response to COVID-19?
Dr. Denigan-Macauley. We do. We do. We have work that we
will begin, looking at the disparities for COVID, specifically
for the reasons that you mentioned. And it will be very
important to see the results of that work.
We also issued a report recently--I believe it was in April
of this year--on maternal mortality. And you see the same
disparities there that we are seeing here, with Native Alaskans
and Hispanics and black women dying more frequently of maternal
mortality-
related deaths than other ethnicities in the United States. So
it is very concerning. And it is important too that, as we go
forward with COVID, that we look not only at the data, but how
we are collecting it, and that we look at how we are reporting
it.
Because one of the findings that we made about maternal
mortality was that the data that was being collected was very
difficult to get--real-time data--and to get it out there in
time to make it useful for the researchers. Sometimes it lagged
as much as 3 years.
So during this pandemic, right now we need data more
quickly than that. So hopefully the CDC, I am sure, is taking
that under consideration for lessons learned going forward with
COVID.
Senator Carper. Thank you for that response. Let me ask a
follow-up question. Does GAO have any work examining the
collection of health-care data that raises issues important to
the COVID-19 responses, based on what you just said?
Dr. Denigan-Macauley. Yes. Well, I think number one is
ensuring that those data can be collected in a way that can be
collated, and ensuring that the States are doing it equally. As
you noted, data is collected at a local level, and then it is
rolled up. And so that would be very important. Our past work
has shown that it needs to be collected in a way that it can be
standardized and equal across all of the States.
Senator Carper. Thank you. And a question to be shared by
Dr. McMeekin and Dr. Throckmorton. What are you and your
colleagues doing to ensure that the rules of the road for
COVID-19 tests and PPE manufacturers are clear and consistent
and stable enough to ensure that we, as a country, can produce
and procure a sufficient and high-quality supply of tests and
PPE?
Dr. McMeekin?
Dr. McMeekin. So we would continue with our tools to help
as these products are imported in. We have additional tools to
complement the inspection; we utilize and import screening
tools that predict where we can adjust based upon different
devices or different products. We also conduct physical
examinations of product samples, and we will continue that
effort.
Senator Carper. Dr. Throckmorton, do you have anything to
add?
Dr. Throckmorton. I do not have anything to add. The
devices are regulated in a different center. Our major
interactions center around the shortage groups. We have been
trying to share whatever shortage information we could obtain
with that group around PPE to make sure they had that.
Senator Carper. Thank you, Mr. Chairman.
Charles Throckmorton, who was a Marine--I understand he is
a Lieutenant Colonel now--was an attache in our office for a
year or two. And he is about to go back to Dover Air Force Base
and is doing great work for our country. I just want to say, he
reflects well on the Throckmorton family.
The Chairman. Before I call on the next Senator, without
objection, I want to put in the record letters of oversight
that I sent to HHS and FDA, regarding their foreign inspection
regime. Those letters were sent on June the 27th, 2019. And on
August the 6th, 2019, I sent a second oversight letter to HHS
and FDA. We received responses to both, including thousands of
pages of records, and these letters will be inserted in the
record without objection.
[The letters appear in the appendix beginning on p. 74.]
The Chairman. Now I will go to Senator Sasse.
[No response.]
The Chairman. Is Senator Cantwell ready?
[No response.]
The Chairman. Then is Senator Cardin ready?
Senator Cardin. I am here, Mr. Chairman; thank you.
The Chairman. Go ahead.
Senator Cardin. Thank you, Mr. Chairman, and let me thank
all of our witnesses. I want to ask a question to Dr.
Throckmorton as it relates to the supply chain issue and the
shortages of drugs.
We recognize that COVID-19 makes life more challenging in
regards to the supply chain, and we want to make sure that the
supply chain is safe. We also want to make sure that, to the
extent possible, we have our domestic supplies and we do not
have that risk factor.
But before COVID-19, we found drug shortages in the United
States, not because of foreign sources, but because it just was
not as profitable for drug companies to manufacture particular
drugs than other drugs. And in cases where there was a single
U.S. source for those drugs--and I am talking about important
drugs dealing with infant safety, dealing with cancer
maintenance treatments, dealing with diabetes--we had a
shortage in the domestic supply because of the economics
involved.
Now, we are going to do some bills to try to do something
about it, but does the FDA have a strategy to make sure that we
do not have drug shortages in this country? Even when there are
adequate supply chain issues, it is more the economics of the
private drug manufacturer deciding not to make enough of that
drug available to the population.
Dr. Throckmorton. Senator Cardin, you raise an incredibly
important point. COVID basically superimposes new demands on
the drug supply on top of existing drug shortage demands.
So we started with a situation where we were challenged for
many critically important drugs, and then COVID hit us. And now
we have a sort of additional challenge. Yes, I believe there
are things that we can do to address economic disincentives
that are leading to choices made by manufacturers either to
leave the market or to seek less-expensive places for
manufacturing.
We put out a drug shortage report, as I know you are aware,
last fall. And it laid out some of the solutions that we
believe are important. One critically important one I am very
fond of, that I talk about now, is the quality management
maturity. The idea is that if we can find a way to improve the
transparency about the quality of the drug supply chain,
purchasers could make better choices about what products to
choose to pay just a little bit more for to be assured that
they were high-quality. Quality management maturity, we
believe, would help lead the way to get that kind of
transparency by, at least in part, giving us the ability to set
up a rating system to identify products that were manufactured
to very high quality, higher than just meeting the minimum
standards, and that would allow manufacturers to advertise that
they have received that rating, with the hope that they then
would be paid just that little extra more so that they could
make the choice to manufacture the product instead of the
choice to leave the market.
As you point out, prices for generic drugs continue to
fall, despite their being difficult to obtain. We need to find
a way to change that economic incentive, if we can.
Senator Cardin. I appreciate that answer, and I am all for
providing financial incentives so that less-expensive drugs do
not go into drug shortage. Count me as a supporter of that.
We have been talking about some of these drugs now for a
couple of years, and there is still a shortage. It seems to me
we may have to look for an additional supplier of that drug, in
addition to the drug company that currently manufactures that
product.
So I hope that we would look at broader ways, because
allowing these shortages to continue in the wealthiest nation
in the world is just ridiculous. And there is no supply issue.
It is just price incentive to the manufacturer of the drug, and
we should be able to overcome that together. I would hope that
you would work with us and help us figure out a way to bring
this to an end.
Dr. Throckmorton. I would be delighted to do that, sir.
Senator Cardin. Thank you, Mr. Chairman.
The Chairman. You bet. And now I am going to go back to the
top of the list to Senator Cantwell. And if she is not
answering, Senator Brown would be next.
Senator Brown. Thank you, Mr. Chairman.
Dr. Throckmorton, does the FDA have the authority to
require mandatory recall of a prescription drug? It seems to me
that mandatory recall authority could help expedite FDA's
ability to pull an adulterated product or harmful drug from the
market. Do you agree?
Dr. Throckmorton. Senator, we do not have mandatory recall
authority. Having said that, the vast majority of the time when
we do request a recall by a company, they do it. It is only the
rare case where people have pushed back against the need for
that recall. But we would be happy to talk with you about that.
Senator Brown. Okay; we would like to pursue that. And we
will follow up with congressional affairs at FDA, because we
would like to work on that.
I want to raise one other issue and then make a brief
statement--the issue of active pharmaceutical ingredients. Last
year in front of the Energy and Commerce Committee, Dr.
Woodcock testified there is a gap in FDA authority as it
relates to APIs and reporting requirements when it comes to
over-the-counter medications.
Dr. Throckmorton, can you speak a little more about these
gaps, why they are problematic, and if the FDA is interested in
working with Congress in filling these gaps in authority?
Dr. Throckmorton. I would be happy to talk in general terms
about those gaps. I will begin by saying I think we are in very
similar circumstances to where we were when Dr. Woodcock
testified. So I believe the same issue still exists, which is
that for those kinds of products, those APIs used for
compounding and certain over-the-counter products, they can
give them to Americans without inspections being required by
the manufacturers.
Now, we do sometimes inspect those facilities, as you know.
There are other ways for us to do that. But there is no
requirement for it. We think that is a loophole. Dr. Woodcock
called it a loophole. We would be happy to work with you on
that.
Senator Brown. Okay; we will pursue that.
Mr. Chairman and Ranking Member Wyden, I try not to indulge
too often in the Senate's penchant for grandstanding. I try to
work with colleagues in both parties, bringing substantive
questions, especially in this committee. But I am astounded by
the topic of this hearing.
Our country is in crisis. People are dying of a disease
that continues to spread, particularly among seniors,
particularly among black and brown workers who are keeping our
society afloat, the essential workers who are, frankly,
expendable. They are not paid well. They are not protected in
the workplace.
Black Americans continue to die at the hands of the very
people who are supposed to protect them. The President refuses
to lead. My Senate Republican colleagues refuse to stand up and
speak out about it. We should be the people to fill that
presidential void. I share this chairman's concern over the
weaknesses in our drug supply chain, but we serve in the most
powerful committee in the Senate.
This is the Finance Committee's first hearing since the
onset of the pandemic and since the murders of Mr. Floyd and
Ms. Taylor. And I said this morning in our Banking Committee
hearing, not everything is about money. But that is what this
committee has power over, and it can make a whole lot of
difference to a whole lot of people.
We have power over unemployment insurance taxes, programs
like Medicare and Medicaid, CHIP, the Affordable Care Act. We
ought to be using that power to help the people who make the
country work, and show Americans, all Americans, including our
black and brown sisters and brothers, that their government is
actually on their side.
We could be putting more money directly in those Americans'
pockets, instead of trusting that it will trickle down from
corporations, because, Mr. Chairman--I know Senator Wyden knows
this, and I think you do, Mr. Chairman--it does not trickle
down.
We can be discussing safety standards for nursing homes;
30,000 seniors have lost their lives to this illness. Thousands
of workers, largely women, many people of color, are putting
their own health care at risk for loved ones, and we are doing
a hearing on this instead?
Instead, Chairman Grassley has chosen to hold a hearing on
a topic outside our jurisdiction and unrelated to this crisis.
Simply, Mr. Chairman, putting COVID-19 in the name of the
hearing does not make it about the pandemic. This hearing is
sadly no exception. It is time to step in. If you believe as I
do, in the capacity of this country to meet a challenge, to
continually build, to continually bend the arc a little further
toward justice, we should be doing the work.
Thank you, Mr. Chairman.
The Chairman. The only disagreement I would have with
Senator Brown is the fact that this committee spends tens of
billions of dollars on Medicare, Medicaid, and prescription
drugs. We ought to be buying quality drugs. We have
jurisdiction over trade, and we ought to make sure that what
enters the United States is a quality product.
So, obviously this committee has great concern about FDA's
inspections overseas. And when it comes to everything else he
mentioned about COVID, this committee has done several things
by increasing reimbursement for Medicaid connected with COVID-
19 by 20 percent, more money for Medicaid. We have put $175
million into hospitals as a result of it.
We have given out $300 billion in increased unemployment
compensation. We have reduced payroll taxes for 1 year for
companies that need more liquidity. We have set up a program
for increased liquidity for other companies as well, besides
small businesses. And this committee has been very active in
the $3 trillion that is already out for the pandemic and the
shutdown of the economy and the opening up of the economy as a
result of the government shutting it down.
So I think this committee has been very active in
everything related to the pandemic, and we will be more active.
As we decided 7 weeks ago--whatever decision we were making 7
weeks ago, we did not know if the economy would turn around. We
did not know the condition of the pandemic. And we went into it
with open eyes that, if there was more that needed to be done,
we would do it. And we are in the middle of that process now.
And when we get to the point of making that add-on decision,
whatever needs to be done, this committee will be active at
that particular time.
But we have billions of dollars in the CARES Act 1 that is
still not out. Our work in the first step is not done yet. I
will----
Senator Brown. Mr. Chairman, if I could take the last part
of my time. Lincoln used to tell his White House staff, ``I've
got to go out and get my public opinion bath.'' And I think if
any of us are on the phone--I know a lot of us are on the phone
a lot of the time--we still see the pain and the suffering. And
I see my colleagues from New Hampshire, Oregon, and
Pennsylvania, and I know how hard they work and how they are
hearing about that pain and suffering. And this committee has
got to be talking about extending the unemployment benefits. It
has got to be talking about Medicare and Medicaid, and not
having no hearings for the last, I do not know, 7, or 8, or 10
weeks, when there is so much suffering out there and so much
work to be done. But I will stop there. Thank you, Mr.
Chairman.
The Chairman. I know you are the person who always wants
the last word, so to get on with this hearing, I will let you
get away with what you always get away with.
Senator Casey?
Senator Casey. Mr. Chairman, thanks very much for this
hearing. I want to note that these issues that relate to the
FDA are very important, but I do not think we can forget at
this time in our Nation's history, especially this week after
what happened just a week ago, I do not think we can fail to
remember the murder of George Floyd and all the pain, the
trauma, the anger, and the protests that have resulted from
that death.
We cannot simply condemn the actions that killed him and
lament the failures of our criminal justice system as it
relates to the African American community. We should do both,
but that is not enough. We must act legislatively.
This committee does not have the same jurisdiction as the
Judiciary Committee, but this Finance Committee does have
jurisdiction over health care and economic security, for
example. And there is a lot we could do to examine a whole
range of issues under those broad topics that relate to
communities of color. And part of our set of actions to help
these communities must focus on those actions.
Second, I would note that in the broad category of COVID-
19--the deaths that have resulted and the number of cases--the
death number is disproportionately higher for African
Americans. In some States, it is more than double or triple the
percent of the population; the percent of the deaths are
outpacing by a long shot the percent of the population.
As it relates to what this committee can be doing in
connection to COVID-19, one of the areas that Senator Brown
mentioned would be in the area of nursing homes. We should have
a hearing on nursing homes. It should focus on a couple of
topics. First and foremost, we should hear from the Centers for
Medicare and Medicaid Services to ask them questions, to ask
Administrator Verma questions about transparency, and why
information and data about cases in nursing homes and deaths in
nursing homes have not been on the public record to the extent
that I and Senator Wyden and a number of our colleagues have
asked for.
We have had 40,000-plus deaths in nursing homes--40,000-
plus, when you include nursing home residents and workers.
There has been a failure to collect data. Nursing homes need a
lot of things right now. They need funding, a lot more of it.
They need testing. They need personal protective equipment.
I have a bill to do all of that, Senate bill 3768. It is
the only bill in the Senate that would provide that kind of
help, $20 billion to help States with cohorting, where they
separate the residents with COVID-19 from those who do not have
it, and pay for surge teams and other best practices to get the
professional help that is needed sometimes when a nursing home
is in crisis.
With that as a long predicate, Dr. Denigan-Macauley, the
GAO did an analysis of detection, prevention, and control
problems in nursing homes. Could you quickly summarize that
report?
Dr. Denigan-Macauley. Yes, thank you. We did that. We
looked at data from 2013 to 2017, and we found that nursing
homes have widespread problems. Over 82 percent had
deficiencies, and in some cases more than half of them had more
than one deficiency. And it was basic infection control
problems; for example, staff not washing their hands, or not
disinfecting equipment, and sharing of bathrooms. And that is
pretty dramatic if you are looking at now. If we were to go
back in and look at that during COVID, and the infectious rate
of that disease, it would be pretty devastating.
Senator Casey. Thanks very much, Doctor.
Mr. Chairman, that concludes well short of my time, and I
want to say two things. Number one is, I will submit questions
for the record for Dr. Throckmorton. And, Mr. Chairman, I will
say this about your leadership and this hearing. I may disagree
that we should be covering some other topics, but at least you
are having a hearing that relates to COVID-19, unlike what has
happened on the floor the entire month of May. All nominations.
Nothing on COVID-19, with the limited exception of a few votes
on the Foreign Intelligence Surveillance Act.
Mr. Chairman, I will yield the balance of my time.
The Chairman. Senator Warner?
[No response.]
The Chairman. Senator Whitehouse?
Senator Warner. Hold on; I am here, Mr. Chairman.
The Chairman. Senator Warner, go ahead.
Senator Warner. All right; thank you, Mr. Chairman. I
appreciate it.
I want to talk to the panel, Dr. Denigan-Macauley and our
friends from the FDA, about supply chain issues that I think
this virus has exposed. It would seem to me that our national
strategic stockpile was significantly underprepared for this
virus, and I guess what I want to start with today is, what
kind of partnerships has the FDA looked at, particularly with
outreach to both our Energy and DoD partners and your intel
partners--I am the vice chairman of the Intelligence
Committee--on how we would be better prepared in terms of the
strategic stockpile in any future problems? Do you support any
kind of partnerships there? I am not sure which of the FDA
colleagues will address that.
Dr. Throckmorton. Senator, this is Doug Throckmorton. I can
start, and the others might chime in if they have anything
additional. I can tell you about the interagency partnerships
that we have formed, because I agree they are absolutely
critical for the response to COVID.
So we have been engaged in discussions with FEMA, for
instance, from really Day One in terms of the response to the
COVID outbreak, about distribution, giving them whatever
information we can to help them make good decisions. I know
that engages with the strategic national stockpile.
That is also focused through the Health and Human Services
administration through the ASPRs--that is the name of the group
there. We have also been engaged with them, again on, roughly
speaking, a daily basis because we understood the need for us
to provide whatever support we could for the decisions they
were making about the strategic national stockpile.
Similarly, we have been in close contact with the DEA
regarding controlled substances and the need for controlled
substances. As I am sure you no doubt know, there have been
extensive needs for fentanyl and other opioids for pain and for
ventilator settings and things, and we have had to do
everything we could to support that work that they do regarding
the availability of those products.
And then finally, BARDA, the acquisitions group, is engaged
with us around the work that Flo and other manufacturers have
recently taken up----
Senator Warner. If I could interrupt for a second; I do not
have that much time.
One of the things that we have discovered, as the
administration basically had States versus States searching for
PPE and for testing equipment, is that a lot of that came from
foreign sources, China in particular, you know. In terms of
thinking this through, have you had any kind of outreach to the
intel community or the defense community about how we better
prepare in the future? I think there are a lot of us on both
sides of the aisle who do not want to be reliant on China for
APIs going forward, or on circumstances of not having a
domestic supply of PPE, testing equipment--and you are talking
mostly domestic agencies. What about our intel community or
DoD?
Dr. Throckmorton. I have not been part of those
conversations. That does not mean that they have not occurred,
sir. I would be happy to get back with whatever information we
can.
Senator Warner. Dr. Denigan-Macauley, did you have any
comment there? Did you want to speak to advanced manufacturing
facilities? I think there is someone on the second panel who
will highlight some of the work that is being done at Virginia
Commonwealth University on advanced manufacturing in this space
around APIs, but I am really concerned about the domestic
sourcing of these materials.
Dr. Denigan-Macauley. Yes. And GAO has work that we have
ongoing, looking at not only the strategic national stockpile,
but we are anxious to be able to get out of our homes and talk
to the intel communities that you are referring to, because
they are key with respect to analysis and understanding of how
best to ensure that those supplies are there.
We have a robust body of work looking at APIs, where they
are coming from, how we are going to stockpile, medical
countermeasures, the whole shebang. We will continue to report
out through the CARES report every 60 days, as well as CARES
reports over the longer period of time.
Senator Warner. We are about out of time, but I do hope
that we will have that resilient domestic supply chain,
recognizing where we are sourcing a lot of this material and
looking at this from a national security standpoint. I will
tell you, Mr. Chairman, I know that, for example--Senator Wyden
and I both are on Intel, and I think this is a national
security issue that needs serious attention, and I hope the
committee will come back and revisit it.
I yield back my last seconds.
The Chairman. Okay. Senator Whitehouse?
[No response.]
The Chairman. Senator Hassan?
Senator Hassan. I am right here, Mr. Chairman.
The Chairman. Go ahead, Senator Hassan.
Senator Hassan. Thank you, Mr. Chair, and thank you,
Ranking Member Wyden, for this hearing. And thank you to our
participants, our witnesses who are participating today.
I just want to start out by saying that I share the
concerns that my colleagues have expressed, that this hearing
is the first hearing that the committee has had since the onset
of the pandemic. It is especially troubling, given the pain
that millions of Americans are feeling at this moment in time.
The murder of George Floyd happened at a time when many African
Americans already were feeling despair about the way this
pandemic has disproportionately taken their lives and
livelihoods.
We could be working today on actions that would be
constructive steps towards addressing their rightful concerns.
But we are having this hearing today--and I do want to focus on
the fact that in the last few months FDA has authorized the use
of hydroxychloroquine for COVID-19 without properly evaluating
its safety or effectiveness, and allowed highly inaccurate
COVID-19 tests to enter the market.
These decisions have negatively impacted our day-to-day
response to this pandemic and potentially put lives at risk,
yet we do not have an FDA official here who can speak to those
decisions. Moving forward, I hope this committee can conduct
the type of broad oversight of the Federal response to COVID-19
that the American people deserve, including an examination of
what has happened in our country's nursing homes.
Like so many other States, my State's nursing homes have
been devastated, and the deaths in New Hampshire due to COVID-
19 are unbelievably, disproportionately happening in our long-
term care facilities.
So, Dr. Denigan-Macauley, a couple of questions for you.
Your testimony before the House Energy and Commerce Committee
in December touched on many of the shortcomings of FDA's
foreign inspection process. Can you discuss the potential risks
these shortcomings pose to Americans who rely on these
pharmaceuticals, and how FDA's decision to modify its approach
to foreign inspections during the COVID-19 pandemic may
exacerbate those risks?
Dr. Denigan-Macauley. The GAO has reported that, while FDA
has many tools at its disposal to ensure the safety of our drug
supply, inspections are absolutely critical. And they stood up
the FDA overseas offices specifically to be able to have boots
on the ground, to be able to get the intel to find out which
establishments are good or might be bad actors and to be able
to get in there and to do inspections with very little notice,
like we have here in the United States, to make sure that it is
equivalent.
So the fact that it stopped--I understand the need for
being able to protect their own people, but it is concerning.
And I would want to ensure that the other steps that they have
in place are rigorous.
Senator Hassan. Well, I thank you for that clear response,
because, while I too understand the need to protect FDA
inspectors, their work is essential. And given the risk to
patient safety, I believe the FDA's decision to curtail
inspections is inappropriate. And it sounds to me, given your
answer, that you have deep concerns about it too.
Dr. Denigan-Macauley. We do have concerns, and we continue
our work in this area.
Senator Hassan. Thank you.
To Doctors McMeekin and Throckmorton, last year I had the
opportunity to travel to China and speak with both U.S. and
Chinese officials about the massive production of fentanyl, 90
percent of which originates in China and is not regulated. I
have continued to push efforts around putting a stop to illegal
production and distribution of fentanyl devastating people in
New Hampshire and beyond.
Doctors McMeekin and Throckmorton, can you speak to what
steps FDA is taking to combat illegal fentanyl from China? I
would also be interested in hearing about the work your agency
is doing in China, as well as efforts to stop illegal fentanyl
from crossing our border, including sales on the dark web.
Dr. McMeekin. Thank you very much. Our enforcement efforts
are primarily focused at our ports of entry and the
international mail facilities. In addition, our Office of
Criminal Investigations and our health fraud staff are
investigating online sales of opioids, including fentanyl. In
the States, we are working primarily on counterfeits, and also
working in conjunction with other law enforcement counterparts.
In fiscal year 2019, we had 55 arrests and 53 convictions
related to these products, or involving elicit opioids. So we
continue to work hard on our web and health fraud activities
surrounding these products.
Senator Hassan. Thank you. Dr. Throckmorton?
Dr. Throckmorton. I do not have a lot to add to that. I am
glad that she made the distinction between elicit fentanyl
manufacturing, which is going to elicit drug use, from
prescription fentanyl manufacturing, which is occurring,
obviously, within the U.S. borders, because I think there has
been some confusion there.
In regard to the elicit fentanyl manufacturing, we have
been focusing our efforts especially at the borders, and
especially online sales, working with the online sellers, the
Amazons of the world, to try to stop people from being able to
order elicit opioids like fentanyls on the dark web, or from
other sources. I think that is a really strong focus of that.
Senator Hassan. So, thank you. And thank you, Mr. Chair. I
do not want to lose sight of the fact that, while we have the
pandemic of COVID-19, we continue to have an opioid epidemic.
Thank you.
The Chairman. Thank you. And now, is Senator Whitehouse
available?
[No response.]
The Chairman. Okay; then is Senator Cassidy available?
Senator Cassidy. Senator Cassidy is here.
The Chairman. Go ahead, Senator Cassidy.
Senator Cassidy. Great; thank you. I am sorry I am not on
video.
Doctor--I think this is for the FDA--Senator Toomey had
mentioned about API coming from China. Dr. Throckmorton pointed
out there does not seem to be that much of a shortage. But API
is different than the chemicals that go within it. And it is my
understanding that a greater percentage of the chemicals used
to make API are coming from China. Is that correct?
Dr. Throckmorton. This is Dr. Throckmorton. I am not
familiar with those data. We know substantially less about the
sources of those products than we do about API and, as I think
was mentioned earlier, we know less about API and its
manufacturing and distribution than we do about finished dosage
forms.
Senator Cassidy. I will ask Mr. Abdoo, because he is
involved with trade. Mr. Abdoo, are you familiar with the
percentage of starting materials or fine chemicals coming from
China?
Mr. Abdoo. I am not familiar with that data, but we can
look into it and get back to you.
Senator Cassidy. That actually seems to be the critical
thing here, because API is one step, but the chemicals are
another. And so that actually seems to be our point of
vulnerability unless we have a stockpile thereof.
For example, is the high percentage of production in China
of starting materials? Because it is my understanding that
there is a higher percent of starting materials produced in
China. What would be the reason for that? Is it cost, or is it
access to a base mineral, or some other issue? It does not
sound like you all are familiar with this, but I would ask you
to get back to us regarding that.
I think GAO, though, has made a point that, even in normal
times, it is difficult to get a clear line of sight into
Chinese manufacturing. So just to say, I do think it is
important for us to consider establishing a strategic API or
starting material reserve.
Let me go on to you, Mr. Abdoo. Brazil and Mexico both have
a presence in U.S. pharmaceuticals. Clearly, if there is
geopolitical tension, it is probably better to have
pharmaceutical manufacturing in Mexico and Brazil than in
China, for a variety of reasons. Can you give me a sense of the
challenges for pharmaceuticals in Mexico and Brazil? And how is
the foreign drug inspection process going there? And would that
be an alternative for us?
Mr. Abdoo. I do not have data on that at the moment, but
again, I can look into it and get back to you. Regardless, our
inspection protocols remain the same globally, and we hold
foreign and domestic manufacturers to the same standards.
Senator Cassidy. Let me finish with this. Dr. McMeekin, you
went through a kind of elaborate why we cannot do inspections
as we normally would in foreign countries, in terms of it is
jurisdictional and therefore we have to notify them. There are
two things about that.
In a response right after that, Mr. Abdoo suggested that
we, when we were doing this in 2015, we indeed were doing
inspections but that there was a bias about how these companies
were selected, and that bias therefore may have biased the
results. But the point was, we were doing spot inspections.
And secondly, the FDA has the ability to say, ``If you do
not let us in, your goods are not coming to the United
States.'' And so, give me a sense of why your response to
jurisdictional issues is different than what Mr. Abdoo said.
And then also, why can't FDA just demand to be let in or else
we are not letting your product come over?
Dr. McMeekin. Thank you very much. Actually, you are
correct. If we go to inspect a foreign facility and they refuse
our inspection, we do have the authority and have used the
authority to put the firm and those products on import alert,
which would prevent those products from entering U.S. commerce.
And just so folks know, we do have unannounced inspections.
In a foreign space, they are generally on for-cause basis. When
there is a reason that is identified, such as an informant, or
there is a trade complaint, we will go in and conduct an
inspection. We have, and we do, conduct unannounced inspections
in the foreign space.
And again, if they deny an inspection, we do have authority
to place the facility, along with the products, on the import
alert.
Senator Cassidy. How many unannounced inspections did FDA
do on manufacturing plants in China and India last year?
Dr. McMeekin. Predominantly, they were announced. I do not
have the exact figures. Remember that we do not--we are just
implementing in our IT system the capability to record whether
an inspection has been announced or unannounced. So once we
have that data, we will be able to identify what those
inspections are.
Senator Cassidy. I am a little bit surprised that you do
not have a list of how many, but I will yield back in the
interest of time.
Thank you, Mr. Chairman.
The Chairman. Senator Thune?
Senator Thune. Thank you, Mr. Chairman. And thanks to our
witnesses for being here today.
Ensuring the safety and quality of our Nation's supply of
prescription drugs is a key priority in the Nation's work to
respond to the coronavirus pandemic and the issue of the supply
chain for both prescription drugs and PPE that has been brought
to the forefront, and so I appreciate the discussion today.
To Dr. Throckmorton, as we continue discussions on the
coronavirus response efforts, what updates can the FDA provide
with respect to provisions needed to address supply chain
issues, namely, requirements for greater transparency regarding
supply chain disruptions?
Dr. Throckmorton. Thank you, Senator. I appreciate that
question. One, I would say in general we are very grateful for
the provisions that we got in the legislation. We are in the
process of implementing the legislation. As you likely know, it
implements in September. And so we anticipate that we are going
to be able to make use of the legislative authorities that were
granted in CARES to expand the amount of information that we
get, and information is power in this setting, as we have
discussed throughout this hearing. The more we know about
products moving in the manufacturing chain, the better we can
do as far as preventing shortages, or anticipating spot needs,
or something like that.
So CARES is a very important piece for us, and I am looking
forward to being able to come back and give you an update on
exactly what we were able to do with it. But we have every
expectation that it is going to be really helpful.
Senator Thune. Okay.
Dr. Denigan-Macauley, are you aware of that provision in
the CARES Act?
Dr. Denigan-Macauley. I am, but I do not have any further
information.
Senator Thune. Okay. So, just as sort of a follow-up to
some of the lines of questions--and I am sure much of this
ground has been covered already--but the perception has been
through the course of the pandemic that there have been these
shortages, or disruptions in the supply chain, particularly
with regard to pharmaceuticals and PPE, as relates to those
that are manufactured in, particularly China, but other places
around the world.
So I am wondering if you all could just comment about the
accuracy of those reports, and whether or not in fact the
concerns that people have about the future with respect to
those supply chains are valid, and whether or not we ought to
be providing incentives to bring many of those capabilities
back here and to stand up those capabilities in the United
States. How reliable are these supply chains with the
manufacturers that are operating currently in foreign
countries?
Dr. Throckmorton?
Dr. Throckmorton. Yes, I might start, Senator, if that is
all right. Without any question, COVID is an unprecedented
demand on our drug supply chain. It is layered on top of the
problem with regards to drug shortages, one that we have been
working to confront for several years.
But superimposed on that were unprecedented needs for
medicines. And that has required that the FDA change our
approaches, create new structures to identify and respond
quickly to those drug shortages when they occur, whether it's
propofol in the hospitals in the New York State area, or it is
some other medicine.
We have had to adapt our procedures to put in place ways to
respond quickly, within hours, wherever we can to find new
sources of product for the population, whether it is in a State
or even in the smaller localities.
Going forward, we've got to think about the next challenge.
So COVID will not be the last time we are asked to respond to a
natural emergency, or an emergency of this size. And so we need
to find ways to strengthen the supply chain, find ways to
incentivize a supply chain that is robust and reliable, and
bring things into the U.S. as a way to address that. And we are
firmly supportive of things like advanced manufacturing,
because the U.S. has the advantage in those areas, an advantage
that could well help to steer firms onto the U.S. shore,
helping all of us both with regards to security, availability,
and quality for medicines that we need now, and medicines we
are likely going to need for the next emergency.
Senator Thune. Okay. Mr. Chairman, my time has expired.
Thank you.
The Chairman. The next person is Senator Daines.
[No response.]
The Chairman. If Senator Daines does not speak up, I will
call on Senator Young.
[No response.]
The Chairman. If Senator Young does not speak up, I will
call on September Crapo.
[No response.]
The Chairman. Then the next one is Senator Cortez Masto.
Senator Cortez Masto. Thank you, Mr. Chairman. Thank you,
everyone, for the conversation today. Let me just say that I am
from a State that seems to be experiencing enormous impact of
COVID-19 that is devastating our economy. I too would ask that
the chair consider having a further oversight hearing that
pertains to our nursing homes. Our nursing homes in Nevada have
been ravaged by COVID-19 as well, and I think at this point,
I'd like to follow up on this area and many others.
So I would just put that in and echo the request from some
of my colleagues as well.
Let me start with Mr. Abdoo. As we look ahead to the
development of mass production of a COVID-19 vaccine, how does
the agency expect to balance the efforts to gear up production
quickly with the need for the oversight of these manufacturing
facilities?
Mr. Abdoo. So, thank you, Senator, for that question. As
you know, vaccines are regulated through our Center for
Biologics Evaluation and Research, and our experts there would
be the best situated to get you that information. I am happy to
bring the question back to them.
Senator Cortez Masto. Thank you. I appreciate that. I think
that is going to be very helpful for us in planning for the
future.
Let me ask you this. And also I appreciate Senator
Cassidy's line of questioning, because I too have questions. I
have read through the GAO report about these unannounced
inspections and announced inspections. So whatever information
you can provide as a follow-up, please provide it to my office.
It is my understanding after reading the GAO report that
most of the unannounced inspections--when we are talking about
unannounced inspections, it is giving them 12 weeks or more
that you were going to be presenting to their facility? Is that
correct? So they have enough time to prepare for knowing that
an inspection is going to occur? Is that correct?
Dr. McMeekin. Thank you for the question. It is not a
matter of giving them enough time to prepare. It is really
having enough time for us to prepare to make sure that we have
the visas available, and that our staff have actually been able
to take the State Department clearance training. A foreign
inspection requires more time to plan, and investigators must
complete the necessary documentation for obtaining official
passports, visas, and complete required State Department
training. Any delays in this can actually put it in jeopardy,
or require a last-minute change in travel.
Senator Cortez Masto. Can I ask--and I appreciate that; it
is very helpful. But by giving them advance notice of your
coming, do you have concerns that they are going to take action
in response to that notice? And what type of action would you
have concerns that the facility would be taking?
Dr. McMeekin. Again, remember that the firms, the foreign
and the domestic firms, are inspected the exact same way, using
the same standards and requirements, whether they are domestic
or foreign.
So the expectation is for the firms to be able to have
quality products developed at any time during that process.
Senator Cortez Masto. Right. So what is your distinction
between then a spot inspection versus an unannounced
inspection? To me, there are concerns that something is going
on there and you do not want them to correct it just while you
are there inspecting, and then go back to that practice.
Dr. McMeekin. The firms have a responsibility to have
processes in place so that they can develop quality products.
The inspection is one--it is a moment in time. So they have to
have the quality systems in place throughout the life cycle of
the product. It is not just, you know, while we are there.
But while we are there, we are looking at these quality
systems. But it is up to the individual facilities and
manufacturers to have a role and an ownership in making and
providing quality products.
Senator Cortez Masto. So then why have an unannounced
inspection?
Dr. McMeekin. The unannounced inspections, think of--so if
we are going to do a preapproval inspection, something that is
tied to the application, it is important that we do give notice
on those preapproval inspections because we want to make sure
that they have the data available, that we have the people to
talk to at the firm who can talk to the types of processes that
they have, or the manufacturing capabilities so that we can
talk with them to see how they are prepared to manufacture the
product that is associated with the application. So that is
what we do with a preapproval inspection. So we do announce
that.
And then we will not announce if we have concerns that
there might be issues that have been brought to our attention
from manufacturing, or if there have been patient complaints,
or consumer complaints, or manufacturing complaints. We will
want to go in there unannounced.
Senator Cortez Masto. And why would you want to go in
unannounced?
Dr. McMeekin. You know, sometimes just to not give them any
specific insight, primarily.
Senator Cortez Masto. Because you have concerns that they
might do something in response to the notice that you are
coming?
Dr. McMeekin. There may be some, but what we have seen from
our outcomes is that in general there is not a huge difference
when we have an announced inspection or we do not. If we look
at our ``official action indicated'' where there have been
violations, from our domestic standpoint that is at about 7
percent for drug products versus in the foreign arena, that is
more about 10 percent.
Senator Cortez Masto. Thank you. I notice my time is up.
Thank you. It looks like I have gone over. I appreciate the
indulgence.
Senator Daines [presiding]. Thank you.
Well, I guess I will wrap up here with this first panel,
and I want to thank you for coming to the committee today and
providing your perspective and expertise on this very important
topic.
China's cover-up and their response to the coronavirus
outbreak set the world behind and caused this pandemic to rage
across the globe and devastate the economies and public health.
The Chinese Community Party's reckless actions to downplay and
lie about the severity of this virus has changed the lives of
every American.
Montanans across our State are losing their jobs.
Businesses are closing their doors. Working moms and dads are
struggling to put food on the table. As more information comes
to light on the deadly Chinese cover-up of this virus, we must
hold China accountable to ensure this never happens again.
It is long overdue to end our reliance on China to produce
medical supply equipment like PPE, as well as life-saving
drugs. Over 70 percent of personal protective equipment and
over one-third of our antibiotics are imported from China.
Being dependent on China is a threat to our national health and
our national security. America will be safer, and America will
be stronger when we bring our pharmaceutical and medical
manufacturing supply chains and those jobs back to America.
Commissioner Abdoo, there are substantial concerns that
China's pharmaceutical industry is not effectively regulated by
its government. China's regulatory apparatus is inadequately
resourced to oversee thousands of Chinese drug manufacturers
even if Beijing made such oversight a greater priority. This
has resulted in significant drug safety scandals. What are the
most challenging aspects of maintaining quality control of
Chinese pharmaceutical imports into the United States?
Mr. Abdoo. Thank you for that question, Senator, and I will
start off and then turn to my colleagues. Through our office in
Beijing, we work extensively with the National Medical Products
Administration in China to raise the standard of their ability
to regulate products within their jurisdiction.
We do this by recommending harmonization with international
standards, by promoting membership in pharmaceutical inspection
cooperative schemes, which help create standards for
inspections, and we do this also in addition to work with the
FDA through educating the industry about requirements for FDA
so that they can better comply and improve the quality of the
product that they are exporting to the United States.
With regard to what we do here domestically in terms of
importation and so forth, I am going to turn to Dr. McMeekin.
Dr. McMeekin. So, as Mr. Abdoo mentioned, FDA's
jurisdiction over foreign firms' products begins when the
products arrive at our borders and attempt to enter into
interstate commerce.
And so FDA uses additional tools to complement those
inspections. And this includes utilizing our import screening
tool called PREDICT, and we can and have adjusted that
accordingly. We also conduct physical examinations and/or
product testing at the borders to make sure of that as products
come in.
We are also requesting--we can request records from some
facilities. So we can request records; we have received
authority to request records in advance so that evidence
inspections are actually in lieu of inspection. So we are
collecting these to look at batch records, program data, to be
able to see if they are complying with GMPs.
Thank you.
Senator Daines. Yes; so you are not actually monitoring the
process of operations in the plant for GMPs? You are looking at
documentation but not actually having any physical presence on
their site?
Dr. McMeekin. During the pandemic.
Senator Daines. Okay. And a follow-up question, back to the
Commissioner: what are the biggest impediments to drug
manufacturing in America? And what would be the benefits of
having a stable domestic supply chain for our most critical
drugs?
Mr. Abdoo. Thanks for the question, Senator. I think Dr.
Throckmorton might be in a better position to talk about drug
manufacturing in the United States.
Dr. Throckmorton. Thank you, Senator. When we talked before
about this, we identified a few factors. One obviously is labor
costs. Another factor relates to the environmental regulations.
In parts of the world, there obviously are very different
standards in that regard. And third is the economics of drug
manufacturing.
So, if you look back at the drug shortage report that we
created last fall, we believe there is fundamentally a
disconnect in terms of the incentives to create high quality,
and the reimbursements for the products that are of high
quality. And we think we can change that if we could provide
additional transparency, potentially grading, identifying
products that are made to a very high quality, and make those
known to the American public so that buyers would know that
they could potentially choose those products over products that
barely meet the mark. And we would be very happy to talk to you
about the ideas we have along those lines.
Senator Daines. Thank you. I am out of time as well, and so
this will conclude our first panel. I want to thank our
witnesses for being here today and sharing their very
insightful testimony in answering these questions.
With that, we are now ready to seat panel two.
[Pause.]
Senator Daines. Okay. We'll get started with the second
panel. I'd like to start with the introduction of, first of
all, David Light.
David is a biotech entrepreneur and scientist with over 10
years' experience in the field. He is the founder and CEO of
Valisure. Valisure tests its drugs for toxins, carcinogens, and
dilution rate before dispensing to patients. David helped
found, fund, and invent the core technology at Valisure and is
named inventor on numerous patents.
Our second member of the panel today is Martin VanTrieste,
who is president and CEO of Civica, Inc. Civica, Inc. is a
nonprofit, non-stock corporation founded in 2018 and is part of
a new U.S. Government-funded partnership to produce essential
generic medicines and their ingredients in the U.S.
The immediate priority for the partnership will be a COVID-
19 response. Today over 50 health systems are Civica members,
representing more than 1,200 U.S. hospitals and over 30 percent
of all licensed U.S. hospital beds. Since we do not have time
restraints, each witness has 5 minutes for their opening
statement, and we will begin with Mr. Light.
STATEMENT OF DAVID LIGHT, FOUNDER AND CEO,
VALISURE, NEW HAVEN, CT
Mr. Light. Chairman Grassley, Ranking Member Wyden, and
members of the committee, thank you for the honor of being able
to speak before you today. I am the founder and CEO of
Valisure, where our mission is to help ensure the safety,
quality, and transparency of medications, and we do this with a
very simple but novel approach: we check. Valisure is the only
pharmacy that checks the chemistry of every batch of every
medication at no additional cost to patients. This is
particularly important, given our Nation's heavy reliance on
overseas manufacturing and COVID-19 putting additional strain
on an already stressed system.
Valisure currently rejects over 10 percent of the
medication batches we test due to a variety of product defects.
The pharmaceutical supply chain is extremely complex and
heavily reliant on the self-regulation of overseas
manufacturers. When you buy a bottle of medication, it is like
buying a used car. Those pills are often already a year or two
old, have traveled thousands of miles and touched dozens of
hands. No one buying a used car is satisfied to know that the
original manufacturer said, ``It's good.'' You want a CARFAX
report. You want to see a 100-point inspection on that car.
None of that transparency is available for medications.
While the FDA cannot do everything or be everywhere, we
strongly believe that more can and must be done. The idea of
independently checking drugs may be new to industry, but not to
the academic world. However, warnings from academics have
unfortunately been largely ignored. A grim example of this is
the drug Zantac. In 1977, Senators sat in this very building
and listened to testimony that certain drugs are unstable and
form the extremely potent carcinogen NDMA.
Similar concerns were raised a year later at a summit held
by the World Health Organization and the United Nations. Zantac
has the exact chemical structure to form NDMA that the
scientific community warned about, and yet the drug was
approved only a few years later. In the following decade,
dozens of studies implicated Zantac as chemically unstable and
easily prone to forming NDMA, but these papers had practically
zero impact. By the 1990s, Zantac had become the top-selling
drug globally and among the most commonly prescribed to treat
acid reflux in pregnant women and infants.
It was not until 2019, 36 years after the drug's approval,
that Valisure performed the simple action of independently
checking generic Zantac syrup prescribed to our co-founder's
infant daughter. The results were so dramatic we immediately
took the drug off our formulary. But we were not satisfied by
simply publishing our findings in a journal.
We petitioned the FDA directly. We spoke to the press. We
did not back down from the crystal-clear science that Zantac is
fundamentally unstable and should be taken off the market. Two
months ago, after dozens of countries had already banned this
dangerous drug, the FDA finally granted our petition, and
Zantac was officially taken off the U.S. market.
Without independent testing and the drive to make it
broadly transparent, Zantac would have remained on the market
for many more decades to come. The immense value of independent
testing does not have to be limited just to Valisure's
pharmacy.
I believe there are two clear paths to applying independent
analysis throughout the U.S. First is a data-driven approach:
drug quality scores. Results from independent chemical analysis
can be combined with broad regulatory data and boiled down into
quality scores that can be as simple as a red, yellow, green
rating that provides transparency to any drug purchaser. Buyers
can use this guidance to buy green, occasionally yellow, and
avoid red. A landmark paper by leaders from eight prominent
health-care institutions was just published on this approach
last week.
Additionally, for a handful of important drugs that are
particularly vulnerable to quality issues, there is a more
definitive solution: what we call ``certified drugs.'' By
employing independent batch testing of drugs up to the
manufacturer level, we can weed out poor-quality batches and
bring certified medications to millions of Americans regardless
of which pharmacy they go to.
This is entirely reasonable to do for critical drugs such
as metformin. Metformin is the top diabetes drug and the fourth
most prescribed medication in the U.S., with over 80 million
prescriptions a year. Valisure has published two studies
showing that approximately 40 percent of metformin products are
contaminated with the carcinogen NDMA above FDA acceptable
limits. This means millions of Americans are taking a drug
every day that contains a carcinogen that absolutely should not
be there.
In summary, we have very serious problems in the drug
supply chain that are caused by a very complex set of factors,
all of which are made worse by COVID-19. It is imperative that
we act quickly to better protect the American public. And above
all, independent scientific analysis cannot continue to be
ignored and must be a part of a new, transparent path forward.
Thank you very much, and I look forward to your questions.
[The prepared statement of Mr. Light appears in the
appendix.]
The Chairman. We will now go to Martin Van Trieste.
STATEMENT OF MARTIN VanTRIESTE, RPh,
PRESIDENT AND CEO, CIVICA, INC., LEHI, UT
Mr. VanTrieste. Thank you, Chairman Grassley, Ranking
Member Wyden, and members of the committee. I am Martin
VanTrieste, the CEO of Civica. I am honored to be here and to
follow a group of dedicated public servants. Civica is a
nonprofit 501(c)(4) established by health systems and
philanthropies to reduce chronic drug shortages in the United
States. Our mission is to serve patients by making quality
medications that are always available and affordable. More than
1,200 U.S. hospitals and 50 U.S. health systems have joined
Civica. We also supply the Veterans Administration, Department
of Defense, as well as 340B-
eligible hospitals.
Many of our drugs are used in the management of COVID, and
we have been able to supply them without fail. We even
contributed 1.6 million vials of medication to the strategic
national stockpile. Several features of the Civica model may
offer insights into the broader supply chain.
We rely on long-term take-or-pay contracts to provide the
certainty for us and our suppliers to invest in quality
systems, capacity, and staff. We have backup suppliers to
create redundancy. And we maintain 6 months of safety stock.
Civica prefers to buy American where possible, then from
other highly regulated economies, avoiding Chinese ingredients
in all our drugs, if possible. Finally, Civica selects
medicines to make based on the needs identified by pharmacists
and physicians on the front lines.
To further support a resilient supply chain, Civica
recently entered partnership with Flo and the Federal
Government to make essential drugs here in the United States.
This agreement will result in an end-to-end U.S. manufacturing
supply chain for essential drugs which will be sold at Civica's
nonprofit pricing.
As Congress considers other measures to improve the supply
chain, we urge you to keep these principles in mind: define and
focus on a set of essential drugs; support U.S. manufacturing;
ensure redundant supplies and stockpiles; and purchase from
companies with robust quality systems.
My written statement addresses specific policy tools, and I
welcome your questions. Thank you.
[The prepared statement of Mr. VanTrieste appears in the
appendix.]
The Chairman. Before I ask questions, I want to make a
comment--not to you two people on this panel, but to my
colleagues on this committee raising issues of whether or not
this committee, with this hearing or anything else that has
been done since the pandemic hit, whether or not we have been
putting our attention in the proper direction. And obviously a
lot of my Democrat colleagues feel otherwise.
So it appears that these number of Democrat colleagues who
commented today--and maybe some who did not comment, because
the usual courtesy that goes on in this committee was absent
today--whether it is the colleagues who commented or not, they
surely have been out of touch with what the committee has been
doing recently, based on their comments.
I mentioned in a previous response to Senator Brown the
billions of dollars this committee was involved in with
responding to the COVID crisis and the economic turmoil that
has resulted from it. And I guess some of my colleagues think
that you just somehow pass a bill and then you forget about it.
But our staffs, and at least some members, have spent weeks
following up and assisting in implementing the $3-trillion
relief package that we passed.
In addition, I have heard other complaints today. So I
guess these colleagues on other issues are not aware that I
have been working with Ranking Member Wyden to have an
unemployment insurance hearing next week.
I also have sent oversight letters regarding the nursing
homes that I am awaiting information on before any potential
hearing, because you ought to have your ducks lined up before
you take all the action that goes into a hearing, if you want
that hearing to be productive.
So the bottom line is this: I request, before complaining
in the future, it would be helpful to talk to me or have your
staff talk to the staff of this committee. So in the end, then,
if you did that, you would have a better idea of what we are
talking about and what we have been doing, besides what is
already on the public record, in regard to our response to the
pandemic and our response to the economic turmoil caused by the
shutting down of the economy by our government and our efforts
now to bring it back up.
So I am going to start my questions with Mr. VanTrieste of
Civica, who collaborated with HHS, Veterans Affairs, Department
of Defense, CMS, and is working with the Trump administration
Biomedical Advanced Research and Development Authority on a new
manufacturing plant in the United States. What the purpose of
the plant is, as I understand it, is to expand generic
pharmaceutical manufacturing in the United States and create
stockpiles of active pharmaceutical ingredients for public
health agencies, which I guess in turn would make us less
dependent on China and other countries.
So my first question is, has the Trump administration been
a good partner in trying to overcome the issues of generics in
short supply?
Mr. VanTrieste. I started my testimony today by
acknowledging the hard work and dedication of many public
servants who are working to protect the American people. Even
before the pandemic hit, we had been talking with officials at
BARDA, ASPR, and HHS who were focused on securing the
pharmaceutical supply chain who have been interested and very
helpful.
Because we have a direct relationship with pharmacists and
physicians on the front lines of the pandemic, we have been
able to provide information that helped inform their priorities
concerning what are the essential generic medications during
COVID.
I have to also add that since COVID, my faith in public
servants has only gone up. These individuals have worked 24/7
around the clock to make sure that they can do the best job
possible to bring good PPE, medical devices, testing, and drugs
to those in the American public who need them the most.
The Chairman. My last question to you would be this: based
upon your experience working with various government agencies,
how could Congress assist in strengthening and promoting U.S.
drug manufacturing companies to return to the United States?
Mr. VanTrieste. So I think clearly--I hear frequently of
organizations or individuals interested in starting their own
nonprofit pharmaceutical company. Some are interested in the
trouble with drug shortages; others in reducing drug prices;
and still others are looking to solve a market failure, such as
a need for new antibiotics or therapies for neglected diseases
in which the traditional commercial model is not working.
Nonprofit pharma has a great potential, not as an
alternative to for-profit industry but as an adjunct for or a
complement to it. But there are several things that would help
this emerging model succeed. We should recognize that
nonprofits cannot raise capital the same way that the private
sector does. Civica benefits from the financial commitments of
our health systems and philanthropies, but in some cases the
government itself may want to look at the model as a solution
to the problem.
Using grants, low-interest loans, or other public/private
mechanisms would help the nonprofit pharma industry blossom.
But in addition, there are a great number of bills that have
been introduced in Congress recently, some very bipartisan like
with Senator Warner and Senator Rubio, that talk about
incentives to re-shore the American pharmaceutical industry and
bolster the supply chain. Civica has publicly said that they
acknowledge and applaud those efforts.
The Chairman. I thank you very much, and my last two or
three questions will be to Mr. Light. So I will ask you, do I
understand that your business model includes testing drugs
before dispensing them to patients? Would you provide the
committee a couple of examples of toxins and other impurities
your testing process has detected in drugs to make them safer
and more effective?
Mr. Light. So we test, actually, for a whole variety of
components in drugs, including dosage; the inactive
ingredients; the dissolution rate, which is how a pill
dissolves in one's stomach or intestines; and a variety of
carcinogens, such as NDMA, which has been discussed
extensively.
I will say that everything that we have looked for, we have
found problems with, some more than others, and I think there
has been a lot of attention--rightly so--to the carcinogens.
Just last week there have been recalls on a new drug,
metformin, due to the same carcinogen, NDMA. And we test for a
variety of these on all the batches through our pharmacy.
The Chairman. My second question would be about your
relationship with FDA. When you discover contaminated drugs, do
you report it to the FDA? And if so, what has been the FDA's
response?
Mr. Light. Because we are actually outside of the
manufacturing system, we are not a good manufacturing facility
because we do not manufacture. We are a pharmacy that has a
laboratory. And so the guidance we receive from the FDA is to
report these findings to industry, which has the freedom not to
pay close attention to them, given that we are not a GMP
facility.
I think it really underscores the point that independent
analyses, certainly a lot from academics, have been largely
ignored because we are not part of this pharmaceutical
regulatory bubble. However, we have effectively utilized the
mechanism FDA has of an FDA citizen petition where, when we
have sufficient data in-depth on particular problems like
Zantac or metformin, we file a petition with this data and ask
for actions of the FDA, such as to make these recalls.
The Chairman. Can you describe the process you use to test
those drugs, and how much does the process cost?
Mr. Light. The process we use will certainly depend on the
particular analysis. We have some amount of proprietary
technology that we also use industry-standard technologies
with. We have optimized these systems so that we add less than
a penny per pill of cost generally, and we sell these
medications at no additional cost to patients. So this cost of
independent analysis adds very little to the actual pill cost
of being able to dispense it to a patient at the pharmacy
level, and we believe that at larger levels, potentially even
doing this with manufacturers, there is a very small additional
cost.
The Chairman. My last question to you: how do you see your
system impacting drug manufacturing?
Mr. Light. We certainly hope to improve the system as a
whole. I think we have already seen the proof of principle in
key drugs like metformin and Zantac, and we certainly hope that
quality manufacturers will see this as an opportunity, which
has been discussed a few times during this hearing, of
rewarding quality manufacturers, whether that is through
advanced quality management maturity or, from our perspective,
a science- and evidence-based approach where we can actually
infuse this independent analysis in addition to what the
manufacturers already do, and make that transparent to
patients, buyers, and payers throughout the United States.
The Chairman. Before I close, I want to thank the two
witnesses right now who are still here. But I was away voting
on the Senate floor when the first panel left. I did not get a
chance to thank them, as chairman of this committee. I want to
do that.
So, whether you are government or private-sector witnesses,
we appreciate your attendance today. COVID has created many
logistical hurdles in making today's hearing--oh, did I forget
Senator Wyden?
Senator Wyden. Yes, Mr. Chairman, I have a couple of
additional questions.
The Chairman. I really apologize. I am sorry. I will leave
my closing statement to when you get done.
Senator Wyden. Okay. I just have a couple of questions here
for the gentleman from Civica, Mr. VanTrieste, if I am
pronouncing that right. And then I want to make a comment to
see if we can take some constructive measures going forward.
Let me just make sure we have got this. Mr. VanTrieste,
your company is part of a contract that the Trump
administration recently awarded to make COVID-19 drugs. Which
drugs are you manufacturing right now?
Mr. VanTrieste. So the intent of the grant that was given
to us by BARDA was not to be making drugs or APIs, it was to
put the infrastructure in place for the next pandemic, or the
next crisis.
However, Civica already had a series of drugs that we
provide our members for use during a pandemic, and those
include antibiotics, cross-spectrum antibiotics, sedation
agents, heart medications, and local anaesthetics. We have sent
over 1.6 million vials at the request of the government to the
strategic national stockpile, and we are prepared to provide
more if asked.
Senator Wyden. So I just want to make sure we are clear.
You got this contract, and you said something about working on
infrastructure for the future--always useful--but I am not
clear what you are doing with this contract as it relates to
COVID-19 drugs now. Have you given some COVID drugs to the
government that we do not know about?
Mr. VanTrieste. Yes. We provided over 1.6 million vials of
drugs to support COVID patients like cross-spectrum
antibiotics, sedation agents, heart medications, and local
anaesthetics. These are the same products that we provide our
members on a routine basis. They include vancomycin, ketamine,
lidocaine----
Senator Wyden. You were doing that before the COVID-19
pandemic, were you not?
Mr. VanTrieste. We were not supplying the national
stockpile.
Senator Wyden. But you had the drugs?
Mr. VanTrieste. We had the drugs.
Senator Wyden. Okay. I am just trying to find what value-
added the government got for its money, and I would like to
know what drugs is the prime contractor making?
Mr. VanTrieste. So the prime contractor is making an API
facility that will produce active pharmaceutical ingredients
and their precursors, which we are really dependent on China
for, as people talked about earlier, especially the precursors.
And this is using brand new technology called ``advanced
manufacturing,'' but it is not for today, it is for the future.
And this contract has not been designed to set up manufacturing
for today, but in the future, Senator.
Senator Wyden. I appreciate that, and I am always
interested in the future. But I am interested in the urgency of
communities devastated by COVID-19 now and getting them help
now, and I am still unclear how anything you are going to do
with these new efforts addresses that. My time is short, and I
am going to have to just make one last point that addresses
what the chairman talked about.
Mr. Chairman? I am looking for where the chairman is. Is
the chairman still----
The Chairman. Yes?
Senator Wyden. Okay, there is the chairman, all right.
I want to just make a brief comment to my friend with
respect to the afternoon. Because I have been here, like the
chairman, for about 3\1/2\ hours, and I think that what my
colleagues and I have raised is not a question primarily of
courtesy--because I think all have been reasonable in tone--but
it reflects an urgency.
The racial injustice, for example, in American health care
is an immediate need. The African American community, as we
have been talking about, has been hit by COVID-19 like a
wrecking ball. And on our side of the aisle, we want to make
sure the Finance Committee--which has such enormous power in
health care over Medicare and Medicaid and the exchanges, and
literally $2 trillion annually--is going to use its
extraordinary muscle in order to make sure the African American
community that has been hit so hard, that is responding right
now to injustices all across the country, is going to see us
use our influence to get those communities of color a fair
shake in American health care.
And so we had colleagues on our side raise this repeatedly,
and unless I am missing something--because I could have been
out for a minute--no one on the other side of the aisle raised
it. I think that is unfortunate.
So to try to see if we could end on a positive note, Mr.
Chairman, can we agree, you as the chair and I as the ranking
minority member, that we will task our staffs and members on
both sides to move very quickly to put together a hearing and
an agenda, an actual specific action agenda, to use the muscle
of our committee to deal with these racial injustices? You and
I are the only ones left. We have been here for 3\1/2\ hours,
and that is something that we can take from this in a positive
way that, going forward, we will work together with our staff,
with our colleagues, to put together a hearing quickly and an
action agenda to deal with these racial injustices that so many
African Americans are telling us about, literally for hours
each day.
Is that something we can agree on?
The Chairman. We can always sit down and discuss anything
you want to discuss, as you will sit down with me any time I
suggest we discuss things. I guess the only thing I would ask
you to take into consideration is, almost every program that we
are involved in on this committee, whether it is Social
Security going back to 1936, whether it is Medicare and
Medicaid going back to 1966, or whether it is unemployment
compensation that has been around I think since the 1930s, all
of these programs are color-blind. You have to realize that.
And we will continue to work in a color-blind way, because we
are all Americans, and we have to pull together, and we should
not leave anybody behind. And my goal is not to leave anybody
behind.
Senator Wyden. Mr. Chairman, just, if I might, I will tell
you, respectfully, it is very clear that these health-care
programs are not color-blind. We have seen study after study
showing that communities of color are disproportionately
affected by these health problems that we are talking about,
and that services, for example, do not even come to their
communities.
We have been hearing, as I have in the last few days, that
in the health legislation, the affluent hospitals did
incredibly well. And in communities of color, there were not
very many hospitals, and those there did not have the services
that folks need.
So I will leave this, and I hope that we can work this out
quickly. And, respectfully, I will say again, Mr. Chairman, the
facts show that these programs are not color-blind. The hard
evidence shows the disproportionate effects on communities of
color by these health programs. And for that reason, we would
like to work as the Finance Committee has always done in a
constructive way to get a hearing quickly to develop an action
plan to reverse these injustices.
The Chairman. It is against the law for all these programs
to discriminate against anybody.
I will close with this. Before we formally close today, I
once again, for the second time, thank our witnesses,
government and private-sector, for their attendance today.
COVID has created many logistical hurdles in making today's
hearing happen. I appreciate all that people have done, for
being a part of this very important discussion. In addition, I
want to thank the clerk staff for their hard work, time, and
attention in making this hearing happen.
Today we have discussed many important issues that have
existed for decades. However, because of the pandemic they are
now more important than ever before. Congress must ensure that
the executive branch takes all the necessary steps to properly
oversee the drug supply chain. We must work together to ensure
safe and effective drugs. We have a good idea of who the bad
actors are in the drug supply chain. We also know that
aggressive and unannounced inspections provide the best way to
catch those bad actors.
I fully expect HHS and its subcomponents to laser-focus on
them aggressively, engaging in inspections as well as
enforcement. Today we have highlighted one aspect of the drug
supply chain: that supply chain ends in the United States.
Going forward, we must entertain serious policy discussions
about how we can efficiently and safely bring manufacturing
back to the United States. In the coming weeks, I will be
working on the next focus: the personal protective equipment
supply chain.
With that, the hearing is over, and members have 1 week to
provide questions for the record. And whether it is this panel
or the previous panel, I hope you will respond appropriately
and as quickly as you can.
Meeting adjourned.
[Whereupon, at 5:30 p.m., the hearing was concluded.]
A P P E N D I X
Additional Material Submitted for the Record
----------
Prepared Statement of Mark Abdoo, Associate Commissioner for Global
Policy and Strategy; Judith McMeekin, Pharm.D., Associate Commissioner
for Regulatory Affairs; and Douglas C. Throckmorton, M.D., Deputy
Director for Regulatory Programs, Center for Drug Evaluation and
Research, Food and Drug Administration, Department of Health And Human
Services
Chairman Grassley, Ranking Member Wyden, and members of the
committee, thank you for the opportunity to testify today on a matter
of the utmost importance to the agency: protecting the safety, quality,
and availability of medicines for Americans.
The U.S. drug supply is among the safest in the world. FDA
thoroughly reviews drug applications to ensure that medications are
safe and effective before they reach the market and oversees drug
quality post-approval. The agency inspects drug manufacturing
facilities located around the world with comparable depth and rigor
based on an assessment of risk to public health. FDA laboratories test
for drug quality, using testing standards set by the United States
Pharmacopeia, or standards submitted in marketing applications, or
methods developed by FDA. This testing has consistently shown that
medicines manufactured in foreign countries that are imported into the
United States meet U.S. market quality standards. When FDA identifies
significant manufacturing or safety issues, it quickly acts to protect
Americans.
During the COVID-19 pandemic, FDA is continuing to utilize and
implement additional alternative inspection tools and approaches while
postponing foreign and domestic routine surveillance facility
inspections. This will continue as conditions warrant, with the
exception of certain mission critical inspections, including pre-
approval and for-cause assignments. Mission critical inspections are
identified on a case-by-case basis and conducted with appropriate
safety measures in place.
Importantly, during this interim period we're evaluating additional
ways to conduct our inspectional work that would not jeopardize public
safety and protect both the firms and the FDA staff. This can include,
among other things, evaluating records in advance of or in lieu of
conducting an onsite inspection when travel is not permissible, when
appropriate. We want to assure the American public that we have full
confidence in the safety and quality of the products we all use every
day and that the FDA will continue to leverage all available
authorities to continue to ensure the integrity of the products we
regulate.
Today we will provide the committee with an overview of the history
of FDA's foreign drug inspection program, and the ways it has evolved
in response to the industry's globalization and changes in law and
regulation. We will also explain our approach when our inspections
indicate that a facility does not operate in keeping with established
quality standards. These standards are known as current good
manufacturing practices (CGMPs). We will also describe some potential
enhancements that would enable FDA to complement our foreign drug
inspection program. The agency believes that over the longer term, we
should encourage investment in advanced manufacturing technology and in
strengthening the approach by which manufacturers assure the quality of
their products. This approach, which we call quality management
maturity, would provide a safer and more secure drug supply because it
can help prevent many quality problems from occurring in the first
place. Advanced technology, which can be more cost-effective and
environmentally friendly than traditional manufacturing technology, may
also enable the United States to play a larger role in pharmaceutical
manufacturing.
the globalization of pharmaceutical manufacturing
Over the past 30 years, pharmaceutical manufacturing has become an
increasingly global enterprise. Beginning in the 1970s, industry moved
away from the mainland U.S., first to Puerto Rico in response to tax
incentives, and then to Europe and nations that were developing at the
time, such as China and India. Developing nations can provide
significant cost savings to pharmaceutical companies because of their
lower labor, energy, and transportation costs. In addition, they often
have weaker environmental regulations than more developed countries. A
World Bank study estimated that in 2004, China and India held a cost
advantage of about 40 percent when compared with the U.S. and
Europe.\1\ FDA's 2011 report, ``Pathway to Global Product Safety and
Quality,'' also noted that both China and India enjoy a labor cost
advantage and that manufacturing active pharmaceutical ingredients
(APIs) in India can reduce costs for U.S. and European companies by an
estimated 30 percent to 40 percent.\2\
---------------------------------------------------------------------------
\1\ Bumpas, Janet; Betsch, Ekkehard. Exploratory study on active
pharmaceutical ingredient manufacturing for essential medicines
(English). Health, Nutrition and Population (HNP) discussion paper.
Washington, DC: World Bank: 12-13, Figure 2. http://
documents.worldbank.org/curated/en/848191468149087035/Exploratory-
study-on-active-pharmaceutical-ingredient-manufacturing-for-essential-
medicines. Accessed September 30, 2019.
\2\ U.S. Food and Drug Administration, ``Pathway to Global Product
Safety and Quality,'' A Special Report, p. 20. Accessed October 4, 2019
at https://www.hsdl.org/?view&did=4123.
As the U.S. drug market shifted toward lower-priced generic drugs,
manufacturers came under increasing cost pressure and found these
efficiencies compelling reasons to locate more of their facilities
overseas, particularly in developing parts of the world. This shift is
reflected in the Center for Drug Evaluation and Research's (CDER's)
Site Catalog (``Catalog''), which lists all drug manufacturing
facilities worldwide that are subject to routine FDA inspections.\3\ As
of May 2020, 26 percent of facilities manufacturing APIs and 46 percent
of the facilities producing finished dosage forms (FDFs) of human drugs
for the U.S. market were located in the U.S. (See Figures 1 and 2)
---------------------------------------------------------------------------
\3\ The agency updates the Catalog continually, so the information
it provides is a snapshot in time.
[GRAPHIC] [TIFF OMITTED] T6220.007
This movement accelerated in the 2000s, but due to statutory
mandates for biennial domestic inspections and limited staffing, FDA's
inspectorate remained focused on domestic manufacturing. Until passage
of the Food and Drug Administration Safety and Innovation Act (FDASIA)
in 2012 (Pub. L. 112-144), the agency was legally required to inspect
manufacturing facilities in the U.S. every 2 years but had no similar
mandate for the inspection frequency of foreign facilities. This
resulted in more frequent inspections for domestic facilities.
The Globalization of FDA's Drug Inspection Program
In response to the move from domestic to global manufacturing and
the passage of FDASIA, FDA developed and implemented a comprehensive
strategy to facilitate greater coordination and oversight of medical
products. In addition to increasing foreign inspections, our efforts
have included:
Developing new enforcement and regulatory tools;
Increasing collaboration with foreign regulators and other
stakeholders;
Developing internationally harmonized standards and standards
convergence;
Educating foreign industry about FDA requirements;
Increasing transparency and accountability in the supply
chain; and
Establishing foreign offices with an overseas footprint in
China, India, Europe, and Latin America.
Responsibility for addressing these global issues is distributed
across the agency. The Office of Regulatory Affairs (ORA) conducts
inspections and reviews imported products offered for entry into the
United States. FDA's product centers focus on international policy and
outreach that touches on their portfolio of regulated products. The
Office of Global Policy and Strategy serves as a focal point for FDA-
wide coordination and information-sharing and a point of access to
multilateral organizations; addresses issues related to international
trade of regulated products and mutual recognition agreements; enters
into arrangements that facilitate the sharing of information with
global regulatory counterparts; and manages FDA's foreign offices
around the world.
FDA's drug inspection program shifted from one focused heavily on
U.S.-based facilities through the early 2000s to a program that, since
2015, has conducted more foreign than domestic drug inspections. (See
Figure 3) FDA's drug inspection program is now risk-based. FDA
prioritizes for inspection facilities deemed higher-risk based on
specific, defined criteria.
[GRAPHIC] [TIFF OMITTED] T6220.008
Types of Inspections
The types of inspections performed in both domestic and foreign
facilities include pre-approval, surveillance, and for-cause
inspections.
Pre-approval inspections: conducted as part of the review of
an application to market a new brand or generic drug.
Surveillance inspections: Used to monitor the manufacturing
process and the quality of distributed drugs. FDA uses the findings to
evaluate whether a manufacturer is complying with CGMPs. In general,
the agency does not announce domestic surveillance inspections to the
company in advance but usually announces foreign surveillance
inspections in advance, partly due to logistics such as arranging
travel and access to facilities, securing visas, and partly because of
the high costs of conducting foreign inspections. Whether inspections
are announced often depends on particular cases and the history of
specific facilities.
For-cause inspections: Triggered when FDA has reason to
believe that a facility has serious manufacturing quality problems or
when FDA wants to evaluate corrections that have been made to address
previous violations. For-cause inspections can be announced or
unannounced, whether domestic or international, depending on the
specific situation.
When the agency has determined the need to do an unannounced
inspection, FDA has conducted such operations. Over the past several
years, FDA investigators have conducted unannounced inspections at
foreign manufacturing facilities, including in India and China. When
significant issues are uncovered at a foreign manufacturing facility,
the agency uses additional tools to protect patients including placing
the facility on import alert, which is used to prevent potentially
violative products from entering the U.S. market.
the site selection model
To address the need to prioritize use of limited resources, in 2005
FDA implemented a risk-based approach to drug facility surveillance
inspections. A mathematical model, the Site Selection Model (SSM), was
designed to select facilities with the greatest potential for public
health risk should they not comply with established manufacturing
quality standards. FDA uses results of the model to prepare a
prioritized list of facilities for inspection.
The passage of FDASIA ratified our risk-based approach and removed
the requirement to inspect domestic facilities on a fixed biennial
schedule. FDASIA also enhanced our inspectional authority by requiring
facilities to provide, upon request, records or other information in
lieu of or in advance of an inspection. Additionally, under another
provision added by FDASIA, if the owner or operator of a foreign
facility delays, denies, or refuses to permit inspection, all drugs
manufactured at that facility would be deemed ``adulterated.''\4\ The
agency thanks Congress for enacting this law.
---------------------------------------------------------------------------
\4\ The Federal Food, Drug, and Cosmetic Act (FD&C Act) describes
different circumstances in which a drug may be considered adulterated.
For example, a drug might be adulterated where it is contaminated with
filth, where its purity departs from certain compendial standards, or
where the conditions of its manufacturing are not consistent with
current good manufacturing practice (CGMP).
In 2007, FDA began planning the shift of its investigator workforce
to cover foreign facilities and to balance allocation between domestic
and foreign inspections. Both the Generic Drug User Fee Amendments
(GDUFA) of 2012 and its reauthorization in 2017 provided new resources
to FDA for inspecting foreign facilities, which as we have noted are
---------------------------------------------------------------------------
often the source for APIs and FDFs of generic drugs.
With new resources, FDA has been able to inspect some facilities
that previously had not been inspected. Catalog showed that as of
December 2016, there were 963 foreign manufacturing facilities that had
never been inspected by FDA. All of the 963 \5\ foreign manufacturing
facilities that GAO reported to be uninspected (as of December 2016)
have now been addressed. By the end of FY 2019, FDA had inspected 496,
or approximately 52 percent, of these previously uninspected
facilities. (See Figure 4) An additional 361 facilities (37 percent)
were removed from the Catalog because they were no longer part of FDA's
inspection obligations for a number of reasons, e.g., they had gone out
of business, were not serving the U.S. market, or had been registered
with FDA erroneously. In addition, 52, or 5 percent, of the facilities
had refused inspection;\6\ 34, or 4 percent, of the facilities were
inaccessible to FDA investigators because they were unable to travel to
them (e.g., as a result of travel warnings); and 20, or 2 percent, had
no imported drug shipments to the U.S.
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\5\ The 2016 GAO report identifies 965 firms that, at that time,
had not been inspected. Since then, there were two separate mergers of
facilities in that count, dropping the number from 965 to 963.
\6\ Under the FD&C Act, as amended by FDASIA, a drug product will
be deemed adulterated if it has been manufactured, processed, packed,
or held in any factory, warehouse, or establishment which delays,
denies, or limits an inspection, or refuses to permit entry or
inspection. In such a case, FDA typically will place the firm on import
alert.
[GRAPHIC] [TIFF OMITTED] T6220.009
The SSM is at the core of FDA's surveillance inspection
prioritization program and ensures a uniform approach for domestic and
foreign facility inspections. The agency uses the model to calculate a
score for every facility in its Catalog using risk-based factors.
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Factors in the SSM include:
Inherent product risk. Different types of products carry
different levels of risk based on characteristics such as dosage form,
route of administration, or whether the product is intended to be
sterile. For example, a manufacturing facility that makes sterile
injectable drug products will have a higher inherent product risk than
a facility that makes oral capsules.
Facility type. Risk levels can vary depending on the
operations that a facility performs. A facility that manufactures drug
product or active ingredients is higher in risk than a facility that
only packages drug product.
Patient exposure. The more products a facility manufactures,
the more likely a patient is to encounter products made at that
facility. This refers to both number and types of products
manufactured. A facility that manufactures many products will have a
higher exposure factor than a facility that makes few products.
Inspection history. A facility that has not met established
quality standards when previously inspected is considered higher risk
than those that have met standards in the past.
Time since last inspection. As the time since a facility was
last inspected increases, the risk that it may not meet established
quality standards increases, as does the need for re-inspection.
Hazard signals. Events such as product recalls or
manufacturers' or patients' reports of quality problems associated with
a facility increase the risk score when compared with facilities that
have fewer or no major hazard signals.
FDA compares a facility's score to others in the Catalog and ranks
them by risk, with the highest risk assigned for inspection regardless
of location.
If the three factors that are fairly static for a facility
(inherent product risk, facility type and patient exposure) are used to
risk rank facilities, for inspections conducted from December 2011 to
May 2020, the median time between inspections was 2.1 years for high-
risk facilities. In general, all high-risk facilities were inspected
with about the same frequency regardless of location. (See Figure 5)
[GRAPHIC] [TIFF OMITTED] T6220.010
Inspection Outcomes
Following inspection of a manufacturing facility, FDA classifies
the inspection as ``no action indicated'' (NAI), ``voluntary action
indicated'' (VAI), or ``official action indicated'' (OAI).
No Action Indicated (NAI) means that no objectionable
conditions or practices (e.g., quality problems) were found during the
inspection (or they were minor problems that do not justify further
regulatory action).
Voluntary Action Indicated (VAI) means objectionable
conditions or practices were found but the agency is not prepared to
take or recommend any administrative or regulatory action.
Official Action Indicated (OAI) means regulatory and/or
administrative actions will be recommended.\7\
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\7\ See ``What Is a Classification?'' at https://www.fda.gov/
inspections-compliance-enforcement-and-criminal-investigations/
inspection-references/inspections-database-frequently-asked-questions.
Not surprisingly, with more frequent inspections directed to
higher-risk facilities since 2012, FDA uncovered more deficiencies,
particularly in foreign facilities that had not been inspected as
frequently as domestic ones prior to the inception of FDASIA and GDUFA.
Notably these were foreign inspections that were generally announced to
facilities in advance (pre-announced). Nevertheless, 90 percent or more
of the final outcomes of inspections were acceptable (NAI or VAI) in
all countries or regions except India. (See Figure 6)
[GRAPHIC] [TIFF OMITTED] T6220.011
Both foreign and domestic drug manufacturers must meet the same
regulatory requirements in terms of complying with established quality
standards (CGMPs). If a facility doesn't meet CGMP standards upon
inspection, FDA has an array of regulatory tools it can use to
encourage a company to remediate their manufacturing processes and
achieve compliance. These tools include warning letters, import alerts,
injunctions, and seizures.\8\ If the agency observes on a follow-up
inspection that a facility still does not meet CGMP standards, it can
escalate the matter as appropriate.
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\8\ Import Alert: Import alerts inform the FDA's field staff and
the public that the agency has enough evidence to allow for Detention
Without Physical Examination (DWPE) of products that appear to be in
violation of the FDA's laws and regulations. These violations could be
related to the product, manufacturer, shipper and/or other information.
If a foreign facility is found to have quality problems serious
enough for FDA to classify it as OAI, the agency can place a facility
on Import Alert, which is used to prevent potentially violative drugs
from the facility from entering the U.S. Generally, FDA will remove a
facility from a CGMP-related Import Alert after an onsite re-inspection
demonstrates that the problems have been remediated and the firm is in
---------------------------------------------------------------------------
compliance with CGMP.
Despite the tools at FDA's disposal, we still face some challenges
in ensuring the safety of imported drugs entering our drug supply.
Current mandates for facility inspection prior to import or marketing
of a drug in the U.S. are typically in the context of premarket
approval requirements. For drugs that are subject to premarket approval
requirements, FDA has an opportunity to evaluate and inspect the
manufacturing facilities as part of the application review process.
However, for drugs that are not subject to premarket approval
requirements, manufacturers may not be subject to FDA inspection before
such products are shipped to or distributed in the U.S. Drugs in this
category typically include OTC monograph drugs and APIs used in
pharmacy compounding. FDA may be required to engage in more challenging
and resource intensive efforts to identify and respond to any problems
that arise subsequently; however, patients may have already been
exposed to the drugs. For example, in 2019 we issued a warning letter
to a discount retailer for receiving OTC drugs produced by foreign
manufacturers with serious violations of CGMPs. The majority of the
foreign facilities involved had distributed drugs to the U.S. prior to
FDA inspections.\9\
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\9\ https://www.fda.gov/inspections-compliance-enforcement-and-
criminal-investigations/warning-letters/greenbrier-international-inc-
dba-dollar-tree-574706-11062019.
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FDA's Program Alignment Initiative and Concept of Operations Agreement
The inspection of drug manufacturing facilities relies on the
collaboration of two organizations within FDA: ORA, which includes the
field force of investigators who conduct the inspections, and CDER,
which includes policy and regulatory experts who establish the policies
governing drug quality, assess risks, and review action
recommendations, including OAI recommendations from ORA and for-cause
inspections to determine the final classification and whether
appropriate regulatory action is required. CDER also includes assessors
who evaluate applications for marketing approval and post-marketing
changes. In May 2017, as part of a broader agency initiative called
Program Alignment, ORA implemented a program-based management structure
aligning staff by FDA-regulated product. This created a specialized
inspectorate focused on human drugs.
FDA modeled its oversight of the increasingly complex and global
drug manufacturing supply chain to better integrate facility
evaluations and inspections for human drugs--to improve our efficiency,
reach, and the public health. In June 2017, CDER and ORA entered into a
Concept of Operations \10\ (ConOps) agreement to more effectively
manage the growing complexity of the pharmaceutical landscape. The
agreement, Integration of FDA Facility Evaluation and Inspection
Program for Human Drugs: A Concept of Operations, outlines the
responsibilities and the workflow for pre-approval, surveillance, and
for-cause inspections at domestic and international facilities.
---------------------------------------------------------------------------
\10\ See https://www.fda.gov/media/107225/download.
As part of ConOps the decision classification workflow process was
redesigned. (See Figure 7) Under the ConOps agreement, when ORA
initially recommends classifying the inspection as OAI, CDER reviews
the report along with any remediation plan or response submitted by the
company. CDER evaluates the evidence supporting inspection
observations, potential impact to patient safety, the company's
responses to the observations, and the adequacy of proposed corrective
actions. CDER may reclassify the inspection based on this review. CDER
also can, and has, upgraded classifications to OAI, even when initial
recommendations from the field are for an acceptable classification.
This typically occurs with for-cause inspections where the proposed
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corrective actions by the firm are determined by CDER to be inadequate.
[GRAPHIC] [TIFF OMITTED] T6220.012
Implementation of the ConOps has improved consistency in evaluation
of inspection observations and classifications and has reduced the time
frames for taking enforcement action. The percentage of cases in which
CDER concurs with ORA's initial recommendation is known as the
``concurrence rate.'' (See Figure 8) In 2019, the concurrence rate had
risen to 73 percent.
[GRAPHIC] [TIFF OMITTED] T6220.013
The median time for FDA to issue a warning letter for drug
manufacturing issues has decreased since ConOps was implemented, even
though the number of warning letters FDA has issued has increased
during that same time period. (See Figure 9)
[GRAPHIC] [TIFF OMITTED] T6220.014
Building an Investigator Work Force
Since 2015, FDA has performed more foreign than domestic
inspections. The agency has done so by using a mixed investigator work
force consisting of (1) U.S.-based investigators who perform both
domestic and foreign inspections; (2) a dedicated foreign cadre of
U.S.-based drug investigators who conduct foreign inspections
exclusively; and (3) foreign office-based experienced investigators who
inspect facilities manufacturing human drugs. (See Table 1) The
majority of foreign inspections are performed by U.S.-based
investigators.
Table 1. FDA's Investigator Work Force for Inspections of Foreign
Facilities Producing Human Drugs, FY 2019
------------------------------------------------------------------------
Number of
Foreign Estimated
Number of Inspections Each Percentage of
Type of Qualified Foreign Investigator is All Foreign
Investigator Drug Investigators Expected to Inspections
in FY 2019 Perform Each Performed in FY
Year 2019
------------------------------------------------------------------------
U.S.-Based 188 3-6 foreign 90%
Investigators inspections per
Performing year
Foreign and
Domestic
Inspections
------------------------------------------------------------------------
Dedicated Foreign 11 (included in 16-18 16% (part of
Drug Cadre Based the 188 listed inspections per the 90% above)
in U.S. above) year
------------------------------------------------------------------------
Foreign Office- 10 15 inspections 10%
Based per year
Investigators
------------------------------------------------------------------------
During calendar year 2019 ORA successfully hired and on-boarded 24
pharmaceutical investigators. In 2020 our investigator hiring efforts
are continuing, and with our new direct hire authority we anticipate
filling all our pharmaceutical investigator vacancies in 2020. In
recent years, the Office of Global Policy and Strategy, which oversees
FDA's foreign offices, has made progress in developing the foreign
office-based inspectorate. At the same time, FDA's participation in the
Mutual Recognition Agreement with the European Union has enabled us to
focus more of our investigator work force on higher-risk facilities
around the world.
The agency continues to face challenges, however, in developing the
investigator work force due to the rigorous nature of the job (e.g.,
foreign travel restrictions and hardship) and competition for qualified
candidates. Once the agency succeeds in hiring a new investigator, it
can take 1.5 to 2 years of training to bring them to a fully proficient
level. FDA also faces challenges to achieving optimum staffing levels,
such as negotiated agreements with host countries that affect the
number of investigators who can permanently attach to a foreign office.
COVID-19 and Inspection Impact
As noted at the beginning of this testimony, as a result of the
COVID-19 pandemic, most foreign and domestic surveillance facility
inspections are currently postponed. Only inspections deemed mission-
critical will be considered on a case-by-case basis as this outbreak
continues to unfold.
We employ additional tools to ensure the safety of products
imported to the U.S., which have proved effective in the past. These
include:
Denying entry of unsafe products into the U.S.;
Physical examinations and/or product sampling at our borders;
Reviewing a firm's previous compliance history;
Using information sharing from foreign governments as part of
mutual recognition and confidentiality agreements; and
Requesting records ``in advance of or in lieu of'' on-site
drug inspections.
Through our risk-based import screening tool (PREDICT), FDA has the
ability to focus our examinations and sample collections based on
heightened concerns of specific products being entered into U.S.
commerce. The PREDICT screening continues to adjust risk scores as
necessary throughout the COVID-19 outbreak.
FDA investigators remain on the front lines at ports of entry,
quickly examining and reviewing import entries to help ensure goods
being imported are consistent with FDA requirements and/or policies. We
are in close communication with our partners at U.S. Customs and Border
Protection to proactively identify and mitigate any potential backlogs.
FDA participates in FEMA Supply Chain Task Force meetings,
providing regulatory support and subject matter expertise to respond to
questions concerning medical products identified by FEMA, to facilitate
the lawful entry and use of imported medical products coordinated
through FEMA, and to inform medical product supply chain discussions.
FDA remains committed to using all available tools to oversee the
safety and quality of FDA-regulated products for American patients and
consumers. As this remains a dynamic situation, we will continue to
assess and calibrate our approach as needed and we stand ready to
resume any postponed inspections as soon as feasible.
FDA's Sampling and Testing Program
Although application assessments and inspections are a foundation
of FDA's efforts to maintain a safe, reliable drug supply, the safety
and effectiveness of drugs depends on a multipronged approach, of which
quality checks by FDA and manufacturers are a part. To help ensure that
safe and effective drugs are sold in the U.S., we test selected drugs
in state-of-the-art FDA laboratories and through research contracts and
grants. This testing program includes APIs and finished drug products.
We test using the same standards that are part of the drug approval
process for identity, strength, and purity.
Some have questioned why we do not test every drug product before
it enters the U.S. FDA performs thousands of tests a year pre- and
post-market. Only a small percentage (about one percent) of drugs that
are tested fail to meet the established quality specifications.\11\
Testing by FDA or third parties of each batch of drug product in U.S.
commerce, which amounts to millions of batches and trillions of
individual tablets, capsules, and other dosage forms, before they enter
the U.S. market would not be feasible at a practical level (in 2018,
there were almost 186 trillion tablets and capsules on the U.S. market
\12\) and the current approach is effective and efficient.
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\11\ These are established in approved applications, and for many
drugs also by USP (https://qualitymatters.usp.org/what-usp-standard).
\12\ IQVIA. National Sales Perspective. 2014-2018. Extracted:
August 2019.
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Additional Drug Safety and Surveillance Efforts
Ongoing review and surveillance efforts can identify new safety
concerns that require quick action. When they do, the agency makes
every effort to investigate potential health risks and provide our
recommendations to the public based on the best available science.
As an example, in April, FDA requested that manufacturers withdraw
all prescription and over-the-counter (OTC) ranitidine drugs from the
market immediately. This was the latest step in an ongoing
investigation of a contaminant known as N-Nitrosodimethylamine (NDMA)
in ranitidine medications (one commonly known brand name is Zantac).
FDA began an investigation into potential NDMA contamination in drug
products containing ranitidine when it first obtained information that
there was a possibility of impurities in those products. NDMA is a
probable human carcinogen (a substance that could cause cancer).
Last summer, the agency became aware of independent laboratory
testing that found NDMA in ranitidine. Low levels of NDMA are commonly
ingested in the diet; for example, NDMA is present in foods and in
water. These low levels would not be expected to lead to an increase in
the risk of cancer. However, sustained higher levels of exposure may
increase the risk of cancer in humans. The agency conducted thorough
laboratory tests and found NDMA in ranitidine at low levels. At the
time, the agency did not have enough scientific evidence to recommend
whether individuals should continue or stop taking ranitidine
medicines. FDA continued its investigation and warned the public last
fall of the potential risks and to consider alternative OTC and
prescription treatments.
New FDA testing and evaluation confirmed that NDMA levels increase
in ranitidine even under normal storage conditions, and NDMA has been
found to increase significantly in samples stored at higher
temperatures, including temperatures the product may be exposed to
during distribution and handling by consumers. The testing also showed
that the older a ranitidine batch is, or the longer the length of time
since it was manufactured, the greater the level of NDMA, possibly
resulting in ranitidine product being above the acceptable daily intake
limit.
Based on this information, FDA took swift action to assure that
ranitidine products will no longer be available for new or existing
prescriptions or OTC use in the U.S.
FDA Encourages Industry to Invest in Mature Quality Management Systems
and Advanced Manufacturing Technology
FDA inspects manufacturing facilities and takes action, if needed,
to enforce CGMP quality standards and applicable regulations. The
agency's investigators look for deficiencies in meeting CGMP standards,
but these assessments do not measure how far the facility is above the
minimum CGMP. Simple adherence to CGMP standards does not indicate that
a firm is investing in improvements or planning or deploying advanced
quality control techniques that could better enable it to prevent
quality problems leading to supply disruptions.
This is why it is critical that industry evolve from meeting the
minimum manufacturing quality threshold to achieving quality management
maturity. Some pharmaceutical firms have been slow to implement robust,
mature quality systems and the accompanying quantitative measures of
quality that have been the foundation of success in other industries,
such as automotive and aerospace.\13\ These industries exercise quality
oversight by continuously monitoring quality in real time during
manufacturing of their products, and promptly correcting operations
when needed. Numerous organizations and quality experts have worked to
develop conceptual models and standards for advancing the maturity of
industrial quality management systems. These models could be used more
broadly in the pharmaceutical industry to improve the quality and
reliability of the drug supply.
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\13\ Fuhr, Ted, et al., 2015, Flawless--From Measuring Failure to
Building Quality Robustness in Pharma, McKinsey and Company.
Many pharmaceutical manufacturers, whether domestic or foreign,
have been slow to invest in these mature quality management systems
because the market currently has no visibility into manufacturing
facilities' quality. This lack of transparency reinforces competition
based solely on price and disincentivizes companies from making
investments in upgrading their facilities and quality practices until
problems become frequent and severe enough to result in supply
disruptions and drug shortages. As we have stated in our recent report,
``Drug Shortages: Root Causes and Potential Solutions,''\14\ a way to
create incentives for manufacturers to invest in product quality is to
develop and implement a rating system for quality management maturity
that is based on objective criteria. Such a rating system could enable
purchasers to compare differences in quality and choose whether to
reward more reliable manufacturers financially and with increased
market share.
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\14\ https://www.fda.gov/drugs/drug-shortages/agency-drug-
shortages-task-force.
In addition to quality management maturity, the agency encourages
pharmaceutical manufacturers to invest in advanced manufacturing
technology to improve their products and processes. Although widely
used in some other industries, such as automotive, aerospace, and
semiconductors, advanced manufacturing is now just beginning to be used
by pharmaceutical companies. New technologies include ``continuous
manufacturing'' (CM), wherein the finished drug product or active
pharmaceutical ingredient is produced as a continuous stream, as
opposed to traditional batch manufacturing where breaks or stops exist
between different processing steps. In some examples of advanced
pharmaceutical manufacturing, production can be continuous from
chemical synthesis of the active ingredient through production of the
tablets or other dosage forms. Product quality can be precisely
controlled with modern automation and control systems and can be
closely monitored during production by using highly sensitive
analytical tools. Other examples of advanced manufacturing include 3D
printing, isolator technology, miniaturization, and robotics.
conclusion
Thank you for the opportunity to discuss FDA's oversight of
pharmaceutical manufacturing. COVID-19 has provided yet more proof that
to protect the reliability and availability of drugs to treat Americans
is of vital importance. We look forward to working with the committee
and others to strengthen investment in modern manufacturing technology,
establish incentives for mature quality management systems, and
consider additional measures.
We are happy to answer any questions.
______
Questions Submitted for the Record to Mark Abdoo; Judith McMeekin,
Pharm.D.; and Douglas C. Throckmorton, M.D.
Questions Submitted by Hon. Chuck Grassley
announced versus unannounced inspections
Question. The Government Accountability Office has noted that
almost all domestic inspections are unannounced; however, the FDA often
pre-announces foreign inspections. In some cases, the FDA has provided
12 weeks of notice before a foreign inspection.
By providing advanced warning that an inspection will take place,
doesn't it give bad actors time to hide the true nature of problems at
their facilities? If not, why not?
Wouldn't unannounced inspections provide a more accurate view of
whether or not foreign manufacturers are complying with quality control
standards? If not, why not?
Answer. There are many critical variables that are weighed and
assessed to determine whether an announced or an unannounced inspection
approach will lead to the best inspectional information.
Unannounced inspections can facilitate the detection of facility
violative conditions when firms are intentionally seeking to deceive
the agency by falsifying records or by hiding violations in advance of
an inspection. However, FDA investigators are trained to review records
and to uncover data integrity issues and fraudulent data with
techniques such as searching data audit trails. Therefore, both the
hiding of reportable deviations and violations, and falsification of
records may be uncovered. When the agency receives complaints, reports
from confidential informants, or other information that suggests that
serious violations are occurring, unannounced inspections may be used.
In many cases there are benefits to announced inspections and these
include fostering a culture of cooperative continuous improvement for
many establishments. Prior notice of an upcoming inspection ensures the
correct subject matter experts will be available for an efficient,
productive inspection and that appropriate firm representatives with
the right expertise are available during the inspection.
Furthermore, unannounced inspections become impractical when
conducting most foreign inspections. Foreign inspections require weeks
of planning, with additional costs and administrative requirements,
such as special visas and country permissions. Foreign travel to many
countries can be difficult due to distance and means of travel, often
involving many flights, plus train or car travel with one-way travel
times encompassing entire days. This time and resource investment may
be wasteful and unproductive if, upon arrival at the facility, FDA
determines that the firm has ceased manufacturing the product of
interest, or the firm is not operational (e.g., shut down for
cleaning), the facility has closed, or key manufacturer representatives
are not available to participate in the inspection and therefore
unavailable to respond to investigator questions. This expenditure of
resources, when unproductive, is a lost resource that would have
potentially been utilized as capacity to conduct other inspections
(indirect cost of lost productivity). It is also important to note that
foreign inspections require visa applications and other notifications
of foreign governments as noted above. This leads to a possibility that
manufacturers may become aware through informal channels of an upcoming
unannounced inspection, eliminating the potential benefits of
unannounced inspections.
We strategically continue unannounced inspection on a for-cause
basis even in the foreign arena. FDA's in-country investigators who are
attached to FDA's foreign offices conduct unannounced FDA inspections,
but those resources are limited due to the challenges of recruiting and
retaining experienced FDA investigators in these positions.
FDA will continue to actively evaluate establishing criteria to
assess unannounced inspections in the foreign arena and how those can
be practically incorporated into operations, balancing the requirements
necessary to carry out inspectional assignments successfully while
being good stewards of U.S. government resources to achieve the
intended public health outcomes.
Question. When an inspection identifies manufacturing quality
problems, what does the FDA do to inform entities along the supply
chain that manufacturing problems have been found?
Answer. Drug product manufacturers have existing requirements to
evaluate the quality of components before use in drug product
manufacturing and conduct investigations and associated follow-up, as
appropriate.
When quality problems are identified, FDA may issue warning letters
to multiple responsible stakeholders within a supply chain. FDA also
posts warning letters on its website and may also add the firm and
product to import alerts, which are available to the public and
industry to inform their compliance decisions. In some instances, FDA
also maintains an Inspection Classifications Database,\1\ which shows
inspections conducted by FDA and assessments of regulated facilities.
It can be used by entities along the supply chain to identify firms
with a final inspection classification indicating whether the firm is
in compliance with applicable laws and regulations.
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\1\ https://www.fda.gov/inspections-compliance-enforcement-and-
criminal-investigations/inspection-classification-database.
Seizure and injunction are other possible actions that may be
considered.
cder reclassifications
Question. This committee has talked with individuals associated
with FDA's inspection and reporting process and CDER's review of those
inspections reports. Some have told us that CDER tends to downgrade, or
reclassify, inspections reports from ``Official Action Indicated'' to
``Voluntary Action Indicated.''
Why does CDER have a tendency, according to information provided to
this committee, to reclassify inspection reports?
Answer. In June 2017, CDER and ORA entered into a Concept of
Operations (ConOps) agreement to more effectively manage the growing
complexity of the pharmaceutical landscape. As part of ConOps, the
decision classification workflow process for inspections was
redesigned. Under the ConOps agreement, when ORA initially recommends
classifying an inspection as Official Action Indicated (OAI), CDER
reviews the report along with any remediation plan or response
submitted by the company. CDER evaluates the evidence supporting
inspection observations, potential impact to patient safety, the
company's responses to the observations, and the adequacy of proposed
corrective actions. CDER may reclassify the inspection based on this
review. CDER also can, and has, upgraded classifications to OAI, even
when initial recommendations from the field are for an acceptable
classification. This typically occurs with for-cause inspections where
the proposed corrective actions by the firm are determined by CDER to
be inadequate.
Implementation of the ConOps has improved consistency in evaluation
of inspection observations and classifications and has reduced the
timeframes for taking compliance actions, even as the volume of
compliance actions has increased. The percentage of cases in which CDER
concurs with ORA's initial recommendation is known as the ``concurrence
rate.'' The concurrence rate has steadily increased over the last 10+
years, indicating a corresponding decrease reclassifications;
concurrence rates on foreign drug inspections designated OAI were 50
percent in 1996 and rose to 73 percent in 2019.
Question. Do you have data on how many inspection reports have been
reclassified by CDER? If not, why not? If so, will you commit to
sharing that data with the committee?
Answer. Since ConOps was implemented, for FY18 and FY19, CDER
received 351 classification recommendations from ORA. There were 74
downgrades (25 percent of initial OAI recommendations) as well as 17
upgrades (30 percent of initial NAI/VAI classifications).
Question. Please describe the factors CDER considers when
reclassifying a finding from ``Official Action Indicated'' to a lower
level.
Answer. Under the ConOps agreement, when ORA initially recommends
classifying the inspection as OAI, CDER reviews the report along with
any remediation plan or response submitted by the company. CDER
evaluates the evidence supporting inspection observations, potential
impact to patient safety, the company's responses to the observations,
and the adequacy of proposed corrective actions. CDER may reclassify
the inspection based on this review. If CDER determines an enforcement
action is not warranted, ORA is notified of the downgraded
classification and provided a written description of the reason(s) for
downgrade within 40 days. CDER may make this determination based on
analyses that included evaluation of the evidence to support the
inspection observations, the impact to patient safety, and the firms'
responses to the observations and whether their proposed corrective
actions were adequate.
Question. In light of the safety issues surrounding foreign drug
manufacturing discussed during this and previous congressional
hearings, is the FDA researching any alternative models of monitoring
the drug supply chain? If so, please explain.
Answer. Several FDA proposals included in the FY 2021 President's
Budget request would help the agency in its efforts to further
strengthen the supply chain and address drug shortages. In particular,
the request included the proposal, ``Improving Critical Infrastructure
Through Improved Data Sharing: Requiring More Accurate Supply Chain
Information.''
This proposal would help FDA better anticipate and react more
expeditiously to drug shortages by enabling us to quickly identify all
manufacturing sites impacted, analyze potential bottlenecks, and
develop options to remediate shortage risks to the product supply
chain. For example, having this information available would reduce the
time FDA staff must spend to determine if a facility is the only
facility distributing a drug product or API, or to determine which
firms rely on an API supplier located in an area impacted by a natural
disaster.
In addition, FDA works to improve its evaluation of the
effectiveness of our inspection programs to ensure that our inspection
capacity, procedures, and techniques are suitable in addressing the
risks and challenges we face in ensuring drug quality for U.S.
consumers.
FDA's Office of Regulatory Affairs (ORA) has an established quality
management system (QMS) that aims to provide consistent investigational
processes and work products, meet organizational requirements, and
enable continual improvement of inspectional operations. The QMS
ensures investigators can access procedures and instructions necessary
to perform operational activities in a consistent manner, and provides
a risk-based approach for capturing, analyzing, and addressing issues.
The system includes quality control activities to review work products
and quality assurance activities (such as audits and management
reviews).
FDA also evaluates the significance of the findings from each
inspection to assess the need for further regulatory activity to
address non-compliance.
drug shortages
Question. In certain instances, the FDA has approved medication
under Medicare and later discovered that manufacturers have not
complied with relevant statutes and regulations. In those instances
where withdrawing approval of a drug would create a shortage, does the
FDA suspend approval of the drug until compliance is met? If not, what
steps does the FDA take to bring the manufacturer back into compliance?
Does the FDA treat drug compliance enforcement action differently
based on the scarcity of a drug?
Answer. FDA does not approve drugs specifically for or under
Medicare; FDA approves drugs for the American public based on the
safety and efficacy standards established in the Federal Food, Drug,
and Cosmetic Act, and the Centers for Medicare and Medicaid Services
(CMS) decides whether and how it will be covered in the programs they
administer. However, below, we explain the coordination that occurs
within FDA with respect to compliance actions and the potential for
shortages of drugs subject to the shortage notification requirement in
section 506C(a) of the Federal Food, Drug, and Cosmetic Act (FD&C Act).
As described in FDA's Drug Shortage Management Manual of Policies
and Procedures (MAPP) (https://www.fda.gov/media/72447/download), the
Center for Drug Evaluation and Research's (CDER's) Office of Compliance
works closely with the Drug Shortage Staff before taking any
enforcement action or issuing a warning letter to determine if the
action or letter could cause or exacerbate a drug shortage. If it is
determined that an action or warning letter could lead to or exacerbate
a shortage, the Office of Compliance works with the Drug Shortage Staff
and other appropriate offices to evaluate the risks to patients
associated with a potential shortage and the risks associated with the
violation involved. As appropriate, the agency may then decide to
exercise enforcement discretion, as a temporary measure, to help
prevent or mitigate the potential shortage.
FDA has used temporary regulatory flexibility and discretion for
the distribution of certain medically necessary products (as defined in
the Drug Shortage Management MAPP) that present quality issues with
measures to mitigate risk in light of the risk to patients of not
receiving the drug, as follows: filters are supplied with a product to
remove particulate matter; extra testing for product quality or
identity is done at the manufacturing facility before releasing the
product into the marketplace; third-party oversight of production is
instituted to monitor quality issues; and special instructions are
provided to health-care professionals/patients.
FDA has also exercised temporary regulatory flexibility and
discretion with regard to continued distribution of a drug product to
mitigate or resolve a drug shortage while FDA reviews a supplement/
proposed change to address a problem with the drug product.
During a drug shortage, whether or not such mitigating measures are
taken as a temporary measure, FDA's priority is to restore supplies of
FDA-approved drugs that comply with applicable standards, and we use
all of our authorities toward this end. This may include, for example,
working with sponsors to resolve quality issues, expediting review of
applications that could address a shortage, or seeking additional
sources of a drug in shortage.
Question. What forms of non-compliance does the FDA consider to be
material to the approval status of a drug?
Answer. FDA-approved drugs have been shown to be safe and effective
under applicable provisions of the FD&C Act and its implementing
regulations. To be legally marketed, approved drugs must meet all
applicable legal requirements. See generally sections 501, 502, 503 and
505 of the FD&C Act (21 U.S.C. 351-53, 355). Approval may be withdrawn
if the standard for withdrawing an approval is met. See section 505(e)
of the FD&C Act (21 U.S.C. 355(e)); see also 21 CFR 314.150-153.
drug testing
Question. You testified that ``only a small percentage, about 1
percent, of drugs that are tested [by FDA] fail to meet the established
quality specifications.''
How does the FDA commonly procure batches of pharmaceutical
products for analysis?
If these products are procured directly from manufacturers, does
this present the potential for fraud and abuse?
Describe FDA's programs, if any, to acquire medication samples
without voluntary submission from manufacturers, including what
percentage of the FDA's testing comes from such programs.
Answer. FDA has a long-standing program to regularly sample and
test marketed drugs and active pharmaceutical ingredients (APIs) for
conformance to specifications. We select hundreds of samples each year
based on certain criteria.
Some testing decisions are event-driven. For example, we might
test product samples after receiving a pattern of complaints about
adverse events, quality issues or reduced effectiveness. These reports
come to FDA consumer complaints, field alert reports and MedWatch: The
FDA Safety Information and Adverse Event Reporting Program.
We also rely on the experience of internal and external
experts to alert us to emerging safety, effectiveness, or quality
issues with currently marketed drug products. For example, results from
independent research may require FDA testing and investigation.
Sometimes, manufacturing or facility concerns may trigger
additional FDA monitoring and testing. For instance, FDA may sample
products with difficult manufacturing processes or drug products with
complex dosage forms such as patches, drugs designed to target a
specific area, and drugs that release the active ingredient in a
controlled manner.
FDA may also sample drugs produced by manufacturing processes that
require additional controls to assure each dosage unit will perform as
expected, such as delivering a precise amount of active ingredient
within a narrower range, because even slight deviations could cause
quality issues.
We use a risk-based approach to quality testing. This means that in
cases where there is a known or likely safety, effectiveness, or
quality issue with a product, FDA scientists perform tests specifically
for this vulnerability. For example, if an API is likely to become
contaminated with a harmful impurity during the manufacturing process,
FDA tests for that specific impurity, rather than testing for all
potential impurities.
Through our risk-based import screening tool, PREDICT (Predictive
Risk-based Evaluation for Dynamic Import Compliance Targeting), FDA
focuses agency import resources, including activities such as
examinations and sample collections, on higher-risk products being
offered for entry into U.S. commerce. PREDICT uses automated data
mining, pattern discovery, and automated queries of FDA databases to
determine the potential risk of a shipment. The analytics tool takes
into consideration the inherent risk of a product and information about
the previous history of importers, manufacturers, and shippers. As part
of our COVID-19 response, FDA has adjusted PREDICT screening to account
for firms whose foreign inspection was postponed due to COVID-19 travel
restrictions.
FDA labs acquire samples for testing by a number of different
mechanisms, including directly from consumers and purchases from the
U.S. market via distributors, wholesalers, and retail pharmacies. FDA
has found that approximately one percent of samples tested, both
foreign and domestic, fail to meet quality standards. In addition, FDA
investigators can collect the samples directly at drug manufacturing
sites and deliver or send them to FDA testing labs (maintaining chain
of custody). If required, FDA also has the ability to purchase samples
online while retaining anonymity. Finally, some samples are sent to FDA
labs directly from manufacturers as the result of information request
(IR) letters from FDA assessor staff. In many cases, such samples are
requested to verify test results on the same batches the firms supply
to FDA. Using this ``trust but verify'' approach, the agency can use
the most accurate available data to make regulatory decisions.
india pilot program
Question. In 2013 the FDA implemented the India Pilot Program that
eliminated announced inspections or provided a couple days' worth of
notice, instead of weeks. The result was an increase in the FDA's most
serious finding, ``Official Action Indicated.''
This pilot program was shut down in 2015 by the Obama
administration without explanation and FDA returned to the previous
practice of announcing inspections.
Do any of you know why the Obama administration shut down the India
Pilot Program?
Who at the FDA made the decision to end the India Pilot Program?
Would you describe the pilot program as a success? If not, why not?
What lessons have you learned from the program that have been
implemented into FDA practices today?
Answer. FDA's Office of International Programs, in collaboration
with FDA's Office of Regulatory Affairs, conducted an initiative
between January 2014 and August 2015 to reduce the notification time
for a drug inspection in India to one business day or less. This
initiative (often referred to as a pilot) allowed for the utilization
of in-country FDA and State Department resources for logistics (e.g.,
visa invitation letters, hotel reservations).
In August 2015, FDA decided not to extend the initiative due to the
following: (1) the lack of a sufficient protocol and evaluation
criteria for such an initiative limited to a single country and (2) the
need to analyze the dataset generated during the initiative up until
that point in order to consider its impact on agency resources, on
industry operating within India, and on other aspects of FDA's foreign
inspections program. At this time, FDA is evaluating establishing
criteria to assess unannounced inspections in the foreign arena.
As we have stated, the inspection initiative in India was not a
true ``pilot,'' but we have implemented some best practices that we
determined were useful from our experiences with the initiative. First,
we stopped having firms issue letters so that we could get visas for
our investigators. We also no longer have firms involved in making
hotel selections or help with other travel arrangements. Finally, we
began a program where the investigator receives a pre-inspection
briefing from his or her colleagues at ORA headquarters to improve the
efficiency and effectiveness of the inspection.
supply chain visibility
Question. According to testimony from the FDA in October 2019, the
FDA ``has no visibility into which active pharmaceutical ingredient
supplier a final dosage form manufacturer uses at any given time.''
Should FDA have that type of visibility to better ensure quality and
safety? If not, why not?
Answer. Yes, it is important for FDA to have this information to
ensure quality and safety because the lack of adequate information on
the identity of sites involved in the manufacture of drugs, including
API suppliers, for U.S. consumers makes it difficult for FDA to
identify the scope of products that could be implicated, should a
problem arise.
In 2017, because this information was not readily available, FDA
had to expend significant resources to gather this critical
distribution and supply chain information to address supply disruptions
caused by the multiple hurricanes in Puerto Rico. This lack of adequate
insight is particularly an issue with respect to foreign sites as well
as manufacturers of API used in non-application drugs, such as over-
the-counter (OTC) monograph drugs, (i.e., those for which marketing is
governed by 505G of the FD&C Act). At least with respect to products
with approved applications, we have some insight into which API sources
may be used by the FDF facilities.
All domestic finished dosage form (FDF) and API establishments are
required to register with FDA, and all foreign FDF and API
establishments that manufacture drugs (including APIs) that are
imported or offered for import into the United States are required to
register with FDA. However, some foreign API and FDF establishments
that ship to other foreign establishments prior to the drugs being
imported or offered for import into the United States currently do not
register with FDA. Ensuring that all foreign establishments involved in
the manufacturing of drugs for the U.S. market register with FDA is
important because, among other things, our risk-based inspection
paradigm is based on establishment registration.
Additionally, API intermediate facilities (foreign or domestic) are
not currently required to register with FDA. The lack of registration
of a portion of the drug supply chain leaves the agency with
significant blind spots when working to predict, mitigate, and address
drug shortages. Without sufficient insight into the upstream supply
chain for drug products, the agency is often unaware of whether an
event affecting a particular country or region could potentially
disrupt the U.S. drug supply, and unable to conduct appropriate
oversight of potential risks in the drug supply chain.
Clarifying that registration is required for all foreign
establishments involved in manufacturing drugs for the U.S. market and
expressly requiring the registration of API intermediate establishments
would close a major information gap and help to prevent foreign
manufacturers from introducing unsafe drugs into the U.S. supply chain.
FDA is requesting explicit statutory authority along these lines so
that we can expeditiously collect critical distribution and supply
chain information and more rapidly improve our ability to address the
critical public health issue of drug shortages before the next natural
disaster or unforeseen hazard impacts U.S. patients.
Question. What has the FDA done to solve these limitations? Please
describe in detail what FDA could do to shore up these limitations and
provide greater visibility into the drug supply chain.
Answer. On March 27, 2020, the President signed into law, the
``CARES Act,'' Pub. L. 116-136. Among the provisions included was a
requirement added to the FD&C Act that manufacturers annually report to
FDA on the ``amount of each drug . . . that was manufactured, prepared,
propagated, compounded, or processed'' for commercial distribution.
FDA is leveraging this reporting requirement under the CARES Act so
that registered drug establishments will submit data in a uniform
format regarding the volume of APIs and finished dosage forms
manufactured at each registered facility. However, the volume data
reporting provided for in the CARES Act did not include the level of
detail needed for FDA to accurately assess our reliance on certain
countries to supply APIs for drugs manufactured for distribution in the
United States.
During consideration of legislation ultimately enacted as the CARES
Act, FDA proposed a more extensive set of policy priorities for
inclusion in the legislation, and still maintains that these policies
would position the agency to better predict and mitigate drug
shortages. These policies were included in the FY 2021 President's
Budget and propose to require more detailed and timely information
about a product's current supply chain and distribution to help the
agency better anticipate and react more expeditiously to drug
shortages. The additional information would enable us to quickly
identify all manufacturing sites impacted, analyze potential
bottlenecks, and develop options to remediate shortage risks to the
product supply chain. For example, having this information available
would reduce the time FDA staff must spend to determine if a facility
is the only facility distributing a drug product or API, or to
determine which firms rely on an API supplier located in an area
impacted by a natural disaster.
Specifically, this President's Budget proposal was titled,
``Improving Critical Infrastructure Through Improved Data Sharing:
Requiring More Accurate Supply Chain Information.'' This proposal, if
enacted, would ensure that each FDF facility, API facility, and API
intermediate facility is registered with FDA, including foreign
facilities that manufacture products that are indirectly imported into
the United States. Additionally, the proposal would require regular
(quarterly) reporting of certain disaggregated manufacturing volume
data and supply chain information. Specifically, FDF establishments
would be required to provide information about the volume of each drug
manufactured for the U.S. market, including the source and amount of
API from each source used to manufacture the FDFs. API establishments
would be required to provide information about the volume of API
manufactured for the U.S. market, including the source and amount of
API intermediate from each source used to manufacture the APIs.
Question. What risks to the drug supply chain have been exposed
and/or increased during the COVID-19 pandemic? What has FDA done to
bring solutions to mitigate those risks?
Answer. At this time, FDA is aware that there is an acute demand
for certain products and disruptions in the supply chain due to COVID-
19, and we are taking proactive steps to make sure that patients can
access the medications that are medically appropriate and necessary. We
work with our Federal partners, industry, professional organizations,
and other stakeholders to identify and address supply chain issues. FDA
provides technical assistance to other Federal agencies that are
seeking to prevent and mitigate supply chain disruptions and are
considering a variety of solutions including increasing U.S.
manufacturing when possible. We are also working closely with
stakeholders to establish mitigation strategies and prevent long-term
supply shortages.
We work closely with manufacturers to make sure they continue to
notify FDA, as early as possible, of a permanent discontinuance or an
interruption in manufacturing that is likely to lead to a meaningful
disruption in supply to the extent required under section 506C of the
FD&C Act. This communication and the full cooperation of companies
providing specific and necessary information is imperative for us to
have an accurate understanding of the supply landscape and work to take
proactive steps to mitigate shortages. To help human drug manufacturers
submit timely and informative notifications, the agency published a
guidance \2\ in March about these notifications, the timelines that
manufacturers should follow when notifying FDA, and the details they
should provide about the discontinuance or interruption of
manufacturing. We recognize that although some supply disruptions and
shortages cannot be predicted or prevented, early communication and
detailed notifications from manufacturers to the agency play a
significant role in decreasing their incidence, impact, and duration.
---------------------------------------------------------------------------
\2\ https://www.fda.gov/regulatory-information/search-fda-guidance-
documents/notifying-fda-permanent-discontinuance-or-interruption-
manufacturing-under-section-506c-fdc-act.
FDA's public drug shortages lists are up-to-date with human \3\ and
animal \4\ drugs and biological products \5\ that we have determined to
be in shortage. These shortages are not all the result of COVID-19,
with many existing prior to the public health emergency as the result
of market changes and supply challenges. We are updating these lists
regularly and communicating in real-time so that patients and
healthcare providers have the most current information on product
shortages in the United States.
---------------------------------------------------------------------------
\3\ https://www.accessdata.fda.gov/scripts/drugshortages/
default.cfm.
\4\ https://www.fda.gov/animal-veterinary/product-safety-
information/current-drug-shortages.
\5\ https://www.fda.gov/vaccines-blood-biologics/safety-
availability-biologics/cber-regulated-products-current-shortages.
The pharmaceutical sector relies heavily on foreign sourcing for
critical components, materials, and finished products. However, use of
foreign-sourced materials can create vulnerabilities in the U.S. drug
---------------------------------------------------------------------------
supply chain as evidenced by the COVID-19 public health emergency.
In response to the presidential executive order on Buy American and
Hire American (EO 13944), FDA is identifying those essential medicines,
medical countermeasures, and critical inputs that are essential to have
available at all times. Additionally, FDA continues its efforts to
facilitate that use of advanced manufacturing because FDA believes that
advanced manufacturing technologies could enable U.S.-based
pharmaceutical manufacturing to regain its competitiveness with foreign
countries, and potentially ensure a stable supply of drugs critical to
the health of U.S. patients. Advanced manufacturing offers many
advantages over traditional pharmaceutical manufacturing, and if the
United States invests in this technology, it can be used to reduce the
Nation's dependence on foreign sources of active pharmaceutical
ingredients (APIs), increase the resilience of our domestic
manufacturing base, and reduce quality issues that trigger drug
shortages or recalls.
In FY 2020, FDA's Center for Drug Evaluation and Research received
$9M of one-time, supplemental funding that will be used to continue to
modernize and enhance science in areas related to advanced
pharmaceutical manufacturing. Knowledge generated from these
activities, together with the information provided by sponsors or
applicants, could help enable science- and risk-based assessment and
inspection; establish best assessment and inspection practices; support
standard, policy and guidance development; and provide important
training on novel manufacturing technologies.
All domestic finished dosage form (FDF) and API establishments are
required to register with FDA, and all foreign FDF and API
establishments that manufacture APIs or FDFs that are imported or
offered for import into the United States are also required to
register. However, some foreign API and FDF facilities that ship to
other foreign facilities prior to the drugs reaching the United States
currently do not register with FDA.
Foreign or domestic facilities producing API intermediates are not
required to register with FDA. (An API intermediate is a material
produced during steps of the processing of an API that undergoes
further molecular change or purification before it becomes an API.) The
lack of registration of a portion of the drug supply chain leaves the
agency with significant blind spots when working to predict, mitigate,
and address drug shortages. Without sufficient insight into the
upstream supply chain for drug products, the agency is unaware of
whether an event affecting a particular country or region could
potentially disrupt the U.S. drug supply, and is unable to effectively
conduct appropriate oversight of potential risks in the drug supply
chain. This is particularly the case for APIs used in non-application
products (such as over-the-counter (OTC) monograph drugs, i.e., those
marketed under section 505G of the FD&C Act) because, at least with
respect to products with approved applications, we have some insight
into which API sources may be used by the FDF facilities as part of the
application assessment process.
Additionally, there are importers that appear to be registering
manufacturers without their knowledge. As a result, when the agency
identifies that a potentially hazardous product is in the market or at
the border pending evaluation, our investigation and discussion with
the importer and manufacturers are unnecessarily delayed while we work
to determine the facts of the case, the responsible parties, and the
most effective path to minimize harm to consumers and patients.
Another important challenge discussed in the hearings concerns our
oversight of APIs and FDFs coming into the United States, including
non-sterile and sterile drugs that do not require an application to be
marketed, such as APIs for compounding, and APIs for OTC monograph
drugs as well as FDFs of such drugs. For such drugs not subject to
premarket approval requirements, manufacturers may not be inspected by
FDA before such products are shipped to or distributed in the United
States. FDA can take action if we become aware of a quality problem
with these drugs; however, patients may have already been exposed to
the drugs. Compounding this problem, if the agency identifies problems
with the facilities after the drugs are already on the market, the
agency lacks authority to mandate recalls for most drugs.
Question. What percent of total volume of API used to make
pharmaceuticals intended for the U.S. market comes from China? Please
answer the same with respect to India.
Answer. For the reasons described in more detail below, we are
unable to provide data on the percent of total volume of APIs used to
make pharmaceuticals intended for the U.S. market that comes from China
or India. The best data we are able to provide are the percent of
registered API manufacturers in these countries.
As of May 2020, 13 percent of the API facilities that supply
all product types to the United States were located in China.
As of May 2020, 19 percent of the API facilities that supply
all product types to the United States were located in India.
Prior to enactment of the CARES Act on March 27, 2020, registered
drug establishments were not required to submit consistent data
regarding the volume of APIs and finished dosage forms manufactured at
each registered facility. The CARES Act imposed annual volume data
submission requirements on all drug establishments registered with FDA
(section 510(j)(3) of the FD&C Act).
During consideration of the CARES Act, FDA proposed a more
extensive set of legislative enhancements, reflecting the agency's
policy priorities, and still maintains that these policies would
provide the agency with more information about drug supply chains,
bolstering our ability to predict, prevent, and mitigate shortages. The
key elements of this proposal are to amend the FD&C Act to:
Ensure that each finished dosage form (FDF) facility, API
facility, and API intermediate facility is registered with FDA,
including foreign facilities that manufacture products that are
indirectly imported into the United States (i.e., used in foreign
manufacturing of drug products that are subsequently shipped to the
U.S.); and
Require regular (quarterly) reporting of certain disaggregated
manufacturing volume data and supply chain information. Specifically,
FDF establishments would be required to provide information about the
volume of each drug manufactured for the U.S. market, including the
source and amount of APIs from each source used to manufacture the
FDFs. API establishments would be required to provide information about
the volume of APIs manufactured for the U.S. market, including the
source and amount of API Intermediate from each source used to
manufacture the APIs.
However, the additional volume data provided for in the CARES Act
did not include this level of detail and limits our ability to
accurately assess our reliance on certain countries to supply APIs for
drugs manufactured for the United States.
Question. What percentage of registered fine chemical facilities
used in the production of API for pharmaceuticals intended for the U.S.
market are located in China, and what percent of total volume of fine
chemicals used to make API for pharmaceuticals intended for the U.S.
market come from China? Please answer the same with respect to India.
Answer. We are unable to provide this information because as noted
above, manufacturers of fine chemicals (what we generally refer to as
API intermediates) are not required to register with FDA, and API
manufacturers are not required to provide FDA with information about
the extent of their reliance on their sources of API intermediates. FDA
has asked for express statutory authority to begin collecting this
information.
The CARES Act imposed annual volume data submission requirements on
all drug establishments registered with FDA (section 510(j)(3) of the
FD&C Act). However, it did not require the submission of certain
disaggregated volume data regarding drugs produced by API and FDF
establishments, such as information about the sources of APIs and API
intermediates, nor about the amount of APIs and finished dosage forms
manufactured from each source. Additionally, the CARES Act did not
impose registration or listing requirements on fine chemical (API
intermediate) manufacturers.
national security
Question. Please describe the relationship that each of your units
has with the Office of National Security within the Department of
Health and Human Services.
Answer. FDA's Office of Global Policy and Strategy (OGPS) has a
strong relationship with the Office of National Security (ONS) within
the Department of Health and Human Services. When appropriate, OGPS
leadership receives classified briefings from ONS, including briefings
related to counterintelligence. OGPS leadership also receives a weekly
unclassified briefing document from ONS. OGPS shares information
generated at headquarters as well as at the FDA foreign offices with
ONS when relevant.
CDER engagement with other Agencies focused on national security is
coordinated through the Office of Counter-Terrorism and Emerging
Threats (OCET) in the Office of the Commissioner. Through them, we have
extensive contacts on matters relating to drug manufacturing and the
integrity of the supply chain.
Question. Please describe the steps that you will take to create a
better relationship between your units and the Office of National
Security. If such a relationship is not needed, please explain why that
is the case.
Answer. Currently OGPS engages with ONS when a specific situation
requires it to do so. OGPS plans to establish regular meetings with ONS
to discuss issues of mutual interest. OGPS will work with ONS to
determine the frequency of such meetings.
CDER engagement with other Agencies focused on national security is
coordinated through the Office of Counter-Terrorism and Emerging
Threats (OCET) in the Office of the Commissioner. Through them, we have
extensive contacts on matters relating to drug manufacturing and the
integrity of the supply chain.
Question. Please describe the national security risks that China
presents to the drug supply chain.
Answer. As a sole source for certain essential pharmaceuticals,
such as crude heparin, antibiotics, essential APIs and API starting
materials/critical intermediates, China presents as a vulnerability and
security risk to the U.S. drug supply chain. This has been made clear
earlier in 2020 as China's role as a major U.S. and global supplier of
certain medical products led to shortages of critical medical supplies
during the COVID-19 pandemic.
The following is a list of potential conditions that could lead to
further security risks. The list is broken out by short-term/less
predictable risks and long-term/government policy- or trade-related
risks.
Short-Term Risks:
Unexpected supply chain disruptions (e.g., COVID-19, flooding,
shutdowns, explosions).
In the event of a natural disaster or pandemic, requirements in
China to focus on domestic supply, limiting exports to countries like
the United States.
Introduction of falsified or substandard products into the
supply chain.
Diversion of the supply chain within China or shipping from
China to an alternate location before arriving in the United States.
Longer-Term Risks:
Politically motivated shutdown of exports from China.
Politically motivated price controls by China.
Lack of intellectual property protection of innovative products.
Subsidies given to domestic firms in China causing an imbalance
in competition, driving foreign companies out of the market.
______
Questions Submitted by Hon. John Cornyn
supply chain transparency
Question. Congress took important action as part of the Coronavirus
Aid, Relief, and Economic Security (CARES) Act (H.R. 748) enacted in
March. The CARES Act includes several important steps intended to help
strengthen the pharmaceutical supply chain. Specifically, section 3112
of the CARES Act increases the transparency of the pharmaceutical
supply chain by providing FDA with additional information on potential
disruptions in the supply chain, on manufacturers' contingency plans to
ensure continued supply and on the volume of medicines manufactured.
FDA was provided with 180 days to implement these new requirements.
What is FDA's plan for issuing guidance and ensuring these provisions
are implemented in a timely manner?
Answer. The CARES Act amended the Federal Food, Drug, and Cosmetic
Act (FD&C Act) to require that manufacturers provide FDA with certain
information about permanent discontinuances and interruptions in
manufacturing of finished products and active pharmaceutical
ingredients (APIs). In addition, the CARES Act amended the FD&C Act to
require that manufacturers develop, maintain, and implement, as
appropriate, a redundancy risk management plan for certain drugs, APIs,
and associated devices. These requirements took effect on September 23,
2020. FDA staff are working to issue guidance for industry to assist
manufacturers in complying with these new requirements.
The CARES Act also includes authorities that enhance FDA's ability
to identify, prevent, and mitigate possible drug shortages by, among
other things, enhancing FDA's visibility into drug supply chains.
Specifically, section 3112(e) amends the FD&C Act to require that each
registered drug establishment annually report the ``amount of each drug
. . . that was manufactured, prepared, propagated, compounded, or
processed'' by the registrant for commercial distribution. This CARES
Act amendment also provides that such ``information may be required to
be submitted in an electronic format.''
FDA staff are working to define the data to be reported, create an
electronic portal for the submission of this information, and determine
when to begin collecting this information. We will provide further
updates as our implementation planning continues.
active pharmaceutical ingredient testing
Question. Before active pharmaceutical ingredients (APIs) are used
in finished dosage form manufacture, are they generally tested?
Answer. Current regulations require drug product manufacturers to
test all components (ingredients) before use in manufacturing.
Manufacturers are required to test representative samples of each lot
of drug product before releasing the product to market. Testing
requirements also include testing raw materials and API batches before
use and, where appropriate, testing during the processing of APIs and
final products. Generally during CGMP inspections, we review the
records that manufacturers must maintain regarding required testing,
including testing for the expected and controlled impurities and
degradation compounds.
Question. Mr. Abdoo, testimony states that FDA has conducted more
foreign inspections than domestic since 2015.
Is there a focus on facilities that produce final dosage forms
(FDFs) over active pharmaceutical ingredients (APIs)?
Answer. Any facility that registers their establishment in FDA's
electronic drug registration and listing system (eDRLS) is subject to
an inspection as soon as possible following initial registration. If
the establishment is only associated with a pending NDA, ANDA, or BLA,
FDA may conduct a pre-approval facility evaluation and inspection as
part of the application assessment process. If the application is
approved, all manufacturing facilities identified in the approved
application that are required to register annually with FDA will be
included in CDER's Catalog of Manufacturing Sites and will be subject
to a surveillance inspection on a risk-based schedule in accordance
with section 510 of the FD&C Act.
FDA has a publicly available Manual of Policies and Procedures
(MAPP) 5014.1 that describes the agency's risk-based approach to
prioritizing and scheduling manufacturing sites for CGMP surveillance
inspections. One goal of this approach is to achieve parity in
inspection frequency, meaning equal frequency for sites with equivalent
risk, regardless of geography (foreign versus domestic). API and FDF
facilities are prioritized for inspection in accordance with the same
Site Selection Model.
Question. If a foreign facility is subject to a for-cause
inspection, are facilities that source their products notified, and
what is the procedure for doing so?
Answer. No, firms that source products from companies that undergo
a for-cause inspection are not notified of the inspection. FDA
considers a for-cause inspection to include: (i) follow-up compliance
inspections performed to verify corrective actions after a regulatory
action has been taken; (ii) inspections performed in response to
specific events or information (Field Alert Reports (FARs)), Biological
Product Defect Reports (BPDRs), industry complaints, recalls, and other
indicators of defective products, etc.) that bring into question the
compliance and/or quality of a manufacturing practice, facility,
process, or drug.
Follow-up compliance inspections provide focused coverage and
include the areas of concern, the proposed corrective action plan for
impacted operations, any implemented corrective actions, and/or the
deficiencies noted on the Form FDA 483.
pharmaceutical product testing
Question. What percentage of drugs that are sampled and tested by
FDA fail to meet the established quality specifications?\6\
---------------------------------------------------------------------------
\6\ Only about 1 percent of drugs that are tested fail to meet
quality specifications (http://www.fda.gov/news-events/congressional-
testimony/securing-us-drug-supply-chain-oversight-fdas-foreign-
inspection-program-12102019).
---------------------------------------------------------------------------
Do the products that fail tend to be domestically manufactured?
Answer. FDA has found that approximately one percent of samples
tested, both foreign and domestic, fail to meet quality standards. As
noted in a recent JAMA article authored by FDA scientists, difficult-
to-make prescription pharmaceuticals marketed in the U.S. consistently
meet quality standards whether they are manufactured in the United
States or elsewhere. Please see https://jamanetwork.com/journals/
jamanetworkopen/fullarticle/2769690.
focus on china and india
Question. In recent years, the agency has prioritized India and
China with respect to inspections. This inspectional emphasis is
further supported by the facts that China and India account for 13
percent and 18 percent of the global API manufacturing, respectively.
However, the U.S. and EU still account for 28 percent and 26 percent of
the global API manufacturing.
Can you discuss the factors that FDA considers when prioritizing
inspections in certain countries?
Answer. The agency utilizes a risk-based mathematical model, the
Site Selection Model (SSM), to select facilities with the greatest
potential for public health risk should they not comply with
established manufacturing quality standards. FDA uses results of the
model to prepare a prioritized list of facilities for inspection from
its Catalog of Manufacturing Sites. Factors in the SSM include inherent
product risk, facility type, patient exposure, inspection history, time
since last inspection, and hazard signals. FDA compares a facility's
score to others in the Catalog of Manufacturing Sites and ranks them by
risk, with the highest risk assigned for inspection regardless of
location (foreign versus domestic).
Question. In 2013, FDA created the India Pilot Program that
eliminated the practice of advanced notice inspections and implemented
short notice or unannounced examinations of Indian drug manufacturing.
The new inspection program exposed numerous safety issues and FDA
issued a nearly 60 percent increase in Official Action Indicated
findings. The program was shut down in 2015.
Has FDA applied any lessons learned from the India Pilot Program in
their approach to foreign inspections since 2015?
Answer. We have implemented some best practices that we determined
were useful from our experiences with the initiative. First, we stopped
having firms issue letters so that we could get visas for our
investigators. We also no longer have firms involved in making hotel
selections or help with other travel arrangements. And finally, we
began a program where the investigator receives a pre-approval briefing
from his or her colleagues at ORA headquarters to improve the
efficiency and effectiveness of the inspection.
access to translators for foreign investigators
Question. GAO found that FDA was not generally providing
translators on foreign inspections and was relying on those provided by
the establishments being inspected.
Does FDA provide guidelines to foreign facilities for the
qualifications of the translators they provide?
Answer. No, FDA does not have formal guidelines for the
qualifications of translators present at inspections. FDA's current
practice is to use firm personnel for interpreter/translation services
when possible. If firm personnel do not primarily speak English, FDA
will use other sources, such as FDA staff fluent in the language
appropriate to the inspection or using an agency-contracted interpreter
through an Interagency agreement with the U.S. Department of State.
Question. Do you believe there could be a conflict of interest when
the establishment being investigated is employing the translator?
Answer. At this time, we rely on information provided by the firm
during all inspections, including those inspections in the United
States. As mentioned earlier, investigators are skilled to detect
inconsistencies in data. We currently do not have data to show that
firm translation activities have negatively impacted the accuracy of
information provided. We do intend to evaluate this issue and had
planned a study to evaluate using our own translation services; this
has been delayed due to the current public health emergency.
Questions Submitted by Hon. Patrick J. Toomey
Question. How did the FDA gather the information necessary to make
the following statement in March posted to its website: ``The FDA has
identified about 20 other drugs, which solely source their active
pharmaceutical ingredients (API) or finished drug products from China.
We have been in contact with those firms to assess whether they face
any drug shortage risks due to the outbreak. None of these firms have
reported any shortage to date. Also, these drugs are considered non-
critical drugs.''
Answer. FDA conducted a resource-intensive data analysis to gather
this information. We used multiple FDA sources that maintain data on
approved application products (New Drug Application (NDA), Abbreviated
New Drug Application (ANDA), and Biologics License Application (BLA))
and sites. These data sources include the Orange Book, CDER Product and
Site Catalogs, CDER Informatics Platform (Integrity and Panorama),
Document Archiving, Reporting and Regulatory Tracking System (DARRTS),
and Electronic Drug Registration and Listing Systems (EDRLS). In
addition, information was extracted from application forms (356H PDF
files) submitted by applicants for changes in manufacturing facilities
linked to applications to verify data accuracy. To identify facilities,
the data used include the FDA Establishment Identifier (FEI), Data
Universal Numbering System (DUNS), and location of facility. FDA
contacted firms, as appropriate, to make assessments about potential
impacts. Despite our rigorous process to gather this information, there
continue to be gaps in the visibility that FDA has into foreign supply
chains.
Question. Did the FDA gather information on drugs either solely
made or API solely sourced in any other countries? If not, why? If so,
what is the comparable data from those other countries?
Answer. In February 2020, FDA conducted sole source analysis to
identify drugs whose APIs and/or FDFs were only available from China.
As the outbreak spread, we began to focus on other impacted and
potentially impacted countries, such as India, Italy, and the Republic
of Korea. However, the outbreak quickly became a global pandemic and
there were many impacted countries. At that point, our analysis changed
from focusing on individual countries to focusing on drugs deemed
essential and their global supply chain with any vulnerabilities.
Question. Can the FDA perform a broader review of drugs that are
either solely made or contain an API solely sourced outside of the U.S.
and provide this information on a monthly basis to the public?
Answer. We monitor all drugs with the potential for shortage,
including those products which are sole source. Any of these products
that do fall into shortage are then posted to FDA's shortage list and
closely monitored, and their status is regularly updated on the drug
shortage website.
Question. What are the primary reasons for drug shortages during
the COVID-19 pandemic?
Answer. The primary reasons for drug shortages during the COVID-19
public health emergency are basically two-fold: (1) Increased demand
for certain drugs to treat patients with COVID-19; and (2) drug supply
chain disruptions. For the latter, supply chain problems can result
from interruptions in manufacturing that may be caused by disruptions
in supply of ingredients, labor shortages, or quality problems.
Question. Was the information required of manufacturers in the
CARES Act enough (it required manufacturers to report volume of
particular medicines by manufacturing site) or is more data needed for
FDA to fully and accurately determine which drugs have particularly
vulnerable supply chains?
Answer. The additional volume data provided for in the CARES Act
does not include enough detail to enable FDA to accurately assess
reliance on certain countries to supply APIs for drugs manufactured for
the United States. The CARES Act imposed annual volume data submission
requirements on all drug establishments registered with FDA (section
510(j)(3) of the FD&C Act). However, it did not require the submission
of certain disaggregated volume data regarding drugs produced by API
and FDF establishments, such as information about the sources of APIs
and API intermediates, nor about the amount of APIs and finished dosage
forms manufactured from each source. Additionally, the CARES Act did
not impose registration or listing requirements on manufacturers of API
intermediates.
During consideration of the CARES Act, FDA proposed a more
extensive set of legislative enhancements, reflecting the agency's
policy priorities, and still maintains that these policies would
provide the agency with more information about drug supply chains,
bolstering our ability to predict, prevent, and mitigate shortages. The
key elements of this proposal are to amend the FD&C Act to:
Ensure that each finished dosage form (FDF) facility, API
facility, and API intermediate facility is registered with FDA,
including foreign facilities that manufacture products that are
indirectly imported into the United States (i.e., used in foreign
manufacturing of drug products that are subsequently shipped to the
U.S.); and
Require regular (quarterly) reporting of certain disaggregated
manufacturing volume data and supply chain information. Specifically,
FDF establishments would be required to provide information about the
volume of each drug manufactured for the U.S. market, including the
source and amount of APIs from each source used to manufacture the
FDFs. API establishments would be required to provide information about
the volume of APIs manufactured for the U.S. market, including the
source and amount of API Intermediates from each source used to
manufacture the APIs.
Question. Given a large percentage of API manufacturers are located
outside of the U.S., what are the options for increasing data
reporting? Has FDA engaged with their European counterparts and other
internal regulatory bodies to triangulate data on API? Is there
information that other regulatory bodies are requiring or collecting
that could or should be shared to provide a more complete picture of
potential API dependence on other countries?
Answer. FDA participates in the International Active Pharmaceutical
Ingredient Inspection Programme \7\ that began operating in 2008. The
international collaboration allows FDA to work with the European
Medicines Agency (EMA), European Union (EU) authorities, the European
Directorate for the Quality of Medicines (EDQM), Australia's
Therapeutic Goods Administration (TGA), Health Canada, the Japanese
Ministry of Health, Labour and Welfare (MHLW) and Pharmaceuticals and
Medical Devices Agency (PMDA), and the World Health Organization (WHO)
to share information on good manufacturing practice (GMP) inspections
of manufacturers of APIs that are located outside of the participating
countries. These facilities are largely in India, China, Mexico, and
southeast Asia.
---------------------------------------------------------------------------
\7\ https://www.ema.europa.eu/en/news/increasing-oversight-api-
manufacturing-through-international-collaboration.
In 2018, the group published the Report on the International Active
Pharmaceutical Ingredient Inspection Programme 2011--2016.\8\ Over 6
years, 1,333 inspections were carried out at 458 manufacturing sites of
common interest. These sites were located in 18 different countries,
most of them in India (49 percent) and China (36 percent). Although the
group focuses on site-level information, they often discuss product-
level data as needed. The collaboration is ongoing.
---------------------------------------------------------------------------
\8\ https://www.ema.europa.eu/en/documents/report/report-
international-active-pharmaceutical-ingredient-api-inspection-
programme-2011-2016_en.pdf.
Additionally, FDA relies on our Mutual Recognition Agreements (MRA)
with the EU and confidentiality agreements that we have in place with
other foreign countries with comparable inspectorates to share
information from drug inspections conducted within each other's
borders. A full list of countries with whom we have these agreements
can be found on FDA's website.\9\ MRAs are a tool FDA employs during
the COVID-19 pandemic when FDA has not been able to conduct onsite
inspections.
---------------------------------------------------------------------------
\9\ https://www.fda.gov/international-programs/international-
arrangements/mutual-recognition-agreement-mra.
______
Questions Submitted by Hon. Todd Young
dependence on china/india for apis
Question. According to FDA's own data, the number of registered
facilities making active pharmaceutical ingredients (APIs) in China
more than doubled between 2010 and 2019--and according to Dr. Woodcock,
the Director of FDA's Center for Drug Evaluation and Research, the
``increasing number of API manufacturing sites in China and other
countries suggests that the United States' reliance on Chinese and
other foreign sources of API is growing.''
How dependent are we on China, India, or other countries for the
APIs used in drugs produced for patients in the United States?
Answer. As of May 2020, the breakdown of facilities manufacturing
APIs for human drugs in the U.S. market are as follows:
------------------------------------------------------------------------
Country or Region Percent of API Manufacturing Facilities
------------------------------------------------------------------------
United States 26
------------------------------------------------------------------------
European Union 26
------------------------------------------------------------------------
India 19
------------------------------------------------------------------------
China 13
------------------------------------------------------------------------
Canada 2
------------------------------------------------------------------------
Rest of world 14
------------------------------------------------------------------------
This does not include data on the volume of APIs manufactured, but
rather the number of sites actively manufacturing APIs.
Prior to enactment of the CARES Act on March 27, 2020, registered
drug establishments were not required to submit consistent data
regarding the volume of APIs and finished dosage form drug products
manufactured at each establishment. However, the CARES Act imposed
annual volume data submission requirements on all drug establishments
registered with FDA (section 510(j)(3) of the FD&C Act).
Question. Through the COVID pandemic, what risks have been exposed
by China's increasing manufacturing presence?
Answer. Response included in the answer to the question below.
Question. Is it the FDA's assessment that we would improve our
healthcare in the U.S. and increase our resiliency in future pandemics
by decreasing our reliance on China's manufacturing these drugs?
Answer. Redundancy and geographic diversity are important keys to
ensuring a robust drug supply chain. Manufacturers that have multiple
establishments in different geographic regions have more resilient
supply chains. A manufacturer's supply chain is even more resilient if
the manufacturer sources its active pharmaceutical ingredients (APIs)
from multiple, geographically diverse sources. The resiliency lies in
the fact that if a natural disaster or disease outbreak affects
establishments or suppliers in one geographic region, or one of its
suppliers leaves the market, the manufacturer can utilize other
establishments not affected by the natural disaster or outbreak or can
source the API from one of its other suppliers.
However, FDA cannot prevent manufacturing concentration or require
redundancy of manufacturing capability and capacity. Nor can FDA
require a company to manufacture a drug, maintain a certain level of
inventory of drug product, or reverse a business decision to cease
manufacturing. We note that the CARES Act amended the FD&C Act to
require manufacturers of certain drugs, APIs, and associated medical
devices to develop, maintain, and implement, as appropriate, redundancy
risk management plans, and FDA recommends that manufacturers of all
drugs and APIs do so. Such plans can include opportunities for building
redundant manufacturing capacity, holding spare capacity, or increasing
inventory levels to lower the risks of shortages; and other
stakeholders might explore how to incentivize such practices.
data limitations
Question. According to the Director of FDA's Center for Drug
Evaluation and Research's (CDER) October 2019 Testimony, there are
significant data limitations relating to manufacturing facilities
making drugs for the U.S. market--one being that we ``cannot determine
with any precision the volume of API that China is actually producing,
or the volume of APIs manufactured in China that is entering the U.S.
market, either directly or indirectly by incorporation into finished
dosages manufactured in China or other parts of the world.''
What has the FDA done to address these limitations?
Answer. The CARES Act imposed annual volume data submission
requirements on all drug establishments registered with FDA (section
510(j)(3) of the FD&C Act). FDA has leveraged data required under the
CARES Act for registered drug establishments to submit consistent data
regarding the volume of APIs and finished dosage forms manufactured at
each registered facility. The CARES Act did not require the submission
of certain disaggregated volume data regarding drugs produced by API
and FDF establishments, such as information about the sources of APIs
and API intermediates, nor about the amount of APIs and finished dosage
forms manufactured from each source. Additionally, the CARES Act did
not impose registration or listing requirements on fine chemical (API
intermediate) manufacturers. The additional volume data provided for in
the CARES Act did not include information needed for FDA to accurately
assess our reliance on certain countries to supply APIs for drugs
manufactured for the United States.
Question. What needs to be done?
Answer. The additional volume data provided for in the CARES Act
does not include enough detail to enable FDA to accurately assess
reliance on certain countries to supply APIs for drugs manufactured for
the United States. The CARES Act imposed annual volume data submission
requirements on all drug establishments registered with FDA (section
510(j)(3) of the FD&C Act). However, it did not require the submission
of certain disaggregated volume data regarding drugs produced by API
and FDF establishments, such as information about the sources of APIs
and API intermediates, nor about the amount of APIs and finished dosage
forms manufactured from each source. Additionally, the CARES Act did
not impose registration or listing requirements on manufacturers of API
intermediates.
During consideration of the CARES Act, FDA proposed a more
extensive set of legislative enhancements, reflecting the agency's
policy priorities, and still maintains that these policies would
provide the agency with more information about drug supply chains,
bolstering our ability to predict, prevent, and mitigate shortages. The
key elements of this proposal are to amend the FD&C Act to:
Ensure that each finished dosage form (FDF) facility, API
facility, and API intermediate facility is registered with FDA,
including foreign facilities that manufacture products that are
indirectly imported into the United States (i.e., used in foreign
manufacturing of drug products that are subsequently shipped to the
U.S.); and
Require regular (quarterly) reporting of certain disaggregated
manufacturing volume data and supply chain information. Specifically,
FDF establishments would be required to provide information about the
volume of each drug manufactured for the U.S. market, including the
source and amount of API from each source used to manufacture the FDFs.
API establishments would be required to provide information about the
volume of APIs manufactured for the U.S. market, including the source
and amount of API Intermediates from each source used to manufacture
the APIs.
______
Questions Submitted by Hon. Ron Wyden
Question. On March 28, the FDA issued an Emergency Use
Authorization (EUA) allowing the Strategic National Stockpile (SNS) to
distribute chloroquine phosphate that was not approved by FDA for any
indication, and hydroxychloroquine for COVID-19 treatment. The EUA also
waived requirements Good Manufacturing Practices (GMP) otherwise
applicable to the manufacture, processing, packing, or holding of the
drugs.\10\ The EUA authorized receipt of hydroxychloroquine from Bayer
originating from uninspected manufacturing facilities in Pakistan. A
second company, IPCA Laboratories Ltd., manufacturing the drug, and
reportedly donating 50 million tabs, has been on the FDA Import Alert
list since 2015, but is now been allowed to export hydroxychloroquine
sulfate and chloroquine phosphate to the U.S.\11\
---------------------------------------------------------------------------
\10\ https://www.fda.gov/media/136534/download.
\11\ https://www.accessdata.fda.gov/cms_ia/importalert_189.html
Please list all facilities that were allowed to import chloroquine
and hydroxychloroquine into the United States pursuant to the EUA,
---------------------------------------------------------------------------
noting those that were had CGMP requirements waived.
Answer. Authorization was given to import donated chloroquine
phosphate tablets into the United States twice, as follows:
First Donation of One Million Chloroquine Phosphate Tablets (Original
EUA)
API Facility:
IPCA Laboratories Limited (CGMP requirements were waived)
89A-B/90/91
Industrial Estate
PoloGround, Indore--452003
India
Finished Drug Product Facility:
IPCA Laboratories LTD (Unit-I) (CGMP requirements were waived)
C-6, Sara industrial Estate
Chakrata Road
Rampur, Dehradun
248197, Uttarakhand, India
Second Donation of Two Million Chloroquine Phosphate Tablets (Amended
EUA)
API Facility:
IPCA Laboratories Limited (CGMP requirements were waived)
89A-B/90/91
Industrial Estate
PoloGround, Indore--452003
India
Finished Drug Product Facility:
Bayer Pakistan Private Limited (CGMP requirements were waived)
C-21, S.I.T.E. Area, Karachi--75700
Karachi, Pakistan
Bayer donated 3 million tablets of chloroquine phosphate. For the
first million tablets, the API and product were manufactured at IPCA
facilities in India. The API manufacturer has not been inspected by
FDA. IPCA's facilities have had various compliance actions taken
against them. All known IPCA facilities previously inspected by FDA are
Official Action Indicated (OAI) and on import alert.
For the additional 2 million tablets donated, the API was
manufactured at the same IPCA facility in India as for the first
donation, while the finished drug product was produced at a Bayer
facility in Pakistan. Neither facility had been inspected by FDA. As
FDA has limited information regarding the facility that manufactured
the API, it is presumed that it may also have a similar or worse
compliance profile. The agency did not have information from another
regulatory agency regarding the CGMP status of the Bayer, Pakistan
facility.
Given the lack of an approved application and any inspection
history, FDA conducted tests on samples of the donated chloroquine
phosphate tablets to help determine their level of quality. The product
passed compendial testing requirements. In addition, FDA reviewed
facility and manufacturing information provided by the manufacturers.
All samples met specifications for compendial testing including
identity, assay, organic impurities, dissolution, residual solvents,
and heavy metal analysis. Unknown impurities were identified as ester
flavorants in the samples. The ester compounds were subsequently
identified as being associated with fruit flavoring (banana), in
quantities consistent with low-level contamination. Additional
screening of the tablets was conducted using LC-MS and no indication of
any gross contamination was seen. As such, FDA permitted import of
Bayer's donated chloroquine phosphate tablets into the United States.
We note that none of the chloroquine phosphate donated was ever
distributed from the SNS for use under the EUA.
Question. Please provide all memos and other decision documents
that support the issuance of the EUA, and the need for GMP to be
waived.
Please provide all memos and other decision documents that support
the removal of hydroxychloroquine sulfate and chloroquine phosphate
manufactured by IPCA Laboratories Ltd. from the Import Alert list.
Answer. The import alert has not been lifted for any of the IPCA
FDA-registered facilities. Prior to ``carving out'' these drugs from an
import alert, FDA put in place controls for the chloroquine phosphate
API and hydroxychloroquine sulfate API and tablets from IPCA
facilities.
When FDA implements a ``carve-out'' to an import alert, FDA
stipulates additional controls to balance any particular concerns. The
following conditions were established of IPCA:
Independent third-party certification of all batches prior to
release from site or within 90 days of being released by IPCA's Quality
Unit; FDA must be immediately notified if the third-party review
identified any quality defect or data integrity breach.
None of the batches should involve an OOS result/failure or
breach of data integrity.
Each batch must be tested in triplicate and meet the
appropriate quality standards prior to its release for distribution.
Separate from the donations to the SNS, there was an existing
carve-out for chloroquine phosphate API. Also separate from the
donations to the SNS, FDA subsequently carved out hydroxychloroquine
sulfate API and hydroxychloroquine sulfate tablets manufactured by IPCA
to try to help resolve a potential shortage. Hydroxychloroquine sulfate
tablets and chloroquine phosphate tablets were added to FDA's drug
shortage list on March 31, 2020. The shortage of chloroquine phosphate
tablets was resolved May 8, 2020. Consequently, the carve-out for
chloroquine phosphate was removed on June 22, 2020. The shortage of
hydroxychloroquine sulfate API and tablets resolved on June 26, 2020.
The carve-out for hydroxychloroquine sulfate API and tablets was
therefore removed on June 30, 2020.
On March 28, 2020, FDA issued an Emergency Use Authorization (EUA)
to allow hydroxychloroquine and chloroquine products donated to the
Strategic National Stockpile (SNS) to be distributed and used for
certain hospitalized patients with COVID-19. These drugs were
authorized to be distributed as appropriate from the SNS to States for
doctors to prescribe to certain adolescent and adult patients
hospitalized with COVID-19, as appropriate, when a clinical trial was
not available or feasible. The EUA required that fact sheets with
important information about using chloroquine and hydroxychloroquine in
treating COVID-19 be made available to health care providers and
patients, including the known risks and drug interactions. The EUA also
had mandatory reporting on adverse events.
The March 2020 EUA was reserved for emergency use only and is not
the same as an FDA approval or licensure. At the time the EUA was
issued, the drugs were shown in the lab to prevent growth of the virus
that causes COVID-19 and there were reports of patients who received
these drugs and improved. Because of the possibility that chloroquine
and hydroxychloroquine might have helped very sick COVID-19 patients,
FDA permitted the drugs to be provided only to certain hospitalized
patients under the EUA who were unable to be enrolled in clinical
trials. However, as noted in the authorization letter, clinical trial
data results, and any information derived from clinical trials, as well
as clinical trial results from studies of other investigational medical
products to treat COVID-19, would continue to inform the
appropriateness of the EUA.
The Biomedical Advanced Research and Development Authority (BARDA)
within the U.S. Department of Health and Human Services originally
requested the EUA covering chloroquine and hydroxychloroquine, and FDA
granted the EUA on March 28, 2020, based on the science and data
available at the time. FDA revoked this EUA on June 15, 2020, when it
determined that the legal criteria for issuing an EUA were no longer
met. Based on its ongoing analysis of the EUA and emerging scientific
data, including new clinical trial data, FDA determined that
chloroquine and hydroxychloroquine are unlikely to be effective in
treating COVID-19 for the authorized uses in the EUA. Additionally, in
light of ongoing serious cardiac adverse events and other potential
serious side effects, the known and potential benefits of chloroquine
and hydroxychloroquine no longer outweigh the known and potential risks
for the authorized use. Therefore, the statutory standard for issuance
of an EUA was no longer met. On June 15, in consultation with FDA,
BARDA sent a letter to FDA requesting revocation of the EUA based on
up-to-date science and data. A copy of the letter, FDA's letter
revoking the EUA, and a memorandum outlining the scientific rationale
for this decision can be found on the FDA website.
Question. On April 3, 2020, the FDA issued an EUA for N-95
respirators which included an Appendix A identifying foreign
manufacturers authorized to export these devices to the U.S. On May 7,
2020, the FDA amended the EUA and removed several manufacturers from
Appendix A.\12\ At the time of the modification, millions of dollars'
worth of these previously authorized devices had already been imported
into the U.S.
---------------------------------------------------------------------------
\12\ https://www.fda.gov/medical-devices/letters-health-care-
providers/certain-filtering-facepiece-respirators-china-may-not-
provide-adequate-respiratory-protection-letter.
Please provide all memos and other decision documents that
---------------------------------------------------------------------------
supported the issuance of the April 3, 2020 EUA and the appendix.
Please provide all memos and other decision documents that
supported the May 7, 2020 amendment the EUA, and the appendix.
Answer. The Food and Drug Administration (FDA) has used its
authority to help increase the availability of personal protective
equipment (PPE), including respirators, while helping to ensure
patients and health care workers on the front lines can depend upon
these products to protect them. One way in which FDA has helped to
increase the supply of PPE in the United States is by issuing multiple
emergency use authorizations (EUAs) for filtering facepiece respirators
(FFRs), surgical masks, face shields, and associated decontamination
systems when we determine that the statutory standard has been met. FDA
has continued to evaluate these EUAs and has revised them when
appropriate based on the available information to meet the changing
needs of the public health emergency and to help ensure that patients
and health-care providers have access to the PPE they need.
In terms of the EUA in question, FDA issued the EUA for Non-NIOSH-
Approved Disposable Filtering Facepiece Respirators (FFRs) manufactured
in China on April 3, 2020 to authorize the emergency use of certain
FFRs for use by health-care personnel in health-care settings in
accordance with CDC recommendations during FFR shortages caused by
COVID-19. Respirator models were authorized by the April 3, 2020 EUA
when they were shown to meet the eligibility criteria which included
respirator particular product standards used in other countries that
are similar to the standard NIOSH uses for NIOSH-approved N95
respirators.
FDA first issued an EUA in March to CDC-NIOSH for authorization of
NIOSH approved respirators that appeared in NIOSH's CEL list. FDA also
issued an EUA for ``Imported non-NIOSH-approved disposable FFRs'' based
on respirator standards used in other countries that are similar to the
standard used for NIOSH-approved N95 respirators but excluded
respirator models manufactured in China from this second EUA at the
time because FDA was concerned about substandard respirators
manufactured in China being imported into the U.S. However, as
respirator shortage concerns for healthcare personnel worsened, FDA
sought additional mitigations to increase availability of respirators.
One of those actions included issuing a third FFR-related EUA in April,
2020, the scope of which was limited to respirators manufactured in
China, with narrow parameters (also referred to as eligibility
criteria). FDA has revised these parameters and reissued this EUA as
appropriate based on new information that showed, among other things,
that unscrupulous actors had been using the dire need for PPE to take
advantage of the unprecedented pandemic. For transparency, FDA has
maintained a list of respirator models on its website that FDA has
confirmed meet the eligibility criteria and that are authorized by this
EUA: https://www.fda.gov/media/136664/download.
FDA's activities in connection with this EUA demonstrate FDA's
vigilance in adapting to changing circumstances to help ensure quality
products are available for health-care providers. Among other things,
FDA's reissuances of this EUA have been based on new information
collected as a result of FDA's increased screening of imported
respirators and coordination with CDC/NIOSH to test certain lots of
imported respirators. A summary of the reissuances of this EUA follows:
On May 7, 2020, FDA revised and reissued this EUA in response
to new information from CDC/NIOSH as follows:
Revised the eligibility criterion that authorized
respirator models based on performance to standards documented by
independent laboratory testing. As a result of this revision, some
respirator models were no longer within the scope of the authorization
and so were accordingly removed from Appendix A.
Revised the scope to add a third eligibility
criterion that authorized respirator models previously listed in
Appendix A under the April 3, 2020 letter of authorization if:
The respirator model was tested by NIOSH within 45
calendar days of the EUA issuance; and
Testing results indicated a minimum and maximum
filtration efficiency greater than or equal to 95 percent.
Removed the ability of importers to request
addition of respirator models to Appendix A of the EUA and added a
requirement directing manufacturers to provide a list of authorized
importers to FDA; and
Added recognition of the Chinese National Medical
Products Administration (NMPA) registration certification that can be
verified by the FDA as an eligibility criterion to the scope of
authorization.
As explained in the reissued May 7, 2020, Letter
of Authorization, manufacturers who had respirators that were no longer
authorized had up to 45 days to have their respirators tested by NIOSH
per the revised third criterion. FDA and NIOSH tested respirators from
already-imported lots of respirators or once they arrived at a U.S.
port of entry. Final test results are posted on the NIOSH website,\13\
Respirator Assessments to Support the COVID-19 Response.
---------------------------------------------------------------------------
\13\ https://www.cdc.gov/niosh/npptl/respirators/testing/
default.html.
On June 6, 2020, FDA again revised and reissued the EUA based
on the available information at the time to change the Scope of
Authorization by revising the eligibility criteria to narrow the
jurisdictions under which respirator models would be authorized and to
provide that authorized respirators under this EUA will would no longer
---------------------------------------------------------------------------
be authorized if they had been decontaminated.
On October 15, 2020, FDA again reissued the EUA. Under the
June 6, 2020 version of this EUA, a respirator was authorized if it met
any of three predetermined eligibility criteria. Effective October 15,
2020, the EUA no longer includes the three eligibility criteria,
meaning FDA will no longer review requests nor add to the list of
authorized respirators--known as Appendix A--of this EUA based on those
criteria. Specifically, FDA reissued the EUA to revise the Scope of
Authorization to authorize only those respirators listed in the EUA's
Appendix A as of the date of this reissuance. This reissuance was
prompted, in part, by a respirator shortage assessment conducted by FDA
to understand current product availability for both NIOSH-approved N95s
and KN95 respirators and use practices for each. The assessment showed
that the KN95 respirator models authorized by this EUA meet the demand
for these respirators. As part of this assessment, the agency heard
directly from health-care personnel that the KN95 design has limited
adoption in health-care settings; from distributors that imported, non-
NIOSH-approved product from China is sitting in warehouses unused; and
from manufacturers that NIOSH-approved N95 production is increasing.
Additionally, CDC/NIOSH continues to issue more N95 approvals.
As a result of this EUA's latest reissuance, FDA expects that staff
and agency resources that were devoted to reviewing submissions to be
added to Appendix A under the June 6, 2020 EUA's eligibility criteria
can instead focus on other critical needs during the COVID-19 public
health emergency, including continuing to work with CDC/NIOSH to help
facilitate the availability of respiratory protection that meets the
applicable standards and demands of health-care personnel.
FDA continues to evaluate EUAs and its policies for medical
products during the pandemic and will make additional updates as
appropriate to meet the needs of patients and our health care workers
on the front lines of the United States response. If the committee
would like more information on the FDA EUA for Non-NIOSH Approved
Disposable Filtering Facepiece Respirators Manufactured in China, the
agency would be happy to discuss a follow-up briefing.
Question. The Government Accountability Office has noted the FDA's
history of issuing exceptions that may allow poor quality drugs to be
imported into the United States. Please provide lists of the following:
All instances since October 1, 2015 when the FDA downgraded a field
inspector's recommended Official Action Indicated.
Answer. The data included in this response are limited to foreign
inspections to ensure the data reflects the intent of the question as
posed by the opening paragraph's mention of imported drugs. A downgrade
is defined as an initial ORA recommendation of OAI and a final
classification of VAI or NAI.
------------------------------------------------------------------------
Fiscal Year Concur Downgrade Total
------------------------------------------------------------------------
2014 40 (43%) 52 (57%) 92
------------------------------------------------------------------------
2015 36 (45%) 44 (55%) 80
------------------------------------------------------------------------
2016 75 (51%) 73 (49%) 148
------------------------------------------------------------------------
2017 83 (70%) 35 (30%) 118
------------------------------------------------------------------------
2018 106 (69%) 47 (31%) 153
------------------------------------------------------------------------
2019 69 (71%) 28 (29%) 97
------------------------------------------------------------------------
Question. All instances since October 1, 2015 when the FDA has
allowed imports from a facility that has received an Official Action
Indicated finding.
Answer. If a foreign facility is found to have quality problems
serious enough for FDA to classify it as OAI, the agency can place a
facility on Import Alert, which is used to prevent potentially
violative drugs from the facility from legally entering the United
States. As part of the OAI evaluation process, FDA considers if any
drug shortages could occur or if any existing shortages could be
exacerbated as a result of potential compliance actions. If needed, FDA
will consider Import Alert product carve-outs to alleviate potential or
existing drug shortages. When FDA implements a product carve-out to an
Import Alert, FDA stipulates additional controls to balance any
particular concerns with importing such products. Generally, FDA will
remove a facility from a CGMP-related Import Alert after an onsite re-
inspection demonstrates that the problems have been remediated and the
firm is in compliance with CGMP.
Question. All instances when the FDA has allowed a facility under
Import Alert to import drugs into the United States.
Answer. From FY2016 through FY2019, CDER issued 74 Import Alert
product carve-outs associated with 14 facilities. These products
include drug products, active ingredients, and starting materials. Of
the 14 facilities with Import Alert product carveouts, nine facilities
imported drugs to the United States when the carveout was active. In
this same time period, CDER removed 63 product Import Alert carve-outs
associated with seven facilities.
______
Questions Submitted by Hon. Benjamin L. Cardin
covid-19-related drug shortages
Question. Prescription drug shortages have been a persistent and
troubling occurrence, with at least 200 drugs currently in shortage. In
February, I wrote to FDA Commissioner Hahn on the issue of drug
shortages related to the COVID-19 pandemic. I was concerned then that
COVID-19 would worsen domestic drug shortages.
We have also seen new drug shortages tied directly to COVID-19.
Hospitals have struggled to secure an adequate supply of drugs for
intubating COVID-19 patients who require ventilators as well as common
antibiotics and other drugs used for general surgery.
How is the FDA planning to ensure commonly used, multi-purpose
drugs that are currently in COVID-19 clinical trials, are still
available for people who rely on these medications? For example, the
antibiotic azithromycin is being reported as in shortage by Maryland's
hospitals and the FDA.
Some of the critical medications identified by Maryland's hospitals
have been identified by the FDA as being in shortage for over a month.
As more States begin to re-open and hospitals resume non-emergent
procedures, what is the FDA's plan for supporting the supply chain,
especially for medications used in general surgery and mechanical
ventilation?
Given the increasing cases of Multi-inflammatory Syndrome in
children, how is the FDA planning to ensure certain medications used
for pediatric mechanical ventilation and the treatment of these
patients, are in sufficient supply?
Answer. When FDA identifies potential shortages or supply
disruptions of medical products, we use all available tools to help
prevent the shortage when we can, to mitigate the impact on U.S.
patients and health-care professionals, and to share information with
them.
We work closely with manufacturers to make sure that, to the extent
required by section 506C of the FD&C Act, they notify FDA, as early as
possible, of a permanent discontinuance or an interruption in
manufacturing that is likely to lead to a meaningful disruption in
supply in the U.S. This communication and the full cooperation of
companies providing specific and necessary information is imperative
for us to have an accurate understanding of the supply landscape and
work to take proactive steps to prevent and mitigate shortages. To help
human drug manufacturers submit timely and informative notifications,
the agency published a guidance \14\ in March about these
notifications, the timelines manufacturers should follow when notifying
FDA, and the details they should provide about the discontinuance or
interruption of manufacturing.
---------------------------------------------------------------------------
\14\ https://www.fda.gov/media/136486/download.
In addition to the requirement that certain manufacturers submit
timely notification of discontinuances and interruptions in
manufacturing, we have asked manufacturers to evaluate their entire
supply chain, including active pharmaceutical ingredients, finished
dosage forms, and any components that may be impacted in any area of
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the supply chain due to the COVID-19 outbreak.
COVID-19 has led to an increased population with critical illness,
necessitating sedation drug products for mechanically ventilated
patients. As a result, there is a shortage of FDA-approved propofol
available for use in mechanically ventilated critically ill patients,
as well as shortages of alternative FDA-approved drugs like
dexmedetomidine, which is approved for sedation of mechanically
ventilated patients in the ICU setting. On May 8th, FDA issued an
Emergency Use Authorization (EUA) for emergency use of the Fresenius
Propoven 2 percent Emulsion to maintain sedation via continuous
infusion in patients older than 16 who require mechanical ventilation
in an ICU during the COVID-19 public health emergency. This was
because, based on the totality of scientific evidence available, FDA
concluded that it is reasonable to believe that the Fresenius Propoven
2 percent Emulsion may be effective to maintain sedation via continuous
infusion in patients greater than 16 years old with suspected or
confirmed COVID-19 who require mechanical ventilation in an ICU
setting.
Additionally, FDA has issued guidances setting forth: (1) a
temporary policy for outsourcing facilities to compound certain human
drugs for hospitalized patients when hospitals experience difficulties
accessing certain drugs to treat patients with COVID-19 and (2)
temporary limited flexibility for State-licensed pharmacies (including
hospital pharmacies), Federal facilities and outsourcing facilities
that repackage or combine FDA-approved propofol products for hospitals
that are having difficulty obtaining adequate supplies of the FDA-
approved version in the sizes they use to support or treat patients
with COVID-19. In anticipation of increased demand for certain drugs,
FDA has also published product-specific guidances to support generic
drug development, including for azithromycin, propofol, and
hydroxychloroquine, among others.
FDA prioritizes review of any newly submitted Abbreviated New Drug
Applications (ANDAs) to ensure efficient allocation of limited agency
resources to areas where priority review is most likely to meaningfully
increase generic drug access and ensure fairness to applicants, such as
was done for chloroquine phosphate and hydroxychloroquine sulfate.
Where appropriate we have expedited application assessments--including
supplements--to help ensure adequate drug supply for COVID-19 patients.
Finally, per the executive order issued on August 6, 2020, FDA is
working to identify vulnerabilities in the supply chain for essential
medicines, medical countermeasures, and critical inputs and to mitigate
those vulnerabilities.
national security supply chain lessons
Question. Coronavirus is a wake-up call to the United States to
begin to reclaim the control of our medical supply chain.
What are the key lessons we have learned from crises affecting our
supply chain and how they may impact national security?
Answer. In October 2019, the FDA-led Drug Shortage Task Force
published its report, ``Drug Shortages: Root Causes and Potential
Solutions'' (updated February 2020),\15\ which examines the underlying
factors responsible for drug shortages and recommends enduring
solutions. The report identifies economic forces behind the three root
causes for drug shortages, summarized as: (1) lack of incentives to
produce less profitable drugs, (2) lack of market recognition and
rewards for manufacturers with mature quality management systems, and
(3) logistical and regulatory challenges that make it difficult for the
market to recover from a disruption.
---------------------------------------------------------------------------
\15\ https://www.fda.gov/media/131130/download.
In October 2019 \16\ and again in December 2019,\17\ Dr. Janet
Woodcock, Director, FDA Center for Drug Evaluation and Research (CDER),
testified on safeguarding our pharmaceutical supply chains before the
Health Subcommittee of the House Energy and Commerce Committee. Dr.
Woodcock stated, ``The security of the Nation's supply rests on three
main factors: freedom from dependence on foreign sources of API; the
resilience of our domestic manufacturing base; and the reliability of
the facilities that make products for the U.S. market.'' The COVID-19
pandemic has highlighted the need to repatriate some manufacturing to
the United States and to increase the resilience and reliability of the
supply chain by adopting advanced manufacturing technology.
---------------------------------------------------------------------------
\16\ https://energycommerce.house.gov/committee-activity/hearings/
hearing-on-safeguarding-pharmaceutical-supply-chains-in-a-global-
economy.
\17\ https://energycommerce.house.gov/committee-activity/hearings/
hearing-on-securing-the-us-drug-supply-chain-oversight-of-fda-s-
foreign.
All domestic finished dosage form (FDF) and API establishments are
required to register with FDA, and all foreign FDF and API
establishments that manufacture APIs or FDFs that is imported or
offered for import into the United States are also required to
register. However, many foreign FDF and API establishments incorrectly
interpret the establishment registration requirements to only apply to
those foreign establishments that directly ship to the United States.
As a result, some foreign API and FDF facilities that ship to other
foreign facilities prior to the drugs reaching the United States
---------------------------------------------------------------------------
currently do not register with FDA.
Foreign or domestic facilities producing API intermediates are not
required to register with FDA. (An API intermediate is a material
produced during steps of the processing of an API that undergoes
further molecular change or purification before it becomes an API.) The
lack of registration of a portion of the drug supply chain leaves the
agency with significant blind spots when working to predict, mitigate,
and address drug shortages. Without sufficient insight into the
upstream supply chain for drug products, the agency is unaware of
whether an event affecting a particular country or region could
potentially disrupt the U.S. drug supply and is unable to effectively
conduct appropriate oversight of potential risks in the drug supply
chain. This is particularly the case for non-application products (such
as products marketed pursuant to an over-the-counter (OTC) monograph)
because, at least with respect to products with approved applications,
we have some insight into which API sources may be used by the FDF
facilities.
Additionally, there are importers that appear to be registering
manufacturers without their knowledge. As a result, when the agency
identifies that a potentially hazardous product is on the market or at
the border pending evaluation, our investigation and discussion with
the importer and manufacturers are unnecessarily delayed while we work
to determine the facts of the case, the responsible parties, and the
most effective path to minimize harm to consumers and patients.
Another important challenge discussed in the hearings concerns our
oversight of APIs and FDFs coming into the United States, including
non-sterile and sterile drugs that do not require an application to be
marketed, such as API for compounding, and API for OTC monograph drugs
as well as FDFs of such drugs. Under current law, these drugs can be
distributed to the U.S. market even if FDA has not yet had an
opportunity to evaluate and inspect the manufacturing facilities. This
situation puts patients at risk since they may end up taking these non-
application drugs before the agency can evaluate whether or not the
manufacturing facility is conforming with current good manufacturing
practice (CGMP) requirements. Examples of products include OTC
eyewashes, hand sanitizers, and ointments. In addition, the agency does
not have authority to mandate recalls for most drugs.
Question. How do we protect our supply chain from these issues?
Answer. The Drug Shortage Task Force Report, mentioned above, also
recommended enduring solutions for drug shortages, including: (1)
creating a shared understanding of the impact of drug shortages on
patients and the contracting practices that may contribute to
shortages; (2) developing a rating system to incentivize drug
manufacturers to invest in quality management maturity for their
facilities; and (3) promoting sustainable private sector contracts
(e.g., with payers, purchasers, and group purchasing organizations) to
make sure there is a reliable supply of medically important drugs.
While these recommendations are not directed specifically toward supply
chain disruptions, they may serve to encourage supply redundancy and
more robust supply chains.
These are long-term solutions that will require private as well as
public efforts and a change in business practices. Over the shorter
term, FDA has supported the development of ICH Guideline Q12: Technical
Regulatory Considerations for Pharmaceutical Product Lifecycle
Management, which will improve the resilience of the manufacturing base
by reducing the regulatory burden on companies wishing to expand
production capacity or upgrade their facilities. FDA is also developing
guidances for industry on risk management plans to prevent or mitigate
the risk of drug shortages and improved information sharing.
In 2014, FDA launched the Emerging Technology Program (ETP), which
encourages and supports the adoption of innovative technology to
modernize pharmaceutical development and manufacturing through close
collaboration with industry and other stakeholders starting with early
technology development.
Question. Looking ahead, how do we diversify the American health-
care system's manufacturing supply chain?
Answer. As Dr. Janet Woodcock mentioned in her October 2019
testimony, adoption of advanced manufacturing technologies would
support the repatriation of some of pharmaceutical manufacturing to
U.S. soil. Using traditional manufacturing, the United States is at a
significant disadvantage to China and India because of their lower
labor, materials, transportation, and real estate costs and weaker
environmental regulations. Advanced manufacturing, which is much more
efficient and has a smaller environmental impact, can offset foreign
countries' advantages and enable the United States to rebuild its
pharmaceutical manufacturing base.
Question. How do we incentivize domestic manufacturing?
Answer. FDA continues to work with relevant stakeholders (e.g.,
other Federal agencies and drug manufacturers) to facilitate the
adoption of advanced manufacturing technologies as one of the proactive
approaches to prevent drug shortages and ensure continuous supply of
critical drugs in the United States. Advanced manufacturing technology,
which can be more cost-effective and environmentally friendly than
traditional manufacturing technology, may enable the United States to
play a larger role in pharmaceutical manufacturing. These include
initiatives to enhance the efficiency of drug manufacturing by
utilizing technology (such as through the use of 3D printing,
miniaturization, continuous manufacturing, and other techniques). By
supporting education for a domestic workforce trained in these areas,
skilled U.S. workers would be able to be part of this emerging trend in
drug manufacturing. By moving from batch-to-batch production to
continuous manufacturing, drugs can be produced much more quickly, and
the quality is much more uniform. As part of the COVID-19 response, the
Department has engaged companies to help promote domestic manufacturing
and additional sources of medical products.
______
Questions Submitted by Hon. Robert Menendez
Question. The FDA's contradictory statements and actions related to
hydroxychloroquine and chloroquine have sown confusion and potentially
caused harm and even death among COVID-19 patients. Will the FDA be
revaluating how they issue Emergency Use Authorizations (EUAs) for
other potential COVID-19 treatments to ensure the issues surrounding
the EUAs for hydroxychloroquine and chloroquine are not repeated?
Answer. Under the criteria set forth in section 564 of the Federal
Food, Drug, and Cosmetic Act, FDA considers the totality of scientific
data available when determining whether to issue an Emergency Use
Authorization (EUA). If, based on the totality of the scientific
evidence available, it is reasonable to believe that the product may be
effective for the specified use, FDA may authorize its emergency use,
provided that other statutory criteria for issuing an EUA also are met.
For example, FDA must determine whether the known and potential
benefits of the product, when used to diagnose, prevent, or treat the
identified disease or condition, outweigh the known and potential risks
of the product.
When FDA issued the March 28, 2020, EUA for chloroquine and
hydroxychloroquine, the results of clinical trials were not yet
available; however, lab data and anecdotal clinical evidence suggested
that those drugs could potentially be effective in treating severe
cases of COVID-19. Applying the section 564 criteria to assess the
evidence available at that time, as well as to assess the known and
potential benefit of the products versus the known and potential risks
at that time, FDA issued the EUA.
As further required under section 564, FDA continued to review the
appropriateness of the EUA as the results of clinical trials and other
evidence became available. Based on this continuing review, on June 15,
2020, FDA determined that these drugs were unlikely to be effective in
treating severe cases of COVID-19 and that statutory criteria for
issuance were no longer met. Therefore, FDA revoked the EUA. The agency
notes that during a public health emergency, EUAs are processed
expeditiously to permit the availability of promising treatments. Each
EUA is evaluated independently, as products and circumstances are
unique to each EUA.
Question. Please describe, in detail, the FDA's decision-making
process to issue an EUA for hydroxychloroquine and chloroquine on March
28, 2020, including all communications with White House officials on
this topic. Additionally, please provide copies of any relevant
communications.
Answer. On March 28, 2020, FDA issued an Emergency Use
Authorization (EUA) to allow hydroxychloroquine and chloroquine
products donated to the Strategic National Stockpile (SNS) to be
distributed and used for certain hospitalized patients with COVID-19.
These drugs were authorized to be distributed from the SNS to States
for doctors to prescribe to certain adolescent and adult patients
hospitalized with COVID-19, as appropriate, when a clinical trial was
not available or feasible. The EUA required that fact sheets with
important information about using chloroquine and hydroxychloroquine in
treating COVID-19 be made available to health-care providers and
patients, including the known risks and drug interactions. The EUA also
had mandatory reporting on adverse events.
The March 2020 EUA was reserved for emergency use only and is not
the same as an FDA approval or licensure. At the time the EUA was
issued, the drugs were shown in the lab to prevent growth of the virus
that causes COVID-19 and there were reports of patients who received
these drugs and improved. Because of the possibility that chloroquine
and hydroxychloroquine might have helped very sick COVID-19 patients,
FDA permitted the drugs to be provided only to certain hospitalized
patients who were unable to be enrolled in clinical trials under the
EUA. However, as noted in the authorization letter, clinical trial data
results, and any information derived from clinical trials, as well as
clinical trial results from studies of other investigational medical
products to treat COVID-19, would continue to inform the
appropriateness of the EUA.
The Biomedical Advanced Research and Development Authority (BARDA)
within the U.S. Department of Health and Human Services originally
requested the EUA covering chloroquine and hydroxychloroquine, and FDA
granted the EUA on March 28, 2020, based on the science and data
available at the time. FDA revoked this EUA on June 15, 2020, when it
determined that the legal criteria for issuing an EUA were no longer
met. Based on its ongoing analysis of the EUA and emerging scientific
data, including new clinical trial data, FDA determined that
chloroquine and hydroxychloroquine are unlikely to be effective in
treating COVID-19 for the authorized uses in the EUA. Additionally, in
light of ongoing serious cardiac adverse events and other potential
serious side effects, the known and potential benefits of chloroquine
and hydroxychloroquine no longer outweigh the known and potential risks
for the authorized use. Therefore, the statutory standard for issuance
of an EUA was no longer met. On June 15, in consultation with FDA,
BARDA sent a letter to FDA requesting revocation of the EUA based on
up-to-date science and data. A copy of the letter, the FDA letter
revoking the EUA, and a memorandum outlining the scientific rationale
for this decision can be found on the FDA website.
Regarding your question about communications with the White House
in the decision process for the March 28, 2020, EUA, FDA notes that its
role is to make independent, science-based decisions to bring new
therapies to sick patients as quickly as possible, while at the same
time supporting research to further evaluate whether these therapies
are safe and effective for treating patients infected with this novel
virus. The March 2020 EUA authorizing the drugs' use for certain
hospitalized patients with COVID-19 was prepared by expert FDA career
staff and reflects internal scientific discussion.
Question. Pharmaceutical and diagnostic companies are investing in
the development of products to diagnose and treat COVID-19. In an
effort to assist these companies in bringing a potential vaccine to
market and mitigate the spread (and subsequent deaths) from COVID-19,
has the FDA relaxed or changed any of its regulations or guidance
regarding human clinical trials? If so, please explain these changes
and how they diverge from FDA's normal clinical trial practices.
Answer. Clinical trials are being impacted by the COVID-19 public
health emergency. Challenges may arise, for example, from self-
isolation, site closures, travel limitations, interruptions to the
supply chain for the investigational product, or other considerations
if site personnel or trial subjects become infected with COVID-19.
These challenges may lead to difficulties in meeting protocol-specified
procedures, including administration or use of the investigational
product or adhering to protocol-mandated visits and laboratory/
diagnostic testing.
FDA has not changed any of its regulations regarding the conduct of
clinical trials during the COVID-19 pandemic. However, to address these
and other challenges, FDA promptly issued guidance to assist sponsors
conducting clinical trials during the COVID-19 public health emergency
in meeting regulatory requirements. See FDA Guidance on Conduct of
Clinical Trials of Medical Products during COVID-19 Pandemic.\18\ This
guidance was issued on March 18, 2020, and then updated multiple times,
most recently on September 21, 2020. Since the guidance was issued, FDA
has added 25 question and answers, many in response to the over 500
inquiries to the mailbox [email protected] that
FDA set up with the issuance of the first guidance to assist the
clinical trial community.
---------------------------------------------------------------------------
\18\ http://wcms-internet.fda.gov/media/136238/download.
FDA also established the Coronavirus Treatment Acceleration Program
(CTAP) to facilitate communications with sponsors developing a host of
therapies to treat and prevent COVID-19. CTAP uses every available
method to move new treatments to patients as quickly as possible, while
maintaining our focus on determining whether they are helpful or
harmful. We continue to support clinical trials that are testing new
treatments for COVID-19 so that we gain valuable knowledge about their
---------------------------------------------------------------------------
safety and effectiveness.
In CTAP, CDER and CBER scientific experts, such as virologists,
allergists, pulmonologists, and critical care specialists, continue to
take the lead to advise sponsors how to advance drug development
programs and of course to review actual incoming submissions. These
clinical review teams are supported by a new, robust administrative
backbone to receive a high volume of incoming proposals and inquiries
and make sure they go to the right place. Sometimes the inquiry is from
someone who needs very basic regulatory advice--about the difference
between NIH and FDA, for example--whereas other inquiries may be from
drug developers who are well down the road with clear scientific
rationales and strong evidence. We have posted additional information
about these efforts, including the number of drug development programs
and clinical trials reviewed by FDA for COVID-19, on the CTAP
website.\19\
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\19\ https://www.fda.gov/drugs/coronavirus-covid-19-drugs/
coronavirus-treatment-acceleration-program-ctap.
CTAP does not change pre-existing roles, responsibilities, or
decision rights concerning drug development and approval; instead, CTAP
provides much more robust support to our scientists so they can work
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the science in a more swift, nimble, and focused manner.
Question. The FDA has issued guidance to promote diversity in
clinical trials. However, certain populations continue to be
underrepresented in many clinical trials. With these challenges in
mind, what recent guidance or policies has FDA instituted to ensure
diversity in clinical trials for potential COVID-19 vaccine candidates?
If any written policy or guidance has been issued, please forward
that information to my office. If no new policies or guidance have been
issued, please explain why, particularly in light of FDA's recognition
of diversity in drug trial testing as an issue.
Answer. A significant step in spurring the development of the data
needed to demonstrate the safety and efficacy of vaccines to prevent
COVID-19 was the issuance of FDA's guidance, Development and Licensure
of Vaccines to Prevent COVID-19.\20\ The guidance document outlines
FDA's expectations for the development of these vaccines, including
design of clinical trials, trial populations, safety and efficacy
considerations, and information needed for our assessment of
manufacturing and facility information.
---------------------------------------------------------------------------
\20\ https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/development-and-licensure-vaccines-prevent-covid-19.
We are often asked about clinical trials for COVID-19 vaccines and
the importance of diversity in clinical trial participants. It is
critical for vaccines to work for everyone in the indicated
populations. That is why FDA strongly encourages enrollment of all
people--including racial and ethnic minorities, older adults, pregnant
women and women of childbearing age, and, as appropriate, children--in
clinical trials to test COVID-19 vaccines, as outlined in the
---------------------------------------------------------------------------
recommendations in our guidance.
Similarly, FDA's Guidance COVID-19: Developing Drugs and Biological
Products for Treatment or Prevention Guidance for Industry \21\ states
that racial and ethnic minority persons should be represented in
clinical trials. Sponsors should ensure that clinical trial sites
include geographic locations with a higher concentration of racial and
ethnic minorities to recruit a diverse study population.
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\21\ https://www.fda.gov/media/137926/download.
Question. In 2018, FDA released expectations and recommendations on
the collection of racial and ethnic data to create a standardized
approach for collecting and reporting race and ethnicity data in
submissions for clinical trials for FDA regulated medical products.
Since the release of these expectations and recommendations, has FDA
seen an increase in the standardized collection of racial and ethnic
data? If so, please provide concrete examples of when the collection of
this information has substantially influenced FDA's approval of a
particular drug. If FDA has not seen an improvement of racial and
ethnic data collection, please provide concrete steps the agency
intends to take to improve collection and further incentivize
---------------------------------------------------------------------------
pharmaceutical companies to collect this information.
Answer. In response to the FDA Safety and Innovation Act of 2012,
FDA issued Guidance for Industry in October 2016 on the Collection of
Race and Ethnicity Data in Clinical Trials. The guidance provides FDA's
expectations for and recommendations on collecting and reporting race
and ethnicity data in submissions for clinical trials for FDA-regulated
medical products conducted in the United States and abroad. The
guidance also states that FDA's expectations are that sponsors enroll
participants who reflect the demographics for clinically relevant
populations with regard to age, gender, race, and ethnicity.
Furthermore, the results of FDA's routine review of a medical
product's safety and effectiveness by race and ethnicity can identify
essential information needed for the safe and effective use of the
product. For example, the labeling for ACE inhibitors, a class of
antihypertensive drugs, inform prescribers that controlled trials have
shown that these drugs are less effective in black patients than non-
black patients. These drugs have also been associated with a higher
rate of angioedema in black than in non-black patients. Another drug,
BiDil (isosorbide dinitrate/hydralazine HCl), was approved for the
treatment of heart failure only in self-identified black patients
because there was little evidence of effect among white patients.
Question. Does the FDA have a plan to improve racial and ethnic
data collection from pharmaceutical companies during clinical drug
trials?
Answer. FDA is committed to encouraging diverse participation in
research used to support marketing applications for regulated medical
products. Following the FDA Safety and Innovation Act of 2012,
specifically section 907, and the priorities set forth in FDA's Action
Plan to Enhance the Collection and Availability of Demographic Subgroup
Data, the agency has continued its ongoing efforts to support diverse
participation in clinical trials through hosting public meetings,
developing tools, and issuing guidance documents. Over the past few
decades, FDA policy initiatives have focused on promoting enrollment
practices that lead to clinical trials better reflecting the population
most likely to use the product if the product is approved.
FDA's Office of Minority Health and Health Equity (OMHHE) has
continued to work to advance racial and ethnic minority participation
in clinical trials through its Diversity in Clinical Trials Initiative,
including a variety of culturally and linguistically competent
strategies and resources. This includes an ongoing campaign to provide
positive reinforcements and raise awareness on the need for racial and
ethnic minority populations to participate in clinical trials.
Additionally, FDA issued a draft guidance to assist sponsors in
enrolling and retaining a diverse clinical trial population that
reflects the patient population most likely to use the drug if it is
approved. See Enhancing the Diversity of Clinical Trial Populations--
Eligibility Criteria, Enrollment Practices, and Trial Designs Guidance
for Industry (June 2019).\22\
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\22\ https://www.fda.gov/regulatory-information/search-fda-
guidance-documents/enhancing-diversity-clinical-trial-populations-
eligibility-criteria-enrollment-practices-and-trial.
Question. What resources does the FDA need to ensure the United
States is at the forefront of advanced manufacturing for
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pharmaceuticals?
Answer. FDA believes that advanced manufacturing technologies could
enable U.S.-based pharmaceutical manufacturing to regain its
competitiveness with foreign countries, and potentially ensure a stable
supply of drugs critical to the health of U.S. patients. Advanced
manufacturing offers many advantages over traditional pharmaceutical
manufacturing, and if the United States invests in this technology, it
can be used to reduce the Nation's dependence on foreign sources of
APIs, increase the resilience of our domestic manufacturing base, and
reduce quality issues that trigger drug shortages or recalls.
In FY 2020, FDA's Center for Drug Evaluation and Research received
$9M of one-time supplemental funding which will be used to continue to
modernize and enhance science in areas related to advanced
pharmaceutical manufacturing. Knowledge generated from these
activities, together with the information provided by sponsors or
applicants, can help enable science- and risk-based assessment,
inspection and surveillance, establish best practices, support
standard, policy and guidance development, and provide important
training on novel manufacturing technologies.
Although the success to date demonstrates that the adoption of
advanced manufacturing technology allows for domestic manufacturers to
be competitive in the market place, the limited number of approved
applications demonstrates there are still barriers to entry beyond the
regulatory barriers the Emerging Technology Program is designed to
reduce. Therefore, it is important for other incentives to be made
available to address the non-regulatory barriers to the adoption of
advanced manufacturing. However, FDA does not have significant
expertise in determining what incentives might be effective in spurring
industry adoption of new technology.
______
Questions Submitted by Hon. Sherrod Brown
diversified supply chain
Question. How important is it for the U.S. to diversify sources for
APIs and finished drug products?
Answer. FDA understands the significant impact of the drug supply
chain on patient care. Redundancy and geographic diversity are
important keys to ensuring a robust drug supply chain. A drug supply
chain that has multiple establishments in different geographic regions
is a more resilient supply chain. A supply chain is even more resilient
if there are multiple, geographically diverse sources of active
pharmaceutical ingredients (APIs). The resiliency lies in the fact that
if a natural disaster or disease outbreak affects establishments or
suppliers in one geographic region, or one of the suppliers leaves the
market, there are other establishments not affected by the disruption
that can still supply the market.
Question. Does the FDA have any strategies or policies in place to
ensure the U.S. does not rely on a single source for any APIs or
finished drug products?
Answer. FDA cannot prevent manufacturing concentration or require
redundancy of manufacturing capability and capacity. Nor can FDA
require a company to manufacture a drug, maintain a certain level of
inventory of drug product, or reverse a business decision to cease
manufacturing.
However, the Coronavirus Aid, Relief, and Economic Security Act
(the CARES Act) amended the Federal Food, Drug, and Cosmetic Act (the
FD&C Act) to require that manufacturers develop, maintain, and
implement, as appropriate, a redundancy risk management plan for
certain drugs, APIs, and associated devices. FDA staff are working to
issue guidance for industry to provide manufacturers with information
concerning this new requirement.
Question. What are some ways Congress could facilitate the
diversification of sources for APIs and finished drug products,
particularly for more essential medicines?
Answer. As noted above, FDA cannot prevent manufacturing
concentration or require redundancy of manufacturing capability and
capacity. Nor can FDA require a company to manufacture a drug, maintain
a certain level of inventory of drug product, or reverse a business
decision to cease manufacturing.
The lack of more comprehensive pharmaceutical reporting limits
FDA's insights into the supply chain, including FDA's ability to assess
critical infrastructure as well as manufacturing quality and capacity
for pharmaceuticals. FDA does not currently receive detailed
manufacturing volume information on a quarterly basis from either human
or animal drug manufacturers.
The adoption of advanced manufacturing could enable U.S.-based
pharmaceutical manufacturing to regain its competitiveness with China
and other foreign countries, and potentially ensure a stable supply of
drugs critical to the health of U.S. patients. Advanced manufacturing
technology, which FDA supports through, among other things, its
Emerging Technology Program (ETP), has a smaller facility footprint,
lower environmental impact, and more efficient use of human resources
than traditional manufacturing.
mandatory recall
Question. Does FDA agree that mandatory recall authority could help
expedite the FDA's recall process and get potentially harmful drugs off
the market faster, even when a pharmaceutical company would otherwise
comply with a voluntary recall request?
Answer. The main benefit of mandatory drug recall authority is that
it would expedite the initiation of a recall and get potentially
harmful drugs off the market when a drug company either refuses or is
reluctant to comply with a voluntary recall request. In addition,
although FDA generally prefers not to require a recall when a company
is otherwise willing to comply with a voluntary recall request, there
can be circumstances where the potential for FDA to require a recall
may allow FDA and a drug company to reach an agreement on the scope of
a recall faster.
When companies undertake recalls, they are an effective method of
removing defective FDA-regulated products that have been distributed
commercially, particularly when those products present a danger to
health. Recall actions are conducted by manufacturers and distributors
to protect the public health from products that present a risk of
injury. A recall may be undertaken voluntarily at any time by
manufacturers and distributors, or initiated at the request of FDA. FDA
generally directs a recall request to the firm that has primary
responsibility for the manufacture and marketing of the product. The
Agency works with manufacturers and distributors to develop a recall
strategy and to publicize information to the public. FDA also monitors
the effectiveness of any recall and takes additional actions as
appropriate.
Consumers can be exposed to risks for extended periods of time when
firms refuse to or delay the recall of defective or harmful drugs.
Below we provide examples of hand sanitizers, homeopathic teething
tablets and gels, and other non-application products where mandatory
recall authority would have been helpful to our efforts to remove
dangerous products from the market expediently.
During the COVID-19 pandemic, FDA determined that some hand
sanitizer products distributed or offered for import in the United
States, particularly those manufactured in Mexico, were contaminated
(e.g., contained methanol) and/or subpotent. Methanol is poisonous and
can cause adverse events, such as dizziness, blindness, and death. In
these cases the methanol-contaminated hand sanitizer led to the deaths
of U.S. consumers. FDA quickly reached out to manufacturers to recall
these dangerous drugs. Some of the manufacturers cooperated, but many
did not. Some examples include:
Delayed Recalls of Hand Sanitizers
Eskbiochem was contacted by FDA on June 17, 2020, to recommend
the company recall its hand sanitizer products from the market due to
the risks associated with methanol poisoning. The company took no
action and actually requested its detained product be sent back so the
firm could distribute it to the domestic Mexican market. Some, but not
all product, was eventually recalled 5 weeks later by distributors.
(96,613 liters of hand sanitizer were distributed and distributors were
able to recall 36,886 liters; see: https://www.fda.gov/drugs/drug-
safety-and-availability/fda-advises-consumers-not-use-hand-sanitizer-
products-manufactured-eskbiochem).
Soluciones Cosmeticas was contacted by FDA on July 1, 2020, to
recommend recall of adulterated hand sanitizer but was reluctant to
recall. Only after additional communication in which FDA notified the
firm that a State department of health had reported cases of death
linked to the use of their product did the firm agree on July 10, 2020,
to voluntarily recall 3.3 million liters of hand sanitizer. (See:
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-
investigations/warning-letters/soluciones-cosmeticas-sa-de-cv-609057-
08042020.)
Refusals to Recall Hand Sanitizers
Since June 2020, there have been more than five manufacturers
who have refused to recall their subpotent (including lack of active
ingredient) and/or methanol contaminated hand sanitizer. These
manufacturers had produced over 206,766 liters of adulterated hand
sanitizer. The following warning letters provide more information on
recent incidents relating to hand sanitizers where mandatory recall
authority would have aided our efforts:
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-
investigations/warning-letters/quimica-magna-de-mexico-sa-de-cv-608751-
10152020.
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-
investigations/warning-letters/grupo-insoma-sapi-de-cv-608768-10232020.
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-
investigations/warning-letters/real-clean-distribuciones-sa-de-cv-
608900-10272020.
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-
investigations/warning-letters/asiaticon-sa-de-cv-609162-10292020.
In January 2017, FDA contacted a manufacturer of homeopathic
infant teething tablets to convey serious concerns about the
inconsistent amounts of belladonna alkaloids (also known as deadly
nightshade) contained in the tablets sometimes far exceeding the amount
claimed on the label. Belladonna alkaloids have anticholinergic
effects, including disorientation, hallucinations, fast heart rate, and
may also cause drowsiness in infants. (See: https://www.fda.gov/news-
events/press-announcements/fda-confirms-elevated-levels-belladonna-
certain-homeopathic-teething-products.)
After FDA contacted the firm with these serious concerns, the
firm sent a letter stating it declined to take action on those
products, further stating its belief ``that the public is amply
protected.'' FDA subsequently sent a Requested Recall letter signed by
the Associate Commissioner of Regulatory Affairs to the firm, which
announced a recall almost four months after FDA had initially contacted
the firm. (See: https://www.fda.gov/drugs/drug-safety-and-availability/
fda-announces-standard-homeopathic-companys-nationwide-voluntary-
recall-hylands-teething-tablets.)
In August 2020, FDA twice contacted a repacker of goldenseal
root powder to discuss laboratory findings of high counts of various
bacteria, including multiple pathogens in its product and to request a
voluntary recall. The product was distributed nationwide and purchased
between the dates of January 25, 2015, and August 4, 2020. Because the
firm failed to take action, FDA issued a press release warning the
public about use of the contaminated product, which could lead to
serious infections and death in infants and individuals with weak
immune systems. The firm had received a report from FDA of one infant
death associated with use of this product on the umbilical cord stump.
The firm initiated a voluntary recall three days after FDA issued the
press release.
https://www.fda.gov/drugs/drug-safety-and-availability/fda-advises-
consumers-not-use-goldenseal-root-powder-distributed-maison-terre.
https://www.fda.gov/safety/recalls-market-withdrawals-safety-alerts/
maison-terre-issues-voluntary-nationwide-recall-organic-goldenseal-
root-powder-due-microbial.
In June 2016, FDA alerted both the own-label distributor and
the contract manufacturer of a potentially contaminated Diocto docusate
(oral liquid docusate sodium) product, and the firms agreed to
quarantine the product. The product was suspected as a link to a
Burkholderia cepacia outbreak of pediatric ICU patients in five states.
Use of these contaminated products in patients whose immune system is
compromised could result in infections, which may be life-threatening.
In July 2016, FDA laboratory testing revealed the contamination of
Diocto docusate with B. cepacia, demonstrating a direct link between
the drug and the outbreak. The investigation also detected B. cepacia
in the water system used to manufacture the product. Days later, the
contract manufacturer agreed to recall the Diocto docusate product;
three weeks later, it agreed to recall all of its liquid drug products.
In July 2017, a second outbreak of B. cepacia in oral liquid
docusate sodium products occurred. The contract manufacturer was
uncooperative and FDA extended communication to distributors. While a
voluntary recall was eventually initiated by the five distributors, the
contract manufacturer's lack of cooperation delayed the recall and
lengthened the exposure of hospital patients to the contaminated
product.
https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-
multistate-outbreak-burkholderia-cepacia-infections.
https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-
2017-burkholderia-cepacia-contamination.
These are some examples involving serious risks where firms delayed
recall of harmful products putting consumers and patients at risk. If
the Agency had mandatory recall authority, the Agency could have
facilitated removal of the drugs from the market months earlier,
reducing the time that consumers, including infants, were potentially
exposed to harmful drugs.
api reporting/inspections
Question. Does FDA know what percent of API is produced in the
U.S.? Not the facilities manufacturing, but the percent of actual API
product that comes from the U.S. versus other countries?
Answer. No. As noted above, the lack of comprehensive
pharmaceutical reporting limits FDA's insights into the supply chain.
Although FDA can describe the locations of API manufacturing
facilities, we cannot determine the volume of API produced in a given
location. For a detailed walkthrough of the limitations of FDA's data,
please see Dr. Janet Woodcock's testimony before the House Energy and
Commerce Committee's Subcommittee on Health at an October 2019 hearing
available here: https://www.fda.gov/news-events/congressional-
testimony/safeguarding-pharmaceutical-supply-chains-global-economy-
10302019.
Question. Does FDA know what percent of chemical materials used to
manufacture API are produced in the U.S. versus other countries?
Answer. No; see responses to questions above.
Question. Does the FDA know what percent of FDF of human drugs is
produced in the U.S.?
Answer. No; see responses to questions above.
Question. What more could and should the FDA do to collect
additional information on API and its manufacturing and distribution
under current law?
Answer. The CARES Act amended section 510(j) of the FD&C Act to
require ``Each person who registers with the Secretary under this
section with regard to a drug shall report annually to the Secretary on
the amount of each drug listed under paragraph (1) that was
manufactured, prepared, propagated, compounded, or processed by such
person for commercial distribution . . .'' which when implemented, will
give the agency information about how much and which APIs are
manufactured at different facilities.
Question. What additional authorities could Congress provide the
FDA that would be helpful in collecting additional information on the
manufacturing and distribution of API?
Answer. The agency still needs information to better connect the
API and FDF manufacturers as noted in the responses to questions three
and five. It would also be helpful for FDA to be better able to obtain
information about the API intermediates used to manufacture the API.
Question. What would it take to initiate a strategic API reserve,
as discussed by Senator Cassidy during the June 2020 Senate Finance
Committee hearing?
Answer. The agency understands the significant impact of the drug
supply chain on patient care and does everything within its authority
to help prevent interruptions in the supply chain. Taking steps to
ensure patients have an adequate supply of critical drugs is an
important endeavor. However, care must be taken with respect to any
effort to shore up the supply chain so as not to create new, unintended
risks to the supply chain. The major risks with creating a stockpile or
reserve of specific medicines are that the announcement of the creation
of the stockpile could cause a supply disruption by diverting
production toward particular ingredients and products and it could
cause others to seek to create their own stockpile.
Question. What additional information related to the drug supply
chain would be helpful for FDA to have, but that the agency doesn't
currently have the authority to collect?
Answer. See responses to questions above.
testing
Question. What percent of drugs does the FDA currently test for
established quality specifications?
Answer. Pharmaceutical manufacturers, no matter where they are
located, are responsible for ensuring that quality products reach U.S.
patients. Manufacturers are required to test drug materials and final
APIs and final drug products to verify they conform with existing
standards before distribution. FDA's role is to provide sufficient
oversight to help ensure that companies fulfill their responsibilities
and to take appropriate action when they do not. This oversight
includes testing selected finished drug products and the APIs used to
make these products after they are on the market. See our response to
the question below for more information on our risk-based approach to
quality testing.
Question. Has the FDA ever required a pharmaceutical manufacturer
to provide proof of batch testing or test results for established
quality specifications post-
market?
Answer. Current regulations require drug product manufacturers to
test representative samples of all components (ingredients) from each
lot of each shipment before use in manufacturing the drug product. Drug
product manufacturers are required to test representative samples of
each lot of finished drug product to verify it meets specifications
before releasing the lot to market. Testing requirements also include
testing during the processing of APIs and final products to confirm
quality after significant stages of production. Generally during
current good manufacturing practice (CGMP) inspections, we review the
records that manufacturers must maintain regarding required testing,
including testing for known impurities and degradation compounds, and
we evaluate the implementation of other manufacturing controls and
practices designed to prevent unexpected and objectionable impurities
in a drug.
The FDA has the authority to conduct examinations and/or sample
collections to determine if the product offered for import is in
compliance with the FDA regulations and laws. As part of the entry
review process, the FDA entry reviewers designate entries for
examination. This examination may consist of any combination of a field
examination, label examination, and/or sample collection. For example,
for importation of heparin, FDA routinely reviews test results and
other data accompanying the importation entry on a case-by-case basis.
FDA also tests samples to verify purity.
Question. Is it accurate to say that the FDA is unable to identify
the full range of drugs that fail to meet the established quality
specifications as a result of its limited testing capacity?
Answer. FDA has a longstanding program to regularly sample and test
marketed drugs and APIs for conformance to specifications. We select
hundreds of samples each year based on certain criteria.
Some testing decisions are event-driven. For example, we might
test product samples after receiving a pattern of complaints about
adverse events, quality issues, or reduced effectiveness. These reports
come to FDA through consumer complaints, field alert reports, and
MedWatch: The FDA Safety Information and Adverse Event Reporting
Program.
We also rely on the experience of internal and external
experts to alert us to emerging safety, effectiveness, or quality
issues with currently marketed drug products. For example, results from
independent research may require FDA testing and investigation.
Sometimes, manufacturing or facility concerns may trigger
additional FDA monitoring and testing. For instance, FDA may sample
products with difficult manufacturing processes or drug products with
complex dosage forms such as patches, drugs designed to target a
specific area, and drugs that release the active ingredient in a
controlled manner.
FDA may also sample drugs produced by manufacturing processes that
require additional controls to ensure each dosage unit will perform as
expected, such as delivering a precise amount of active ingredient
within a narrower range, because even slight deviations could cause
quality issues.
We use a risk-based approach to quality testing. This means that in
cases where there is a known or likely safety, effectiveness, or
quality issue with a product, FDA scientists perform tests specifically
for this vulnerability. For example, if an API is likely to become
contaminated with a harmful impurity during the manufacturing process,
FDA tests for that specific impurity, rather than testing for all
potential impurities. Additional reasons products may warrant testing
under FDA's testing program include: products that are the most used
drugs (including prescription brand-name and generic drugs); drugs
considered critical to countering terrorism attacks; and newly approved
or first-time generic prescription drugs.
Through our risk-based import screening tool, PREDICT (Predictive
Risk-based Evaluation for Dynamic Import Compliance Targeting), FDA
focuses agency import resources, including activities such as
examinations and sample collections, on
higher-risk products being offered for entry into U.S. commerce.
PREDICT uses automated data mining, pattern discovery, and automated
queries of FDA databases to determine the potential risk of a shipment.
The analytics tool takes into consideration the inherent risk of a
product and information about the previous history of importers,
manufacturers, and shippers. As part of our COVID-19 response, FDA has
adjusted PREDICT screening to account for firms whose foreign
inspection was postponed due to COVID-19 travel restrictions.
FDA labs acquire samples for testing by a number of different
mechanisms, including directly from consumers and purchases from the
U.S. market via distributors, wholesalers, and retail pharmacies. FDA
has found that approximately 1 percent of samples tested, both foreign
and domestic, fail to meet quality standards. In addition, FDA
investigators can collect the samples directly at drug manufacturing
sites and deliver or send them to FDA testing labs (maintaining chain
of custody). If required, FDA also has the ability to purchase samples
online while retaining anonymity. Finally, some samples are sent to FDA
labs directly from manufacturers as the result of information request
(IR) letters from FDA assessor staff. In many cases, such samples are
requested to verify test results on the same batches the firms supply
to FDA. Using this ``trust but verify'' approach, the agency can use
the most accurate available data to make regulatory decisions.
Question. If the FDA and its third-party partners batch-tested all
of the drugs on the market, do you expect the percent of drugs that
fail to meet the established quality specifications would be greater
than 1 percent, and closer to that of Valisure's 10 percent?
Answer. The agency itself does not have the ability to test samples
from every batch of all drug APIs and drug products on the market. No
lab has that capacity. Millions of drug product batches are sold in the
U.S. every year, which can amount to trillions of individual tablets,
capsules, and other dosage forms. Approximately 800,000 different lots
of API and/or drug product are imported each year. FDA instead utilizes
a risk-based approach to quality testing as described above and
oversees compliance to the required testing performed by each
manufacturer. FDA also works with other national drug regulatory
agencies to leverage resources and testing done outside the U.S., which
can help inform testing priorities of the U.S. drug supply. If the
findings of third-party laboratory testing alert FDA to a quality
issue, FDA may investigate.
The agency has greater confidence in the reliability of its own
testing methods and results. Testing methods developed by FDA are
validated and the results are repeatable.
Sound science is critical for effective action, and even well-
intentioned testing should be confirmed for accuracy before alerting
the public or taking action. FDA has posted testing methods on the FDA
website for industry, third-party laboratories, and international
regulators. We welcome others to use them or to ensure they use
similarly sound and validated methods.
Manufacturers may choose to use an independent third party to
perform certain tests if, for example, they have reason to be concerned
about the reliability of their own results or to access sophisticated
methods or equipment that may not otherwise be available to them.
However, FDA does not believe that independent chemical batch-level
testing and verification of the chemical content of all pharmaceuticals
is necessary or feasible. As a general principle, the degree of
regulatory scrutiny over batch-level testing should be commensurate
with the degree of risk, and an independent tester cannot evaluate the
risk without sufficient knowledge of all manufacturing processes.
Additionally, testing methods can only be developed with a target
analyte in mind; testing of all possible chemical impurities or
contaminants is not feasible. Beyond the problem of the volume of
potential impurities to test, an independent third party would need
information concerning the formulation and manufacturing of a product
to determine which chemical tests are appropriate and to develop
suitable methods for detection of impurities.
As part of FDA's risk-based approach, the agency does take
complaints or third-party laboratory results into account when deciding
which drugs to analyze. However, third-party laboratories may not use
standards as outlined in the USP, or follow scientifically sound
procedures for validating an analytical method. Improper development
and validation of analytical methods can result in inaccurate results.
An example is outlined in the following manuscript, which can be
accessed at https://pubmed.ncbi.nlm.nih.gov/32613429/:
Yang J., Marzan T.A., Ye W., Sommers C.D., Rodriguez J.D. and
Keire D.A. ``A Cautionary Tale: Quantitative LC-HRMS analytical
procedures for the analysis of N-Nitrosodimethylamine in
metformin.'' AAPS J., 22(4), 89- (2020).
Question. Are there additional authorities or funds that would
enable the FDA or its third-party partners to test a greater percent of
the drug product in U.S. commerce?
Answer. Quality cannot be tested into products. Drug manufacturers
must have validated processes and methods, and follow CGMPs to ensure
the quality of the drugs they are manufacturing. While CGMPs require
testing by the manufacturer and FDA has a longstanding program to
regularly sample and test marketed drugs and APIs, testing alone is not
adequate to ensure quality. It is important that drugs are manufactured
under conditions and practices required by the CGMP regulations to
assure that quality is built into the design and manufacturing process
at every step. Facilities that are in good condition, equipment that is
properly maintained and calibrated, employees who are qualified and
fully trained, and processes that are reliable and reproducible are a
few examples of how CGMP requirements help to ensure the safety and
efficacy of drug products.
Question. What other procedures, other than batch testing, could
help ensure all drugs in U.S. commerce meet established quality
specifications?
Answer. It is the responsibility of all drug manufacturers to
ensure their products are of acceptable quality, that is, consistently
safe, effective, and free of objectionable contamination and defects.
Drug manufacturers must ensure that the methods used in, or the
facilities and controls used for, the manufacture, processing, and
packing of drugs are adequate to assure and preserve identity,
strength, quality, and purity. FDA continues to review the quality of
drug products throughout the life cycle of the products, and may take
regulatory action when the agency determines that a product in the
market violates provisions of the FD&C Act or presents a danger to
health.
additional questions
Question. What practices/alternative tools (like sampling, using
authority under 704(a)(4), etc.) do you see carrying forward past
pandemic? In other words, are there practices you use now that you
anticipating continuing even after the public health threat dissipates
and you're able to return to more normal evaluations?
Answer. Prior to the COVID-19 pandemic, FDA had utilized
alternative tools such as sampling and testing of drugs in commerce,
and requesting records and other information under section 704(a)(4) of
the FD&C Act. During the COVID-19 pandemic, FDA expanded the use of
records requests under section 704(a)(4) to evaluate firms and
regulated products to address health concerns, travel restrictions and
advisories which postponed routine on-site inspections. In addition, we
expanded the use of Mutual Recognition Agreements (MRAs) to include use
of third country reports from capable authorities and product sampling
programs. FDA has also begun to add new tools to facilitate remote
interactive evaluations of firms, including live streams,
teleconferences, and screen sharing. FDA expects to continue to utilize
these tools as part of a comprehensive oversight approach beyond the
COVID-19 pandemic and will continue to evaluate these novel tools to
employ best practices in the future.
Question. The two pilot programs mentioned at the very end related
to quality management maturity--what is the timeline for those programs
and next steps on building that assessment system out?
Answer. FDA has formed a multidisciplinary multi-center working
group to facilitate the development of the quality management maturity
(QMM) rating program for drug manufacturers. A framework will be
developed that is intended to objectively assess and rate the QMM of
manufacturing sites using facilitated assessments along with other
surveillance intelligence related to the site. In development of the
framework, FDA will need to consider such things as standardized
assessment tools, policies and regulations, industry incentives,
transparency, and communication.
To better inform the development of a framework for objectively
assessing and rating the QMM of manufacturing sites, the Office of
Pharmaceutical Quality (OPQ) has contracted with two third-party
vendors to conduct two pilot programs. One pilot is focused on domestic
manufacturers of finished dosage form products (FDFs), and the other
pilot is focused on foreign manufacturers of active pharmaceutical
ingredients (APIs). Each vendor will develop a QMM assessment tool,
train FDA staff on performing and scoring QMM assessments, and conduct
facilitated assessments of manufacturing sites. Due to the ongoing
COVID-19 pandemic, most if not all the assessments will be conducted
virtually.
As an incentive for participating in these pilot programs,
volunteer sites will receive QMM reports that can empower their
continuous improvement programs. In addition, these participating
manufacturers could benefit in the future by better understanding QMM
ratings when they roll out and begin to enable health systems, other
purchasers, and payers of drugs to differentiate among drug
manufacturers.
Pilot participants have agreed to share best practices and
experience with the program with FDA and amongst each other to support
the pilot program initiatives and gain a better understanding of QMM.
The information gathered as part of these pilot programs will be
used to shape the future of the QMM program but will not impact or
influence any regulatory decisions, or inspection planning. OPQ will
share aggregated learnings from the pilot programs with the public
through workshops and conferences.
OPQ will use the information learned from the two pilot programs
along with other previous and ongoing research to formalize criteria
that can be used in an assessment tool to objectively measure a
manufacturing site's QMM. Data from assessments will be curated into
FDA data systems to allow for further analysis and use.
Seven manufacturing sites have been selected to participate in the
domestic pilot and seven in the foreign pilot. FDA's multi-center
working group is currently engaged with the two contractors for the
pilot programs in development of the assessment tools. Site assessments
are expected to begin in May 2021 with the final closeout of the pilot
programs at the end of September 2021. More information can be found on
the FDA webpage, https://www.fda.gov/drugs/news-events-human-drugs/
sbia-webinar-fda-announces-quality-management-maturity-programs-
11122020-11122020.
______
Prepared Statement of Mary Denigan-Macauley, Ph.D., Director,
Health Care, Government Accountability Office
Drug Safety: COVID-19 Complicates Already Challenged FDA Foreign
Inspection Program
why gao did this study
The outbreak of COVID-19 has called greater attention to the United
States' reliance on foreign drug manufacturers and further highlighted
the importance of ensuring a safe pharmaceutical supply chain. Much of
the manufacturing of drugs for treating COVID-19 occurs overseas, which
is also true of the majority of other drugs marketed in the United
States. While the volume of drugs manufactured overseas for the U.S.
market is not fully known, FDA reports that about 70 percent of
establishments manufacturing active ingredients and more than 50
percent of establishments manufacturing finished drugs for the U.S.
market were located overseas, as of August 2019.
FDA is responsible for overseeing the safety and effectiveness of
all drugs marketed in the United States, regardless of where they are
produced, and conducts inspections of both foreign and domestic drug
manufacturing establishments.
GAO has had longstanding concerns about FDA's ability to oversee
the increasingly global pharmaceutical supply chain, an issue
highlighted in GAO's High Risk Series since 2009. In particular:
GAO recommended in 2008 (GAO-08-970) that FDA increase the
number of inspections of foreign drug establishments.
GAO found in 2010 (GAO-10-961) that FDA continued to conduct
relatively few foreign inspections than domestic inspections.
GAO found in 2016 (GAO-17-143) that FDA was conducting more of
these foreign drug inspections, and GAO closed its 2008 recommendation
to conduct more foreign inspections. However, GAO also reported that
FDA may have never inspected many foreign establishments manufacturing
drugs for the U.S. market.
In addition, in the summer of 2018, FDA began announcing recalls of
blood pressure medications manufactured overseas that were tainted with
a potential carcinogen, raising further questions about FDA's oversight
of foreign-manufactured drugs.
This statement is largely based on GAO's December 2019 testimony
(GAO-20-262T) and discusses:
1. The number of foreign inspections FDA has conducted;
2. Inspection staffing levels; and
3. Challenges unique to foreign inspections.
For that testimony, GAO examined FDA data from fiscal years 2012
through 2018 and interviewed investigators from FDA's 2019 cadre of
investigators (who are based in the United States but exclusively
conduct foreign drug inspections) and from FDA's foreign offices in
China and India.
what gao found
In December 2019, GAO found that a growing number of foreign drug
manufacturing inspections conducted by the Food and Drug Administration
(FDA) were in China and India (43 percent in 2018), where most
establishments that manufacture drugs for the United States were
located. In fiscal year 2015, FDA, for the first time, conducted more
foreign inspections than domestic inspections. However, from fiscal
year 2016 through 2018, both foreign and domestic inspections
decreased--by about 10 percent and 13 percent, respectively. FDA
officials attributed the decline, in part, to vacancies among
investigators available to conduct inspections. In March 2020, FDA
announced that, due to Coronavirus Disease 2019 (COVID-19), it was
postponing almost all inspections of foreign manufacturing
establishments. While FDA has indicated it has other tools to ensure
the safety of the U.S. drug supply, the lack of foreign inspections
removes a critical source of information about the quality of drugs
manufactured for the U.S. market.
[GRAPHIC] [TIFF OMITTED] T6220.001
GAO also found that FDA had vacancies among each of the groups of
investigators who conduct foreign inspections. FDA had 190
investigators in the United States who conduct the majority of foreign
inspections, but an additional 58 positions were vacant. At the time of
GAO's December 2019 testimony, FDA was in the process filling 26 of
these vacancies, with 32 remaining. However, according to FDA
officials, it could be 2 to 3 years before new staff are experienced
enough to conduct foreign inspections. FDA also faced persistent
vacancies among investigators in its foreign offices.
GAO further found in December 2019 that FDA investigators
identified persistent challenges conducting foreign inspections,
raising questions about the equivalence of foreign to domestic
inspections. Specifically, GAO found:
While FDA inspections performed in the United States were
almost always unannounced, FDA's practice of preannouncing foreign
inspections up to 12 weeks in advance may have given manufacturers the
opportunity to fix problems ahead of the inspection. Investigators from
FDA's China and India offices had conducted some unannounced
inspections, but these staff do not perform most of the inspections in
these countries (27 percent and 10 percent, respectively).
FDA Estimates of the Amount of Notice Provided to Foreign Drug
Establishments PPrior to Inspection, Fiscal Year 2018
------------------------------------------------------------------------
Percentage of inspections
Type of Amount of notice involving this investigator
investigator provided type
------------------------------------------------------------------------
China office 0-5 days Involved in 27 percent of total
Pinvestigator number of inspections in China
------------------------------------------------------------------------
India office 0-5 days Involved in 10 percent of total
Pinvestigator number of inspections in India
------------------------------------------------------------------------
U.S.based Generally 12 Involved in:
Pinvestigator weeks 73 percent of total number
of inspections in China
90 percent of total number
of inspections in India
100 percent of total number
of inspections in other foreign
countries
------------------------------------------------------------------------
Source: Interviews with Food and Drug Administration (FDA) officials and
GAO analysis of FDA data. | GAO-20-626T.
FDA was not generally providing translators on foreign
inspections. Rather, FDA continued to rely on translators provided by
the foreign establishments being inspected, which investigators said
raised questions about the accuracy of information FDA investigators
collected. For example, one investigator said there was more risk of
conflict of interest if the establishment used its own employees to
translate. In addition, the establishment representative providing the
translation may be someone who does not have the technical language
needed, which can make it harder to communicate with establishment
staff and facilitate the inspection.
The overseas travel schedule can present challenges for FDA's
domestically based investigators, who conduct the majority of foreign
inspections. Domestically based investigators told us there is little
flexibility for them to extend foreign inspections during an overseas
trip. The inspections they conduct on an overseas trip are scheduled
backto-back in 3-week trips and may involve three different countries.
Therefore, extending one inspection would limit the amount of time the
investigator has to complete their other scheduled inspections. FDA
officials said that inspections conducted by investigators based in
China or India (and domestic inspections in the United States) are
generally scheduled one at a time and can thus more easily be extended
if the investigator needs additional time to pursue potential
deficiencies. However, these in-country investigators are not involved
in the majority of FDA inspections conducted in China or India.
_______________________________________________________________________
Chairman Grassley, Ranking Member Wyden, and members of the
committee:
I am pleased to be here today to discuss our work on the Food and
Drug Administration's (FDA) oversight of drugs manufactured
overseas.\1\ The outbreak of Coronavirus Disease 2019 (COVID-19) has
called greater attention to the United States' reliance on foreign drug
manufacturers and further highlighted the importance of ensuring a
secure pharmaceutical supply chain. Like the majority of other drugs
manufactured for the U.S. market, much of the manufacturing of drugs
for treating COVID-19 occurs overseas.
---------------------------------------------------------------------------
\1\ Drugs are defined to include, among other things, articles
intended for use in the diagnosis, cure, mitigation, treatment, or
prevention of disease and include components of those articles. See 21
U.S.C. Sec. 321(g)(1)(B), (D). An active pharmaceutical ingredient
includes, among other things, any component that is intended to provide
pharmacological activity or other direct effect in the diagnosis, cure,
mitigation, treatment, or prevention of disease. See 21 CFR Sec. 207.1
(2019). In this testimony, we refer both to drug products--drugs in
their finished dosage forms--and to active pharmaceutical ingredients
as ``drugs.'' Our work focuses on human drugs and not on most
biologics, veterinary medicines, or other items or products for which
FDA conducts inspections. (Biologics are materials, such as viruses,
therapeutic sera, toxins, antitoxins, vaccines or analogous products,
to prevent, treat, or cure human diseases or injuries and are derived
from natural sources, such as humans, animals, and microorganisms. See
42 U.S.C. Sec. 262(i); 21 CFR Sec. 600.3(h) (2019).)
We have had longstanding concerns about FDA's ability to oversee
the increasingly global pharmaceutical supply chain, an issue
highlighted in our High Risk Series since 2009.\2\ A critical element
in FDA's oversight of overseas manufacturing is the inspections it
conducts of foreign manufacturing establishments. For more than 2
decades, we have raised concerns about FDA's foreign drug inspection
program. In 1998, and again in 2008, we found that FDA inspected
relatively few foreign drug manufacturing establishments--an estimated
8 percent of those subject to inspection for our 2008 report--and that
challenges unique to foreign inspections influenced the manner in which
FDA conducted such inspections.\3\ In our 2008 report we recommended
that FDA increase the number of foreign inspections it conducts.\4\ In
2010, and again in 2016, we found that FDA was conducting more
inspections of foreign establishments (inspecting about 11 percent and
21 percent of those subject to inspection for our 2010 and 2016
reports, respectively). However, in 2010 we reported that FDA continued
to conduct relatively fewer foreign drug inspections than domestic
inspections, and in 2016 we also reported that many foreign
establishments manufacturing drugs for the U.S. market may never have
been inspected by FDA.\5\ In addition, in the summer of 2018, FDA began
announcing recalls of blood pressure medications manufactured overseas
that were tainted with a potential carcinogen, raising further
questions about FDA's oversight of foreign-manufactured drugs.\6\
---------------------------------------------------------------------------
\2\ See GAO, High-Risk Series: Substantial Efforts Needed to
Achieve Greater Progress on High-Risk Areas, GAO-19-157SP (Washington,
DC: Mar. 6, 2019).
\3\ See GAO, Food and Drug Administration: Improvements Needed in
the Foreign Drug Inspection Program, GAO/HEHS-98-21 (Washington, DC:
Mar. 17, 1998) and Drug Safety: Better Data Management and More
Inspections Are Needed to Strengthen FDA's Foreign Drug Inspection
Program, GAO-08-970 (Washington, DC: Sept. 22, 2008).
\4\ See GAO-08-970, 43. FDA agreed with our recommendation and then
started conducting more foreign inspections and changed how it selects
establishments for inspection to ensure that foreign establishments be
inspected at a frequency comparable to domestic establishments with
similar characteristics. As a result, we closed this recommendation.
\5\ See GAO, Drug Safety: FDA Has Conducted More Foreign
Inspections and Begun to Improve Its Information on Foreign
Establishments, but More Progress is Needed, GAO-10-961 (Washington,
DC: Sept. 30, 2010) and GAO, Drug Safety: FDA Has Improved Its Foreign
Drug Inspection Program, but Needs to Assess the Effectiveness and
Staffing of Its Foreign Offices, GAO-17-143 (Washington, DC: Dec. 16,
2016).
\6\ Food and Drug Administration, FDA Updates and Press
Announcements on Angiotensin II Receptor Blocker (ARB) Recalls
(Valsartan, Losartan, and Irbesartan), accessed December 1, 2019,
https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-
press-announcements-angiotensin-ii-receptor-blocker-arb-recalls-
valsartan-losartan.
My remarks today primarily discuss the findings from our December
2019 testimony on FDA's foreign drug inspection program.\7\
Accordingly, this statement provides observations on:
---------------------------------------------------------------------------
\7\ See GAO, Drug Safety: Preliminary Findings Indicate Persistent
Challenges With FDA Foreign Inspections, GAO-20-262T (Washington, DC:
Dec. 10, 2019).
1. The number of FDA's foreign inspections;
2. Inspection staffing levels; and
3. Challenges unique to foreign inspections.
For our December 2019 testimony, we analyzed FDA data from fiscal
year 2012 through fiscal year 2018 on inspections of foreign drug
manufacturing establishments. We also interviewed FDA drug
investigators from FDA's 2019 cadre of investigators, who are based in
the United States but exclusively conduct foreign drug inspections, and
investigators based in FDA's foreign offices in China and in India.
More detailed information on our objectives, scope, and methodology for
that work can be found in the December 2019 testimony. The work on
which this statement is based was conducted in accordance with
generally accepted government auditing standards. Those standards
require that we plan and perform the audit to obtain sufficient,
appropriate evidence to provide a reasonable basis for our findings and
conclusions based on our audit objectives. We believe that the evidence
obtained provides a reasonable basis for our findings and conclusions
based on our audit objectives.
background
Globalization of Drug Manufacturing
Drugs sold in the United States--including active pharmaceutical
ingredients (APIs) and finished dosage forms--are manufactured
throughout the world. According to FDA, as of August 2019 about 70
percent of establishments manufacturing APIs and more than 50 percent
of establishments manufacturing finished drugs for the U.S. market were
located overseas.\8\ As of March 2019, FDA data showed that India and
China had the most manufacturing establishments shipping drugs to the
United States, with about 40 percent of all foreign establishments in
these two countries. (See fig. 1.)
---------------------------------------------------------------------------
\8\ Janet Woodcock, M.D., Director, Center for Drug Evaluation and
Research, Food and Drug Administration, Securing the U.S. Drug Supply
Chain: Oversight of FDA's Foreign Inspection Program, testimony before
the House Committee on Energy and Commerce, Subcommittee on Oversight
and Investigations, 116th Congress, December 10, 2019. According to
FDA, although the agency has information on the location of drug
manufacturing establishments, it does not have information on the
volume of drug ingredients these establishments manufacture for the
U.S. market.
[GRAPHIC] [TIFF OMITTED] T6220.002
Types of Inspections
FDA is responsible for overseeing the safety and effectiveness of
all drugs marketed in the United States, regardless of where they are
manufactured. Drugs manufactured overseas must meet the same statutory
and regulatory requirements as those manufactured in the United States.
FDA's Center for Drug Evaluation and Research (CDER) establishes
standards for the safety, quality, and effectiveness of, and
manufacturing processes for, over-the-counter and prescription drugs.
CDER requests that FDA's Office of Regulatory Affairs (ORA) inspect
both domestic and foreign establishments to ensure that drugs are
produced in conformance with applicable laws of the United States,
including current good manufacturing practice (CGMP) regulations.\9\
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\9\ CGMPs provide for systems that assure proper design,
monitoring, and control of manufacturing processes and facilities. See
21 CFR pts. 210, 211, 212 (2019). FDA considers nearly all drug
establishment inspections to include an assessment of CGMPs.
FDA investigators generally conduct three main types of drug
manufacturing establishment inspections: preapproval inspections,
surveillance inspections, and for-cause inspections, as described in
table 1. At times, FDA may conduct an inspection that combines both
preapproval and surveillance inspection components in a single visit to
an establishment.\10\
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\10\ Most combined inspections occur when FDA conducts a
surveillance inspection at an establishment where a preapproval
inspection was also being conducted.
Table 1: Types of Drug Manufacturing Establishment Inspections Conducted
by the Food and Drug Administration (FDA)
------------------------------------------------------------------------
Type of inspection Purpose of inspection
------------------------------------------------------------------------
Preapproval inspections FDA conducts preapproval inspections
before approving a new brand name or
generic drug to be marketed in the United
States. These inspections are designed to
verify the accuracy and authenticity of
drug application data (such as
manufacturing records) and assess whether
the establishment can manufacture the
product in the application in conformance
with applicable regulations to assure a
drug's identity, strength, quality, and
purity.a
------------------------------------------------------------------------
Surveillance inspections Surveillance inspections are conducted at
establishments when drugs are already
marketed in the United States--either
after FDA approval or after marketing for
drugs that do not require FDA
preapproval--and focus on compliance with
system-wide controls for ensuring that
the manufacturing processes produce high-
quality drugs.b Systems examined during
these inspections include those related
to materials, quality control,
production, facilities and equipment,
packaging and labeling, and laboratory
controls. These systems may be involved
in the manufacture of multiple drugs.
------------------------------------------------------------------------
For-cause inspections For-cause inspections are conducted to
investigate specific issues, such as
those raised in consumer complaints,
indications of potential manufacturing
problems submitted by the manufacturers
themselves, or to follow up on previous
FDA regulatory action, among other
reasons.
------------------------------------------------------------------------
Source: GAO analysis of FDA information. | GAO-20-626T.
a When FDA receives an application for drug approval (or a supplement to
that application related to a manufacturing change), officials review
the inspection history of each establishment listed on the
application, among other things. According to FDA officials, if an
establishment listed on the application has received a satisfactory
good manufacturing practices inspection in the previous 2 years for a
similar or more complex product, and the agency has no new concerns,
FDA may consider this inspection sufficient and not perform a
preapproval inspection of this establishment.
b Certain drugs, such as some over-the-counter drugs, may not require
FDA approval before marketing in the United States.
FDA uses multiple databases to select foreign and domestic
establishments for surveillance inspections, including its registration
database and inspection database. Because the establishments are
continuously changing as they begin, stop, or resume marketing products
in the United States, CDER creates a monthly catalog of establishments.
The establishments in the catalog are prioritized for inspection twice
each year.
In our 2008 report we found that, because of inaccurate information
in FDA's databases, the agency did not know how many foreign drug
establishments were subject to inspection.\11\ For example, some
establishments included in FDA's registration database may have gone
out of business and did not inform FDA that they had done so, or they
did not actually manufacture drugs for the U.S. market. In our report,
we noted that some foreign establishments may register because, in
foreign markets, registration may erroneously convey an ``approval'' or
endorsement by FDA, when in fact the establishment may never have been
inspected by FDA.\12\ We recommended that FDA take steps to improve the
accuracy of this registration information. In our 2010 and 2016 reports
we found that FDA had taken steps to improve the accuracy and
completeness of information in its catalog of drug establishments
subject to inspection, such as using contractors to conduct site visits
to verify the existence of registered foreign establishments and
confirm that they manufacture the products that are recorded in U.S.
import records.\13\
---------------------------------------------------------------------------
\11\ GAO-08-970.
\12\ Foreign and domestic establishments that manufacture drugs for
the U.S. market are required to register annually with FDA.
Establishments provide FDA with, among other things, their names and
addresses and a listing of the drugs that they manufacture for the U.S.
market. 21 U.S.C. Sec. 360(b), (i), (j).
\13\ See GAO-10-961 and GAO-17-143.
To prioritize establishments for surveillance inspections, CDER
applies a risk-based site selection model to its catalog of
establishments to identify those establishments (both domestic and
foreign) that, based on the characteristics of the drugs being
manufactured, pose the greatest potential public health risk should
they experience a manufacturing defect. This model analyzes several
factors, including inherent product risk, establishment type,
inspection history, and time since last inspection, to develop a list
of establishments that FDA considers to be a priority for
inspection.\14\ Through this process, CDER develops a ranked list of
foreign and domestic establishments selected for inspection that is
submitted to ORA. To be efficient with its resources, ORA staff may
shift the order of establishments to be inspected on CDER's prioritized
list based on geographic proximity to other planned inspection trips,
according to FDA officials.
---------------------------------------------------------------------------
\14\ Establishments may also be selected for surveillance
inspections for other reasons, such as FDA's focus on a particular
product.
---------------------------------------------------------------------------
FDA Inspection Workforce
Investigators from ORA and, as needed, ORA laboratory analysts with
certain expertise are responsible for inspecting drug manufacturing
establishments.\15\ FDA primarily relies on three groups of
investigators to conduct foreign inspections:
---------------------------------------------------------------------------
\15\ ORA investigators lead inspections and are responsible for
performing or overseeing all aspects of an inspection. ORA laboratory
analysts are chemists or microbiologists and have expertise in
laboratory testing. In some instances, staff from CDER, such as subject
matter experts or drug application reviewers, may participate in
inspections.
ORA investigators based in the United States, who primarily
conduct domestic drug establishment inspections but may sometimes
---------------------------------------------------------------------------
conduct foreign inspections.
Members of ORA's dedicated foreign drug cadre, a group of
domestically based investigators, who exclusively conduct foreign
inspections.
Investigators assigned to and living in the countries where
FDA has foreign offices, who include both staff based in the foreign
offices full time and those on temporary duty assignment to the foreign
offices. FDA began opening offices around the world in 2008 to obtain
better information on the increasing number of products coming into the
United States from overseas, to build relationships with foreign
stakeholders, and to perform inspections.\16\ FDA full-time foreign
office staff are posted overseas for 2-year assignments. FDA staff can
also be assigned to the foreign offices on temporary duty assignments
for up to 120 days. In fiscal year 2019, there were full-time and
temporary duty drug investigators assigned to FDA foreign offices in
China and India.
---------------------------------------------------------------------------
\16\ Currently, FDA has foreign offices in China, Europe, India,
and Latin America but does not have drug investigators in the Europe or
Latin America offices.
---------------------------------------------------------------------------
Post-Inspection Activities
FDA's process for determining whether a foreign establishment
complies with CGMPs involves both CDER and ORA. During an inspection,
ORA investigators are responsible for identifying any significant
objectionable conditions and practices and reporting these to the
establishment's management. Investigators suggest that the
establishment respond to FDA in writing concerning all actions taken to
address the issues identified during the inspection.
Once ORA investigators complete an inspection, they are responsible
for preparing an establishment inspection report to document their
inspection findings. Inspection reports describe the manufacturing
operations observed during the inspection and any conditions that may
violate U.S. statutes and regulations. Based on their inspection
findings, ORA investigators make an initial recommendation regarding
whether regulatory actions are needed to address identified
deficiencies using one of three classifications: no action indicated
(NAI); voluntary action indicated (VAI); or official action indicated
(OAI).\17\ Inspection reports and initial classification
recommendations for regulatory action are to be reviewed within ORA.
For inspections classified as OAI--where ORA identified serious
deficiencies--such inspection reports and classification
recommendations are to be reviewed within CDER. CDER is to review the
ORA recommendations and determine whether regulatory action is
necessary. CDER also is to review inspection reports and initial
classification recommendations for all for-cause inspections,
regardless of whether regulatory action is recommended by ORA.
---------------------------------------------------------------------------
\17\ FDA officials told us that investigators are responsible for
checking on previously identified deficiencies in any subsequent
inspections of the same establishment. Officials told us that repeated
identification of the same deficiency could result in regulatory
action.
Inspection classifications are publicly available for some
inspections on FDA's website: https://www.fda.gov/inspections-
compliance-enforcement-and-criminal-investigations/inspection-
references/inspection-classification-database/.
According to FDA policy, inspections classified as OAI may result
in regulatory action, such as the issuance of a warning letter. FDA
issues warning letters to those establishments manufacturing drugs for
the U.S. market that are in violation of applicable U.S. laws and
regulations and may be subject to enforcement action if the violations
are not promptly and adequately corrected. In addition, warning letters
may notify foreign establishments that FDA may refuse entry of their
drugs at the border or recommend disapproval of any new drug
applications listing the establishment until sufficient corrections are
made.\18\ FDA may take other regulatory actions if it identifies
serious deficiencies during the inspection of a foreign establishment.
For example, FDA may issue an import alert, which instructs FDA staff
that they may detain drugs manufactured by the violative establishment
that have been offered for entry into the United States.\19\ In
addition, FDA may conduct regulatory meetings with the violative
establishment. Regulatory meetings may be held in a variety of
situations, such as a follow-up to the issuance of a warning letter to
emphasize the significance of the deficiencies or to communicate
documented deficiencies that do not warrant the issuance of a warning
letter.
---------------------------------------------------------------------------
\18\ Warning letters are publicly available on FDA's website:
https://www.fda.gov/inspections-compliance-enforcement-and-criminal-
investigations/compliance-actions-and-activities/warning-letters.
\19\ An import alert can apply to specific drugs or all drugs
manufactured by an establishment. Import alerts are publicly available
on FDA's website: https://www.fda.gov/industry/actions-enforcement/
import-alerts.
---------------------------------------------------------------------------
the number of foreign inspections declined in recent years,
and the majority of such inspections identified deficiencies
Total Number of FDA Foreign Drug Inspections Has Decreased Since Fiscal
Year 2016 After Several Years of Increases
In December 2019, we found that from fiscal year 2012 through
fiscal year 2016, the number of FDA foreign drug manufacturing
establishment inspections increased but then began to decline after
fiscal year 2016. In fiscal year 2015, the total number of foreign
inspections surpassed the number of domestic inspections for the first
time. However, from fiscal year 2016 through 2018, both foreign and
domestic inspections decreased--by about 10 percent and 13 percent,
respectively. FDA officials attributed this decrease to vacancies in
the number of investigators available to conduct inspections (which we
discuss later in this testimony statement) and to inaccurate data used
to select establishments for inspection in fiscal years 2017 and 2018.
Despite steps taken to improve the accuracy and completeness of FDA
data on foreign establishments, in December 2019, we found that the
data challenges we identified in our 2008 report continue to make it
difficult for FDA to accurately identify establishments subject to
inspection. Specifically, since 2017, FDA had pursued an initiative to
inspect approximately 1,000 foreign establishments that lacked an
inspection history. As of November 2019, officials said all of these
establishments had either been inspected or were determined not to be
subject to inspection because it was determined they did not actually
manufacture drugs for the U.S. market, or had not recently shipped
drugs to the United States.\20\ However, officials told us that this
effort contributed to the decline in the number of foreign inspections
conducted because of how data inaccuracies affected the process for
selecting establishments for inspection. Specifically, after selecting
uninspected foreign establishments for inspection, FDA determined that
a sizeable percentage of these establishments were not actually subject
to inspection (e.g., about 40 percent of those assigned to the China
Office in fiscal years 2017 and 2018).\21\ These foreign establishments
were thus removed from the list for inspection for the given year. FDA
officials told us that the next highest priority establishments
identified through the risk-based model to replace those establishments
were domestic establishments. As a result, the number of foreign
establishments actually inspected decreased. As part of our ongoing
work, we plan to examine the accuracy and completeness of information
FDA maintains about foreign establishments and the application of its
risk-based site selection process.
---------------------------------------------------------------------------
\20\ We previously reported that as of 2016, FDA lacked the
inspection history of 33 percent of the foreign establishments in its
catalog of establishments subject to inspection.
\21\ FDA officials said that some of these establishments were
registered with FDA but did not actually manufacture drugs for the U.S.
market, and others were drug manufacturers but had not shipped drugs to
the United States in the previous 3 years. FDA officials told us that,
once identified, they removed such establishments from the catalog of
establishments subject to surveillance inspection to which the agency
applies its risk-based model each year, but they retained information
on these establishments in the larger inventory of establishments
should these establishments begin shipping drugs to the United States
in the future.
We further found that FDA continued to conduct the largest number
of foreign inspections in India and China, with inspections in these
two countries representing about 40 percent of all foreign drug
inspections from fiscal year 2016 through 2018. (See table 2.) In
addition to India and China, the rest of the countries in which FDA
most frequently conducted inspections has generally been the same since
---------------------------------------------------------------------------
our 2008 report.
Table 2: Total Number of FDA Foreign Drug Inspections, by Country,
Fiscal Years 2012 through 2018
------------------------------------------------------------------------
Country 2012 2013 2014 2015 2016 2017 2018
------------------------------------------------------------------------
India 140 110 114 204 207 219 252
------------------------------------------------------------------------
China 59 74 113 127 173 165 153
------------------------------------------------------------------------
Germany 59 60 72 68 72 69 68
------------------------------------------------------------------------
Canada 49 51 39 52 56 72 48
------------------------------------------------------------------------
Italy 38 45 50 41 69 46 45
------------------------------------------------------------------------
Japan 49 28 47 31 65 46 43
------------------------------------------------------------------------
South Korea 4 7 8 5 13 56 40
------------------------------------------------------------------------
France 25 37 44 45 55 42 36
------------------------------------------------------------------------
Switzerland 23 23 37 31 37 25 32
------------------------------------------------------------------------
United Kingdom 29 27 33 43 41 40 12
------------------------------------------------------------------------
All other 150 175 222 193 247 213 206
countries
------------------------------------------------------------------------
Total foreign 625 637 779 840 1,035 993 935
------------------------------------------------------------------------
Total domestic 1,184 1,030 897 784 882 772 742
------------------------------------------------------------------------
Source: GAO analysis of Food and Drug Administration (FDA) data. | GAO-
20-626T.
Note: The total number of inspections includes those conducted for
preapproval, surveillance, and for-cause purposes.
Since we last reported on this issue, FDA announced in March 2020
that, due to COVID-19, it was postponing most inspections of foreign
manufacturing establishments. Only inspections deemed mission-critical
would still be considered on a case-by-case basis.\22\ According to the
announcement, while the pandemic has added new complexities, FDA has
other tools to ensure the safety of the U.S. drug supply. For example,
FDA announced that it was evaluating additional ways to conduct its
inspectional work that would not jeopardize public safety and would
protect both the establishments and the FDA staff. Such ways, according
to FDA, could include reviewing the compliance histories of
establishments, using information shared by foreign regulatory
partners, and evaluating establishment records in lieu of an onsite
inspection. In addition, the FDA Commissioner's May 11, 2020 press
statement stated that while FDA's regulatory oversight is vital to the
long-term health of America, product safety and quality are ultimately
the establishment's responsibility.\23\ Most firms, according to FDA,
strive to reliably provide quality products and maintain the integrity
of the supply chain. However, the lack of foreign inspections removes a
critical source of information about the quality of drugs manufactured
for the U.S. market.
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\22\ According to FDA, the agency's assessment of mission-critical
drug inspections includes consideration for whether the products are
innovative breakthrough products or are considered medically necessary.
FDA indicated that both for-cause and pre-approval inspections can be
deemed mission critical.
\23\ Food and Drug Administration, Coronavirus (COVID-19) Update:
FDA Updates on Surveillance Inspections During COVID-19, FDA press
announcement (May 11, 2020).
It is not clear when FDA will resume regular inspections. The
agency originally announced the postponement would last through April
2020. However, on May 11, 2020, it stated that the postponement would
continue. According to FDA, the agency continues to closely monitor the
global situation. FDA stated that it remains in contact with its
foreign regulatory counterparts and would work with the Centers for
Disease Control and Prevention to develop a process that would govern
how and where to return to on-site facility inspections as conditions
improve.
Most Foreign Inspections Were for Surveillance
In December 2019, we found that each year from fiscal year 2012
through 2018 at least 50 percent of FDA's foreign inspections were
surveillance inspections. In contrast to preapproval inspections,
surveillance inspections are used to ensure drugs already on the market
are manufactured in compliance with FDA regulations. In recent years,
the proportion of foreign surveillance inspections has increased. As
figure 2 shows, in fiscal year 2012, 56 percent of foreign inspections
were surveillance-only inspections; in contrast, from fiscal year 2016
through 2018, about 70 percent of foreign inspections were
surveillance-only, which was comparable to the percentage for domestic
inspections during that period. This is a significant increase from the
13 percent of foreign inspections that were surveillance-only when we
made our 2008 recommendation that FDA inspect foreign establishments at
a comparable frequency to their domestic counterparts (85 percent of
which were surveillance-only at that time).\24\
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\24\ See GAO-08-970, 27.
[GRAPHIC] [TIFF OMITTED] T6220.003
In our December 2019 testimony, we also reported that FDA
implemented changes to its foreign drug inspection program since our
2008 report that may have contributed to the increase in surveillance
inspections. Prior to 2012, FDA was required to inspect domestic
establishments that manufacture drugs marketed in the United States
every 2 years, but there was no similar requirement for foreign
establishments. As a result, and as we reported in 2008, foreign
inspections were often preapproval inspections driven by pending
applications for new drugs. FDA thus conducted relatively few
surveillance-only inspections to monitor the ongoing compliance of
establishments manufacturing drugs that were already on the market,
with just 13 percent of foreign inspections conducted for surveillance
purposes at the time of our 2008 report. However, in 2012, the Food and
Drug Administration Safety and Innovation Act eliminated the 2-year
requirement for domestic inspections, directing FDA to inspect both
domestic and foreign establishments on a risk-based schedule determined
by an establishment's known safety risks, which was consistent with our
2008 recommendation.\25\
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\25\ Pub. L. No. 112-144, Sec. 705, 126 Stat. 993, 1066 (2012)
(codified at 21 U.S.C. 360(h)). This established a comparable
inspection frequency for foreign and domestic establishments with
similar characteristics, consistent with our 2008 recommendation.
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FDA Identified Deficiencies During the Majority of Foreign Inspections
In December 2019, we found that from fiscal year 2012 through 2018,
FDA identified deficiencies in approximately 64 percent of foreign drug
manufacturing establishment inspections (3,742 of 5,844 inspections).
This includes deficiencies necessitating a classification of VAI, or
the more serious OAI, as described in the text box.
------------------------------------------------------------------------
Inspection Classifications
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Based on their inspection findings, FDA investigators make an initial
recommendation regarding the classification of each inspection:
No action indicated (NAI) means that insignificant or no deficiencies
were identified during the inspection.
Voluntary action indicated (VAI) means that deficiencies were
identified during the inspection, but the agency is not prepared to
take regulatory action, so any corrective actions are left to the
establishment to take voluntarily.
Official action indicated (OAI) means that serious deficiencies were
found that warrant regulatory action.
------------------------------------------------------------------------
Source: GAO | GAO-20-626T.
About 59 percent of domestic inspections (3,702 out of 6,291)
identified deficiencies during this time period. (See fig. 3.) This
proportion is similar to what we found when we last looked at this
issue in 2008, when FDA identified deficiencies in about 62 percent of
foreign inspections and 51 percent of domestic inspections from fiscal
years 2002 through 2006.\26\
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\26\ In our 2008 report we found that FDA's data did not provide
reliable information about the number of foreign inspections with
serious deficiencies classified specifically as OAI. Therefore, we
reported data on the percentage of inspections classified as either VAI
or OAI together. See GAO-08-970, 29. We recommended that FDA correct
this issue, and they did so beginning in October 2011, but, for
comparison purposes, we continue to report combined VAI and OAI
inspection data here.
[GRAPHIC] [TIFF OMITTED] T6220.004
Our December 2019 analysis showed that serious deficiencies
identified during foreign drug inspections classified as OAI--which
represented 8 percent of inspections from fiscal year 2012 through
2018--include CGMP violations such as those related to production and
process controls, equipment, records and reports, and buildings and
facilities.\27\ For example:
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\27\ The identification of serious deficiencies is not unique to
foreign inspections. For example, at a domestic establishment producing
finished drug products, the investigator observed brown stains, white
residues, and brown stagnant water in manufacturing equipment.
Failure to maintain the sanitation of the buildings used in
the manufacturing processing, packing, or holding of a drug product (21
CFR Sec. 211.56(a) (2019)). At an establishment in India producing
finished drug products, the investigator reported observing a live moth
floating in raw material used in the drug production, and that the
facility staff continued to manufacture the drug products using the raw
material contaminated by the moth, despite the investigator pointing
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out its presence.
Failure to perform operations relating to the manufacture,
processing, and packing of penicillin in facilities separate from those
used for other drug products (21 CFR Sec. 211.42 (d) (2019)). At an
establishment in Turkey that manufactured penicillin and other drugs,
the investigator reported that the manufacturer had detected penicillin
outside the penicillin manufacturing area of the establishment multiple
times. According to FDA, penicillin contamination of other drugs
presents great risk to patient safety, including potential anaphylaxis
(even at extremely low levels of exposure) and death.
Some investigators who conduct foreign inspections expressed
concern with instances in which ORA or CDER reviewers reclassified the
investigator's initial inspection classification recommendations of OAI
to the less serious classification of VAI.
fda continued to face challenges filling vacancies
among staff conducting foreign inspections
In December 2019, we found that FDA's foreign inspection workforce
had staff vacancies, which FDA officials said contributed to the recent
decline in inspections. As previously mentioned, FDA used multiple
types of staff resources to conduct foreign drug inspections--including
ORA investigators based in the United States, members of ORA's
dedicated foreign drug cadre based in the United States, and
investigators assigned to FDA's foreign offices.\28\ However, we found
that each of these groups had current vacancies. At the time of our
December testimony, FDA officials told us that the agency was trying to
fill vacancies in each of these groups, but the lower staff numbers may
limit FDA's ability to conduct more foreign inspections.
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\28\ In addition to these categories, there are a variety of other
FDA staff who, on occasion, may participate in an inspection if certain
subject matter expertise is needed.
ORA investigators based in the United States. This group of
investigators conducted the majority of foreign inspections; about 76
percent of foreign inspections in fiscal year 2018 involved an ORA
investigator based in the United States who conducts both foreign and
domestic inspections.\29\ FDA officials said that the more experienced
investigators from this group are expected to conduct three to six
foreign inspections per year, and investigators hired using generic
drug user fees are expected to inspect nine to 12 foreign
establishments per year.\30\ As of June 2019, there were 190
investigators eligible to conduct foreign drug inspections, but
officials said that as of November 2019, the agency had an additional
58 vacancies in this group. At the time of our December 2019 testimony,
officials said that the agency was in the process of hiring 26 ORA
investigators based in the United States to fill these vacancies, with
32 vacancies remaining.\31\
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\29\ Inspections can be conducted by one investigator or multiple
investigators. Therefore, investigators from more than one group could
be involved with a single inspection.
\30\ Beginning in 2014, FDA began to use the user fees collected
from manufacturers of generic drugs to hire additional investigators
focused on inspecting generic drug manufacturers. According to FDA
officials, these investigators have primarily been assigned to conduct
foreign inspections.
\31\ FDA officials indicated that filling these vacancies was a
priority for the agency and noted that their recent implementation of
direct-hire authority has helped them fill these positions.
FDA officials attributed the vacancies to multiple factors:
investigator retirements, investigator movement to other parts of FDA,
and the need to hire to additional investigator positions using generic
drug user fees. Officials also said that a reorganization within ORA
led to a reduced number of investigators who conduct drug manufacturing
establishment inspections. While FDA had recently filled several of the
vacancies, officials told us that new investigators are not typically
used for foreign inspections until they have been with the agency for 2
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to 3 years.
ORA dedicated foreign drug cadre. About 15 percent of foreign
inspections in fiscal year 2018 involved an investigator from ORA's
dedicated foreign drug cadre--a group of ORA investigators based in the
United States who exclusively conduct foreign inspections. FDA
officials said that members of the cadre are expected to conduct 16 to
18 foreign inspections each year. According to FDA, the cadre had 20
investigators in 2012 and 15 investigators in 2016. However, the cadre
had only 12 investigators as of November 2019, out of 20 available
slots. At the time of our December 2019 testimony, FDA officials told
us that the agency was attempting to fill these positions from the
current ORA investigator pool, but officials were not confident that
all 20 slots would be filled.
Investigators assigned to FDA's foreign offices. Approximately 7
percent of foreign inspections in fiscal year 2018 involved
investigators from FDA's foreign offices. The investigators conducting
these inspections were those based in the China and India foreign
offices--the countries where most drug inspections occur--and also
included those investigators on temporary duty assignment to these
offices.\32\ According to FDA officials, these investigators are
expected to conduct 15 foreign inspections each year. We have noted
high vacancy rates for these foreign offices in past reports.\33\ While
these vacancy rates have decreased over time, vacancies persist. As of
November 2019, FDA's China office had three of 10 drug investigator
positions vacant (a 30-percent vacancy rate), while FDA's India office
had two of six drug investigator positions vacant (a 33-percent vacancy
rate).
\32\ The percentage of inspections involving these groups of
investigators do not equal 100 percent because some inspections may
involve only non-investigator staff, such as CDER drug application
reviewers.
\33\ See GAO, Food and Drug Administration: Overseas Offices Have
Taken Steps to Help Ensure Import Safety, but More Long-Term Planning
Is Needed, GAO-10-960 (Washington, DC: Sep. 30, 2010), and GAO-17-143.
In our December 2019 testimony, we reported that FDA had taken
steps to address vacancies in the foreign offices but continued to face
challenges. In our 2010 report, we recommended that FDA develop a
strategic workforce plan to help recruit and retain foreign office
staff.\34\ FDA agreed with our recommendation and released such a plan
in March 2016, but the long-standing vacancies in the foreign offices
raise questions about its implementation. FDA officials told us that
one challenge in recruiting investigators for the foreign offices is
that well-qualified investigators for those positions need foreign
inspection experience. For example, an official in FDA's India office
told us that foreign inspections can be challenging, and the India
office does not have the resources to develop or train new
investigators. Therefore, it is important to recruit investigators who
have experience conducting foreign inspections, and such investigators
are recruited from ORA. Thus, vacancies in the other two groups of
investigators can influence the number of staff available to apply for
positions in the foreign offices.
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\34\ GAO-10-960.
Further, according to FDA officials, after employees have accepted
an in-country position, the agency can experience significant delays
before they are staffed in the office due to delays in processing
assignments. For example, an official in FDA's India office said that
investigators need to complete a week-long security training program
and must obtain the security clearance needed to work at the U.S.
Embassy, which is where FDA's foreign office is located. However, the
official told us that there are limited availabilities for that
training, and background checks for security clearances can take
time.\35\ According to this official, FDA investigators did not usually
receive first priority for the training. FDA estimated that it can take
as little as 1 month to over 2 years for an investigator to clear
background and medical checks and arrive at a foreign office. For
example, an investigator in FDA's China office told us that as a result
of these requirements and other issues, it took nearly 2 years for the
investigator to arrive at the office after FDA had accepted the
investigator's application. According to FDA's own strategic workforce
plan for the foreign offices, these types of delays have resulted in
staff changing their decision after accepting a position in the foreign
offices.
---------------------------------------------------------------------------
\35\ We have highlighted timeliness concerns with the government-
wide personnel security clearance process in our High Risk series. See
GAO-19-157SP.
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persistent challenges unique to foreign inspections raised questions
about their equivalence to domestic inspections
In December 2019, we found that FDA continues to face unique
challenges when inspecting foreign drug establishments that raise
questions about whether these inspections are equivalent to domestic
inspections. Specifically, based on our interviews with drug
investigators in the dedicated foreign drug cadre and in FDA's foreign
offices in China and India, we identified four challenge areas related
to conducting foreign inspections, which are described below. Of the
four challenge areas identified, three areas--preannouncing
inspections, language barriers, and lack of flexibility--were also
raised in our 2008 report.\36\
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\36\ GAO-08-970.
Preannouncing Inspections. As we reported in 2008, the amount of
notice FDA generally gives to foreign drug establishments in advance of
an inspection is different than for domestic establishments.\37\ Drug
establishment inspections performed in the United States are almost
always unannounced, whereas foreign establishments generally receive
advance notice of an FDA inspection. According to FDA officials, FDA is
not required to preannounce foreign inspections. However, they said the
agency generally does so to avoid wasting agency resources, obtain the
establishment's assistance to make travel arrangements, and ensure the
safety of investigators when traveling in country.
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\37\ GAO-08-970.
In our December 2019 testimony, we found that FDA does conduct some
unannounced foreign inspections, particularly if the investigators
conducting the inspection are based in FDA's foreign offices. However,
FDA officials told us that FDA does not have data on the frequency with
which foreign drug inspections are unannounced, nor the extent to which
the amount of notice provided to foreign establishments varies.
According to FDA officials, this is because FDA does not have a data
field in its database to systematically track this information.\38\
However, the officials estimated that the agency generally gives 12
weeks of notice to establishments that investigators are coming when
investigators are traveling from the United States. While investigators
in FDA's China and India offices do conduct unannounced or short-notice
inspections, these staff do not perform most of the inspections in
these countries. (See table 3.)
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\38\ According to FDA officials, FDA planned to add a new variable
to its data to identify preannounced and unannounced inspections.
Table 3: FDA Estimates of the Amount of Notice It Provides to Foreign
Drug Establishments Prior to Inspection, by Investigator Type, and the
Percentage of Inspections in Which These Investigator Types Are
Involved, Fiscal Year 2018
------------------------------------------------------------------------
Percentage of
inspections
Type of involving this
investigator Amount of notice provided investigator type
in fiscal year
2018a
------------------------------------------------------------------------
China office Announcement: 0-5 days Involved in 27
investigator FDA officials stated that percent of total
investigators based in FDA's China number of
office will announce surveillance inspections in
inspections (those related to China
drugs already on the U.S. market)
to drug establishments 5 business
days in advance of an inspection.
According to FDA officials, for-
cause inspections (those conducted
in response to specific issues or
concerns) conducted by
investigators based in the China
office are unannounced, meaning
that they are not preannounced to
the drug establishments in
advance.
------------------------------------------------------------------------
India office Announcement: 0-5 days Involved in 10
investigator FDA officials stated that percent of total
investigators based in FDA's India number of
office will announce inspections inspections in
to drug establishments 3 to 5 days India
in advance of an inspection and
can conduct short-notice
inspections that are announced 30
minutes before the inspection.
------------------------------------------------------------------------
U.S.-based Announcement: generally 12 weeks Involved in:
investigator FDA officials said that the agency 73 percent of
(including generally announces foreign total number of
dedicated inspections conducted by inspections in
foreign drug domestically based investigators China
cadre) about 12 weeks in advance. 90 percent of
total number of
inspections in
India
100 percent of
total number of
inspections in
other foreign
countries
------------------------------------------------------------------------
Source: Interviews with Food and Drug Administration (FDA) officials and
GAO analysis of FDA data. | GAO-20-626T.
a These percentages add up to over 100 percent as some inspections may
involve more than one type of investigator.
Our work indicated that preannouncing foreign inspections can
create challenges and raises questions about the equivalence to
domestic inspections. Of the 18 investigators we interviewed, 14 said
that there are downsides to preannouncing foreign inspections,
particularly that providing advance notice gives foreign establishments
the opportunity to fix problems before the investigator arrives. For
example, when an inspection is preannounced, it gives establishments
time to clean up their facility and update or generate new operating
procedures ahead of the inspection. However, establishments are
expected to be in a constant state of compliance and always ready for
an FDA inspection, and several investigators told us seeing the true
day-to-day operating environment for an establishment is more likely
during an unannounced inspection.
Of the 18 investigators we interviewed for our December 2019
testimony, 12 said that unannounced inspections are generally
preferable to preannounced inspections. One investigator told us that,
although they believed the best way to ensure industry compliance to
CGMPs was for establishments to not know when FDA is coming for an
inspection, there was no data that would allow the agency to evaluate
whether unannounced inspections were better than preannounced
inspections. In addition, some investigators told us that it was still
possible to identify serious deficiencies during preannounced
inspections. For example, investigators could still identify issues by
looking at the firm's electronic records, including time-stamped data
relating to the creation, modification, or deletion of a record. Three
investigators also told us that in some cases there could be benefits
to announcing inspections in advance. For example, for preapproval
inspections, announcing the inspection in advance gives the
establishment time to organize the documentation and staff needed to
conduct the inspection.
Language Barriers. Work for our December 2019 testimony indicated
that language barriers--which we first reported as a challenge to
conducting foreign inspections in our 2008 report--can add time to
inspections and raise questions about the accuracy of information FDA
investigators collect and thus about the equivalence to domestic
inspections.\39\ FDA generally does not send translators on inspections
in foreign countries. Rather, investigators rely on the drug
establishment to provide translation services, which can be an English-
speaking employee of the establishment being inspected, an external
translator hired by the establishment, or an English-speaking
consultant hired by the establishment.
---------------------------------------------------------------------------
\39\ GAO-08-970.
Of the 18 investigators that we interviewed, 14 said that language
barriers can be a challenge to conducting foreign inspections and were
especially challenging in parts of Asia, including China and Japan.
Seven investigators told us this issue was less of a challenge for
inspections conducted in other foreign countries, including India and
countries in Europe, because workers at establishments in these
countries were more likely to speak English, and documentation was also
more likely to be in English. Investigators told us that compared to
domestic inspections, it can be more challenging and take longer to
complete typical inspection-related activities, such as reviewing
documentation or interviewing employees, if the investigator needed to
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rely on translation.
Fourteen of the 18 investigators we interviewed said that there can
be concerns related to relying on establishment staff and independent
translators. Specifically, 11 investigators told us there can be
uncertainties regarding the accuracy of the information being
translated, particularly when investigators rely on the translation
provided by an employee of the establishment being inspected. For
instance, one investigator said that there was more risk of conflict of
interest if the establishment used its own employees to translate.
Another investigator said that they went to a drug establishment in
China that told FDA it had English-speaking employees to translate the
inspection, but that was not the case, and the investigator had to use
an application on their phone to translate the interviews. In addition,
the firm representative providing the translation may be someone who
does not have the technical language needed, which can make it harder
to communicate with firm staff and facilitate the inspection. One
investigator told us that the independent translators hired by firms
were sometimes consultants and, in those instances, it can seem like
the consultants are coaching the firm during the inspection.
FDA officials told us that when they conduct unannounced for-cause
inspections in China, investigators bring locally employed staff who
work in FDA's China office to act as translators. The investigators we
interviewed said that in such instances, they valued knowing that the
translation they were getting was accurate. However, FDA does not have
the resources to provide locally employed staff on every inspection,
according to an FDA official.
Lack of Flexibility. Work for our December 2019 testimony indicated
that, as we first reported in 2008, the overseas travel schedule can
present unique challenges for FDA's domestically based investigators--
including both ORA investigators and members of the dedicated foreign
dug cadre--who conduct the majority of foreign inspections.\40\ Eight
of the 12 dedicated foreign drug cadre investigators that we
interviewed for our December 2019 testimony told us that there is
little flexibility to extend foreign inspections conducted by
domestically based investigators, because the inspections they conduct
on an overseas trip are scheduled back-to-back in 3-week trips that may
involve three different countries.\41\ This raises questions about
their equivalence to domestic inspections. For instance, extending one
inspection would limit the amount of time the investigator has to
complete their other scheduled inspections, some investigators told us.
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\40\ GAO-08-970.
\41\ According to FDA officials, investigators in the dedicated
foreign drug cadre are expected to conduct 16 to 18 foreign inspections
per year. To meet this expectation, cadre members travel overseas six
times a year, with each trip lasting 3 weeks, and conduct two or three
back-to-back inspections per trip.
In addition, eight investigators told us that domestically based
staff are generally unable to extend the total amount of time spent on
an overseas trip--one investigator told us that an investigator would
have to find something really bad to justify an extension. In contrast,
FDA officials told us that inspections conducted by in-country
investigators in China or India, and domestic inspections in the United
States, are generally scheduled one at a time and can thus more easily
be extended if the investigator needs additional time to pursue
potential deficiencies. However, in-country investigators are not
---------------------------------------------------------------------------
involved in the majority of inspections conducted in China or India.
Three investigators from the dedicated foreign drug cadre told us
that when they travel overseas, they adjust their inspection approach
to help ensure they finish foreign inspections on time. For example,
one investigator told us that an investigator may start the inspection
in an area of the establishment that was noted as having issues during
the last inspection. However, one investigator said that sometimes it
is not possible to cover everything in depth during a foreign
inspection. Another investigator told us that they focus on identifying
the most serious issues during a foreign inspection, and that less
serious issues can be identified in the establishment inspection report
for reference in the next inspection. Five investigators also noted
that they work long hours during their inspection to ensure they can
complete the needed work.\42\ While FDA may assign more than one
investigator to an inspection to complete needed work, one investigator
said that FDA does not usually assign more than one person to an
inspection because investigators are expected to have the experience to
conduct inspections by themselves.
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\42\ According to FDA officials, members of the dedicated foreign
drug cadre can receive up to 15 hours of overtime per week during an
overseas week to complete inspection-related work. For example,
investigators may use overtime hours to extend the amount of time on
site or to review relevant data and documentation when they return to
their hotel at night.
FDA data show that from fiscal years 2012 through 2018, the
majority of both foreign and domestic inspections were conducted by one
person--77 percent and 66 percent, respectively.\43\
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\43\ In addition to the time pressures associated with sending only
one investigator on a foreign inspection, two of the investigators we
interviewed from the dedicated foreign drug cadre expressed a
preference for conducting team inspections as it helps reduce risks to
their personal safety.
Post-Inspection Classification Process. According to FDA officials,
starting in fiscal year 2018, FDA implemented a new post-inspection
classification process: when an ORA investigator recommends an OAI
classification following an inspection, ORA compliance is required to
send that inspection report to CDER for review within 45 calendar days
from the inspection closeout. Among other things, the process was
intended to help ensure FDA can communicate inspection results to
domestic and foreign establishments within 90 days of the inspection
closeout, as committed to under the Generic Drug User Fee Amendments of
2017 (GDUFA II).\44\ FDA officials told us that the changes also
required an additional ORA review for foreign inspection reports to
align that process with the process for domestic inspection
reports.\45\ Although the 45-day reporting time frame for potential OAI
classifications is a requirement for both domestic and foreign
inspections, adding the additional level of review within ORA
effectively shortened the amount of time investigators have to document
findings for foreign inspections.
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\44\ Pub. L. No. 115-52, Sec. 301(b), 131 Stat. 1005, 1020
(codified in pertinent part at 21 U.S.C. Sec. 379j-41 note). Prior to
each user fee program reauthorization, FDA negotiates with
representatives of the generic drug industry to identify goals for how
FDA should spend those user fees over the next 5-year authorization
period.
\45\ Prior to this change, officials told us that all foreign
inspection reports, regardless of classification type, were sent to
CDER for review after being endorsed by ORA supervisors. Under the new
process, all foreign inspections are reviewed by ORA compliance after
being endorsed by ORA supervisors. Foreign inspection reports now only
go to CDER compliance for review in certain circumstances, such as if
there is an OAI recommended, which had been the process for domestic
inspections.
Our work indicated that the post-inspection reporting time frames
can create challenges for domestic investigators who conduct foreign
inspections and raise questions about the equivalence to domestic
inspections. Eight of the 18 investigators we interviewed for our
December 2019 testimony said shortening the time for completing reports
and adding a level of review has made it more challenging to meet
reporting requirements, especially if serious deficiencies are
identified during the inspection. Investigators told us that for a
potential OAI inspection, they now need to send the inspection report
to their supervisor for endorsement within 10 days of the closeout of a
foreign inspection, regardless of when the investigator's next
inspection is scheduled for, or whether the investigator has to travel
from overseas back to the United States after the inspection. For
example, if a domestic investigator finds serious deficiencies on the
first inspection of an overseas trip--thus indicating an initial OAI
classification--the investigator needs to write and send the related
inspection report to the ORA supervisor for endorsement before
returning home from the 3-week overseas trip to meet the required time
frame. One investigator told us that, as a result of the time
pressures, post-inspection reports may be less thorough, and that some
inspection observations could be better supported if investigators had
---------------------------------------------------------------------------
more time to write the reports.
In conclusion, foreign manufacturing establishments continue to be
a critical source of drugs for millions of Americans, and FDA
inspections are a key tool to ensure the quality of these drugs. Over
the years since we first examined this issue, FDA has made significant
changes to adapt to the globalization of the pharmaceutical supply
chain and has greatly increased the number of inspections it conducts
of foreign establishments. However, we found in December 2019 that the
agency faced many of the same challenges overseeing foreign
establishments that we identified over the last two decades. These
included inspector vacancies and unique challenges when inspecting
foreign drug establishments that raised questions about the equivalence
of those inspections to domestic inspections. Since then, the outbreak
of COVID-19 has added a layer of complexity. It also further highlights
the global nature of our pharmaceutical supply chain.
Chairman Grassley, Ranking Member Wyden, and members of the
committee, this completes my prepared statement. I would be pleased to
respond to any questions that you may have at this time.
______
Questions Submitted for the Record to Mary Denigan-Macauley, Ph.D.
Questions Submitted by Hon. Chuck Grassley
Question. According to October 30, 2019, testimony from Janet
Woodcock, former Director of CDER, ``although CDER can describe the
locations of API manufacturing facilities, we cannot determine with any
precision the volume of API that China is actually producing, or the
volume of APIs manufactured in China that is entering the U.S. market,
either directly or indirectly by incorporation into finished dosages
manufactured in China or other parts of the world.'' What can the FDA
do to bring greater transparency to the supply chain'?
Answer. Congress took a step to fill a gap in FDA's knowledge about
the U.S. drug supply chain with the Coronavirus Aid, Relief, and
Economic Security (CARES) Act, which was enacted in March 2020. The Act
requires domestic and foreign manufacturers to annually report on the
amount of each drug manufactured for the U.S. market by each
establishment. The new requirement goes into effect in September 2020,
and some of its utility will depend on how FDA implements this
requirement. We plan to examine the information FDA has on the supply
chain of drugs marketed in the United States as part of ongoing work
stemming from a request from Senators Schumer and Peters.
Additionally, in its fiscal year 2020 budget request, FDA included
a request for legislation to clarify its authority to require
manufacturers to submit information that would improve its ability to
assess manufacturing quality and capacity. For example, FDA proposed
that manufacturers be required to submit detailed listings for finished
drugs or drug ingredients regardless of whether the product was
directly imported into the United States or was first sent to another
country to be made into a finished drug before being imported to the
United States. FDA uses this type of information as part of its
selection of manufacturing establishments for inspection. We have
ongoing work examining FDA's foreign drug inspection program for the
House Committee on Energy and Commerce. As part of that work, we are
examining: the extent to which FDA has inspected foreign establishments
that the agency considers to be the highest priority for inspection,
taken steps to address persistent challenges conducting foreign drug
inspections and ensure a sufficient inspection workforce, and taken
action to ensure serious deficiencies identified during foreign drug
inspections are corrected.
Question. GAO has noted that many administrations have had
challenges hiring FDA personnel to work overseas. What actions can FDA
take to solve that problem?
Answer. FDA has taken some steps to address its workforce
challenges. In our 2010 report, we recommended that FDA develop a
strategic workforce plan for its foreign offices to help ensure that
the agency is able to recruit and retain staff with the experience and
skills necessary for the foreign offices and reintegrate returning
staff into FDA's domestic operations. FDA finalized its plan in March
2016, which included key activities to be performed, such as
establishing a succession plan for anticipated vacancies, among other
things.
In addition, in our 2016 report, we recommended that FDA establish
goals to achieve the appropriate staffing level for its foreign
offices, which would include separating foreign office vacancies from
overall vacancy rates for the Office of International Programs (now
Office of Global Policy and Strategy) and setting goals by position
type. In June 2018, FDA reported it had separated foreign office
vacancies from the Office of International Programs-wide vacancy rate
and also set staffing goals by position type, as we recommended. FDA
also took other actions, including implementing pay incentives to
recruit and retain foreign office staff as well as locality pay for
those deployed overseas, and it temporarily assigned staff to short-
term rotations in the foreign offices.
However, as we stated in our 2019 and 2020 testimonies, while
vacancy rates among investigators assigned to FDA's foreign offices
have decreased over time, these vacancies persist. We found that, as of
November 2019, FDA's China office had a 30-percent vacancy rate among
investigators, while FDA's India office had a 33-percent vacancy rate.
FDA officials told us that one challenge in recruiting investigators
for the foreign offices is that well-qualified investigators for those
positions need foreign inspection experience. Therefore, the agency
recruits investigators who have experience conducting foreign
inspections from the pool of domestic investigators in FDA's Office of
Regulatory Affairs (ORA), including those in FDA's foreign drug cadre.
However, the vacancies we identified among both the cadre and this
larger group of ORA investigators can influence the number of staff
available to apply for positions in the foreign offices. Further, while
FDA recently filled several of the vacancies for domestic
investigators, officials told us that new investigators are not
typically assigned to foreign inspections until they have been with the
agency for 2 to 3 years. Therefore, it may be many years before a
recently hired investigator is eligible to detail to a foreign office.
In addition, the effort to fill vacancies is continuous, as FDA full-
time foreign office staff are posted overseas for 2-year assignments,
and staff can also be assigned to the foreign offices on temporary duty
assignments for up to 120 days. We plan to continue to examine FDA's
efforts to ensure a sufficient inspection workforce in our ongoing
review of FDA's drug inspection program.
Question. Please describe the benefits to performing unannounced
inspections. Would you recommend that FDA implement a policy that makes
unannounced inspections standard operating procedure for domestic and
foreign inspections?
Answer. According to several of the investigators we interviewed
for our December 2019 testimony, a benefit to performing unannounced
inspections is that an investigator is more likely to see the true day-
to-day operating environment of a drug manufacturing establishment.
Most investigators we spoke with told us unannounced inspections are
preferable to preannounced inspections.\1\
---------------------------------------------------------------------------
\1\ This is based on our interviews with investigators in FDA's
2019 dedicated foreign drug cadre and investigators based in the
agency's China and India offices.
We also reported in our testimony that FDA's policy to generally
announce foreign inspections in advance raises questions about the
equivalence of foreign and domestic inspections. Both foreign and
domestic drug manufacturers must meet the same regulatory requirements
in terms of complying with established quality standards (CGMPs).\2\
However-unlike the FDA inspections of drug manufacturing establishments
based in the United States, which are usually unannounced-FDA generally
preannounces inspections to foreign drug establishments. Although some
investigators stated that it was still possible to identify serious
deficiencies during a preannounced inspection, the majority of
investigators we interviewed said preannounced inspections can give
foreign establishments the opportunity to fix some problems in advance
of an inspection.\3\
---------------------------------------------------------------------------
\2\ According to FDA, CGMPs provide for systems that assure proper
design, monitoring, and control of manufacturing processes and
facilities, and adherence to CGMP regulations assures the identity,
strength, quality, and purity of drug products by requiring that
manufacturers of medications adequately control manufacturing
operations; https://www.fda.gov/drugs/pharmaceutical-quality-resources/
facts-about-current-good-manufacturing-practices-cgmps (accessed June
22, 2020).
\3\ In addition we reported three investigators told us in some
cases, such as for preapproval inspections, there can be benefits to
preannouncing inspections as the advanced notice gives establishments
time to organize needed documentation and staff for the inspection.
As noted in our 2019 and 2020 testimonies, FDA did not provide us
with data on the frequency with which foreign inspections are
preannounced and unannounced, nor the amount of notice that is provided
when inspections are preannounced. According to FDA officials, FDA does
not have these data because its database does not include a field to
track whether an inspection is announced or unannounced. FDA officials
indicated that FDA had plans to add a new data field to enable the
agency to begin tracking whether an inspection is preannounced or
unannounced. We are continuing our examination of this issue as part of
---------------------------------------------------------------------------
our ongoing work for the House Energy and Commerce Committee.
Question. What do you believe is behind the FDA's reluctance to
implement a policy of unannounced inspections overseas?
Answer. In our 2008 report we found that logistical challenges
influenced the manner in which FDA conducted foreign inspections,
including announcing foreign inspections in advance. We found that,
unlike inspections of domestic establishments which are almost always
unannounced, FDA routinely preannounced its inspections to foreign drug
establishments. At the time of our 2008 report, FDA was still in the
process of opening its overseas offices and solely relied on volunteers
from its domestic staff based in the United States to conduct foreign
inspections.\4\ FDA officials told us that the time and expense
associated with conducting foreign establishment inspections required
the agency to ensure in advance that establishment staff would be
available and that the production line being inspected would be
operational at the time of inspection.
---------------------------------------------------------------------------
\4\ FDA opened its first office in China in November 2008, and its
first office in India in December 2008. See GAO, Food and Drug
Administration: Overseas Offices Have Taken Steps to Help Ensure Import
Safety, but More Long-Term Planning is Needed, GAO-10-960 (Washington,
DC: Sept. 30, 2010).
In our 2019 and 2020 testimonies, we found that FDA continued to
preannounce inspections to foreign drug establishments for the same
reason. agency officials estimated that FDA generally notified foreign
establishments of an inspection 12 weeks in advance when the
investigator conducting the inspection was traveling from the United
States-which we found was the case for most of the agency's foreign
inspections in fiscal year 2018.\5\ According to FDA officials, FDA is
not required to preannounce its foreign inspections, but the agency
does so partly because of the logistics of traveling overseas and
partly because of the cost of conducting foreign inspections.
Specifically, FDA officials told us reasons to preannounce foreign
inspections include to avoid wasting agency resources, to obtain the
assistance of foreign establishments when making travel arrangements,
and to ensure the safety of investigators when traveling in country.
---------------------------------------------------------------------------
\5\ We reported that in fiscal year 2018 about 76 percent of
foreign inspections involved an investigator based in the United States
who conducts both foreign and domestic inspections, and about 15
percent of foreign inspections involved an investigator from FDA' s
dedicated foreign drug cadre--a group of investigators based in the
United States that exclusively conduct foreign inspections.
We also noted in our 2020 testimony that FDA does conduct some
unannounced or short-notice foreign inspections (i.e., inspections
announced no more than 5 days in advance). For instance, FDA officials
told us that investigators based in FDA's China office do unannounced
inspections when the inspection is being conducted in response to
specific issues or concerns (i.e., for-cause inspections), and that
investigators in its India office can conduct short-notice inspections
that are announced 30 minutes before the inspection or 3 to 5 days in
advance. However, we found that foreign office investigators were not
involved in the majority of its foreign inspections in fiscal year
2018, and that the agency faced persistent vacancies among available
investigator positions in its China and India offices--which are the
two countries where FDA continues to conduct the largest number of
---------------------------------------------------------------------------
foreign inspections.
______
Question Submitted by Hon. Patrick J. Toomey
Question. Was the information required of manufacturers in the
CARES Act enough (it required manufacturers to report volume of
particular medicines by manufacturing site), or is more data needed for
FDA to fully and accurately determine which drugs have particularly
vulnerable supply chains?
Answer. The new requirement goes into effect in September 2020, and
some of its utility will depend on how FDA implements this requirement.
We plan to examine the information FDA has on the supply chain of drugs
marketed in the United States as part of ongoing work stemming from a
request from Senators Schumer and Peters.
In its fiscal year 2020 budget request FDA included a request for
legislation to clarify the agency's authority to require manufacturers
to submit information that would improve its ability to assess
manufacturing quality and capacity. For example, FDA proposed that
manufacturers be required to submit detailed listings for finished
drugs or drug ingredients regardless of whether the product was
directly imported into the United States or was first sent to another
country to be made into a finished drug before being imported to the
United States. FDA uses this type of information as part of its
selection of manufacturing establishments for inspection. We have
ongoing work examining FDA's foreign drug inspection program for the
House Committee on Energy and Commerce. As part of that work, we are
examining: the extent to which FDA has inspected foreign establishments
that the agency considers to be the highest priority for inspection,
taken steps to address persistent challenges conducting foreign drug
inspections and ensure a sufficient inspection workforce, and taken
action to ensure serious deficiencies identified during foreign drug
inspections are corrected.
______
Questions Submitted by Hon. Sherrod Brown
transparency and accountability
Question. Based on GAO's work, are there any specific
recommendations for enhanced transparency across our drug supply
chain--particularly as it relates to APIs--that would facilitate better
understanding of the safety of U.S. pharmaceuticals, and potential
actions policymakers could take to diversify and protect the safety,
quality, and quantity of prescription drugs?
Answer. Congress took a step to fill a gap in FDA's knowledge about
the U.S. drug supply chain with the Coronavirus Aid, Relief, and
Economic Security (CARES) Act, which was enacted in March 2020. The Act
requires domestic and foreign manufacturers to annually report on the
amount of each drug manufactured for the U.S. market by each
establishment. The new requirement goes into effect in September 2020,
and some of its utility will depend on how FDA implements this
requirement. We plan to examine the information FDA has on the supply
chain of drugs marketed in the United States as part of ongoing work
stemming from a request from Senators Schumer and Peters. This work
will also examine the barriers to domestic manufacturing and Federal
efforts to increase it.
Additionally, in its fiscal year 2020 budget request, FDA included
a request for legislation to clarify the agency's authority to require
manufacturers to submit information that would improve its ability to
assess manufacturing quality and capacity. For example, FDA proposed
that manufacturers be required to submit detailed listings for finished
drugs or drug ingredients regardless of whether the product was
directly imported into the United States or was first sent to another
country to be made into a finished drug before being imported to the
United States. FDA uses this type of information as part of its
selection of manufacturing establishments for inspection. We have
ongoing work examining FDA's foreign drug inspection program for the
House Committee on Energy and Commerce. As part of that work, we are
examining: the extent to which FDA has inspected foreign establishments
that the agency considers to be the highest priority for inspection,
taken steps to address persistent challenges conducting foreign drug
inspections and ensure a sufficient inspection workforce, and taken
action to ensure serious deficiencies identified during foreign drug
inspections are corrected.
Lastly, both we and FDA previously reported on potential incentives
to address the causes of drug shortages, which may also be relevant to
the aim of increasing domestic manufacturing. Specifically, our 2014
report identified multiple potential incentives,\6\ including:
---------------------------------------------------------------------------
\6\ Our 2014 report included a synopsis of incentives we identified
that were proposed by drug manufacturers and manufacturing associations
or included in bills introduced in the 112th Congress and the first 6
months of the 113th Congress, as well as comments from manufacturer and
association representatives and FDA. See GAO, Drug Shortages: Public
Health Threat Continues, Despite Efforts to Help Ensure Product
Availability, GAO-14-194 (Washington, DC, Feb. 10, 2014).
Increasing the transparency of domestic and foreign
manufacturing establishments' compliance status, thereby giving
manufacturers an additional incentive for the highest quality products
---------------------------------------------------------------------------
and making quality-related supply disruptions less likely to occur.
Guaranteed purchase , in which the Federal Government
guarantees the purchase of a given volume of certain drugs thereby
allowing manufacturers to ensure capacity for a given market volume
regardless of whether there is sufficient market demand.
Tax incentives or reductions in FDA fees could also be used to
incentivize manufacturers to invest in redundant manufacturing
capacity.
FDA also reported similar incentives for addressing drug shortages
in a 2019 report.\7\ Additionally, we plan on further examining FDA's
preparedness and response to drug shortages related to the Coronavirus
Disease 2019 (COVID-19) in the near future.
---------------------------------------------------------------------------
\7\ U.S. Food and Drug Administration, Drug Shortages: Root Causes
and Potential Solutions (2019).
---------------------------------------------------------------------------
racial and ethnic disparities
Question. Following up on Senator Carper's line of questioning, can
you please elaborate on the investigation and report GAO is planning to
put out on COVID-19-related racial disparities? What is GAO's timeline
for this report?
Answer. We have a body of published work looking at health
disparities in various populations, and we continue to look at issues
of racial and ethnic disparities in health outcomes in ongoing GAO
work, including work on Coronavirus Disease (COVID-19). For example, we
are conducting ongoing work on the availability of data on COVID-19
health outcomes by race and ethnicity as part of our work in response
to the CARES Act, Public Law 116-136. This work is expected to be
released in August 2020 as part of a larger report covering various
topics related to monitoring and overseeing the activities of
governmental entities, grantees, contractors, and others in connection
with the COVID-19 pandemic. In addition, GAO plans to conduct future
work related to racial disparities and COVID-19; however the specific
objectives and timing of this work have not yet been determined.
We have also previously reported on the topic of health
disparities. For example, in a December 2019 report, we outlined steps
the Department of Veterans Affairs (VA) had taken to reduce disparities
in health outcomes linked to race and ethnicity but found that the
agency lacked mechanisms to mea su re progress and ensure
accountability for results . We also reported that VA funds research
efforts that have identified disparities in health-care outcomes
involving minority veterans but relies on data that VA officials and
researchers noted have weaknesses in completeness and accuracy. In
March 2020, we also reported on trends in maternal mortality and found
that the leading causes of pregnancy-related deaths differed by racial
and ethnic groups. For example, from 2007 through 2016, non-Hispanic
black women were more than three times as likely to die than non-
Hispanic white women, while non-Hispanic American Indian/Alaska Native
women were more than two times as likely to die than non-Hispanic white
women. We are conducting ongoing work on maternal mortality and severe
maternal morbidity in rural and underserved areas, which is expected to
be issued in the Spring of 2021.
Question. Knowing that the availability of timely, standardized
data is critical to understanding trends and health outcomes, what are
GAO's general recommendations to Federal agencies to improve on the
quality, timeliness, and standardization of data reporting and
collection? In its work, has GAO identified any areas where legislation
or congressional action is necessary to bolster data collection
practices?
Answer. GAO has previously reported on the importance of high
quality and standardized data and expressed concerns about such data
related to health outcomes in a variety of contexts. For example, we
previously reported on the importance of quality health outcome data in
our December 2019 report on steps VA had taken to reduce disparities in
health outcomes linked to race and ethnicity and our March 2020 report
on trends in maternal mortality. Most recently, in a review of COVID-19
required by the CARES Act, we determined that the testing data that the
Centers for Disease Control and Prevention (CDC) had reported through
May 31, 2020, had not provided sufficiently reliable information on the
amount of COVID-19 viral testing because these data had been incomplete
and inconsistent. CDC acknowledged limitations to these data while
maintaining that they were the best testing data available and provided
critical insights into how much testing had occurred. We also reported
that a recent Department of Health and Human Services (HHS) action
could improve testing data. On June 4, 2020, HHS issued guidance that
requires all laboratories performing viral or other tests to diagnose a
possible case of COVID-19 to submit data for all test results using
consistent data elements. Required data also include patients' race,
ethnicity, and other demographic information. We will continue to
conduct work examining HHS and its component agencies' data reporting
related to COVID-19 testing and make recommendations as appropriate.
______
Questions Submitted by Hon. Benjamin L. Cardin
national security supply chain lessons
Question. Coronavirus is a wake-up call to the United States to
begin to reclaim the control of our medical supply chain.
What are the key lessons we have learned from crises affecting our
supply chain and how they may impact national security?
How do we protect our supply chain from these issues?
Looking ahead, how do we diversify the American healthcare system's
manufacturing supply chain?
How do we incentivize domestic manufacturing?
Answer. The current Coronavirus Disease 2019 (COVID-19) has
heightened the Nation's awareness of the United States' reliance on a
global drug supply chain; however, supply chain disruptions affecting
the U.S. drug supply are not new and occurred long before the COVID-19
outbreak. The reasons for these disruptions are generally economic in
nature. In 2014, we reported on the drug shortage causes that
manufacturers reported to FDA. Based on January 2011 through June 2013
data, we found that the most common reasons for drug shortages included
quality problems (40 percent), manufacturing delays and capacity issues
(30 percent), and issues with active pharmaceutical ingredient (API) or
other drug components (9 percent). We also identified potential
underlying causes specific to the economics of the generic sterile
injectable drug market, such as that low profit margins have resulted
in limited infrastructure investments by manufacturers or led some
manufacturers to exit the market. In 2019, FDA also reported on the
reasons for drug shortages from 2013 through 2017 and similarly found
that manufacturing or product quality problems were behind 62 percent
of shortages.\8\ FDA likewise reported that the root causes of drug
shortages are a lack of incentives for manufacturers to produce less
profitable drugs, a market that does not recognize and reward
manufacturers for mature quality management systems, and logistical and
regulatory challenges that make it difficult for the market to recover
after a supply disruption.
---------------------------------------------------------------------------
\8\ U.S. Food and Drug Administration, Drug Shortages: Root Causes
and Potential Solutions (2019).
Both we and FDA previously reported on potential incentives to
address the causes of drug shortages, which may also be relevant to the
aim of increasing domestic manufacturing. Specifically, our 2014 report
identified multiple potential incentives,\9\ including:
---------------------------------------------------------------------------
\9\ Our 2014 report included a synopsis of incentives we identified
that were proposed by drug manufacturers and manufacturing associations
or included in bills introduced in the 112th Congress and the first 6
months of the 113th Congress, as well as comments from manufacturer and
association representatives and FDA. See GAO, Drug Shortages: Public
Health Threat Continues, Despite Efforts to Help Ensure Product
Availability, GAO-14-194 (Washington, DC, Feb. 10, 2014).
Increasing the transparency of domestic and foreign
manufacturing establishments' compliance status, thereby giving
manufacturers an additional incentive for the highest quality
productions and making quality-related supply disruptions less likely
---------------------------------------------------------------------------
to occur.
Guaranteed purchase, where the Federal Government guarantees
the purchase of a given volume of certain drugs, thereby allowing
manufacturers to ensure capacity for a given market volume regardless
of whether there is sufficient market demand.
Tax incentives or reductions in FDA fees could also be used to
encourage manufacturers to invest in redundant manufacturing capacity.
In its 2019 report, FDA also reports similar incentives for
addressing drug shortages.\10\ Additionally, we plan on further
examining FDA's preparedness and response to drug shortages related to
the Coronavirus Disease 2019 (COVID-19) in the near future.
---------------------------------------------------------------------------
\10\ U.S. Food and Drug Administration, Drug Shortages: Root Causes
and Potential Solutions (2019).
Lastly, we have ongoing work examining the pharmaceutical supply
chain in response to a request from Senators Schumer and Peters. As
part of this work, we plan on further examining the barriers to
---------------------------------------------------------------------------
domestic manufacturing and Federal efforts to increase it.
______
Prepared Statement of Hon. Chuck Grassley,
a U.S. Senator From Iowa
This committee has an obligation to ensure drugs paid for by the
taxpayer via Medicare and Medicaid satisfy quality standards and are
safe and effective for patients. That responsibility, both of Congress
and the FDA, is heightened now that we are living through the COVID
pandemic. Whether we are in the midst of a pandemic or not, these
supply chain issues must be shored up and solved.
Starting June of last year, I began my oversight activities on this
issue. I wrote letters to Secretary Azar and then Acting FDA
Commissioner Dr. Sharpless. I asked a series of questions relating to
manufacturing facilities overseas that manufacture final dosage form
drugs and active pharmaceutical ingredients (APIs). I also asked about
how the FDA manages its foreign inspections regime.
The Government Accountability Office has said that the FDA does
conduct some unannounced inspections overseas but they don't have data
on frequency. However, GAO noted in 2019 that the FDA estimated that
they generally provide 12 weeks of notice before the inspection. Simply
said, you're undermining the ability of field inspectors to do their
job. Twelve weeks is plenty of time to doctor up a facility to make
sure that it passes.
Yet, incredibly, some facilities still get caught. That's how bad
it is. The end result is that the consumer is put at risk.
According to the most recent FDA data, the United States has 46
percent of finished dosage form facilities. That's where APIs are
turned into the final form such as a tablet. That means over 50 percent
of sites manufacturing finished drugs are located overseas.
But, that's just part of the story. What we really need to know is,
where did the API come from?
According to the most recent FDA data, 13 percent comes from China,
and 19 percent comes from India. Combined, that's more than any other
country. And overall, more than 70 percent of facilities that make APIs
are located overseas. These figures, coupled with the COVID pandemic,
have garnered a lot of attention, including what might need to be done
from a national security perspective. But, the figures do make clear
what needs to be done from a drug safety perspective: we need to have a
robust and aggressive foreign inspections program.
Now, with respect to China and India, both those countries have had
serious quality control problems. We all remember the valsartan recall
where that drug was found to contain contaminants used in rocket fuel.
Facilities in China and India produced that drug.
Let's not forget about the Heparin scandal either. In that case,
patients undergoing dialysis began to have severe and life-threatening
side effects because a manufacturing plant in China introduced a toxin
into the production chain. Hundreds of people died and hundreds were
sickened.
Then we have Ranbaxy, an Indian manufacturer. Ranbaxy's production
chain exposed drugs to potential cross-contamination by penicillin and
used APIs from facilities that were not approved by the FDA. Ranbaxy
also manufactured Lipitor and was shut down because it could not
explain why some of those tablets had pieces of glass in them.
I fear these examples are just the tip of the iceberg. They show
why the FDA must maintain an aggressive inspections regime to ensure
drug quality but also impose a strong enforcement regime on bad actors.
In February of this year, FDA Commissioner Hahn told me that in Fiscal
Year 2018 the Center for Drug Evaluation and Research issued almost
five times as many warning letters to human drug manufacturers as
compared to 2015. He said that's a sign that FDA is better able to use
its resources to identify problems. Good. Stay aggressive and don't
hesitate to be more aggressive.
On the front end, though, that process should include unannounced
inspections overseas. After all, why would we give manufacturers time
to prepare their facility for inspection? They ought to be looking over
their shoulder every day. That keeps them honest.
During the Obama administration, the FDA started what was called
the India Pilot Program. It allowed for no-warning inspections or a
couple days' worth of warning. Under it, the FDA issued a 60-percent
increase in ``Official Action Indicated'' findings. In 2015, the Obama
administration shut the pilot program down without explanation. It
sounds like the program was a victim of its own success.
Now, this issue is bipartisan. Republican and Democrat
administrations have come up short. The Government Accountability
Office has a body of work from multiple administrations that proves it.
For example, both the Obama and Trump administrations have struggled to
fill vacancies in foreign offices.
Today, we have witnesses from the FDA who can speak to all of these
issues and how the pandemic has impacted their work. On the first
panel, we have FDA witnesses and a GAO witness. On the second panel, we
have private-sector companies.
It's important to note that I plan to follow up with another
hearing soon examining another problematic aspect to our medical supply
chain, specifically the increase in trade of fake and faulty personal
protective equipment. That is separate from what we will discuss today.
In closing, I want to say two things. First, thank you to the FDA
officials who work tirelessly to inspect facilities overseas. Second,
regardless of party, we must have an honest discussion of the
government's shortcomings so that we can better understand what we, as
Congress, can do to ensure drug safety for the taxpayer. After all, we
work for them and must always answer to them.
______
United States Senate
committee on finance
Washington, DC 20510-6200
June 27, 2019
The Honorable Alex Azar
Secretary
Department of Health and Human Services
Dr. Norman Sharpless
Acting Commissioner
Food and Drug Administration
Dear Secretary Azar and Acting Commissioner Sharpless:
For decades, safe and affordable drugs have been for sale across
our border in Canada, as well as in the United States. I've pressed FDA
on importation policies and introduced legislation to help American
consumers purchase those drugs. With increasing prescription drug
costs, it is important that Americans have options for their much-
needed medication. However, unbeknownst to many consumers, the majority
of the active pharmaceutical ingredients (API) in drugs they take are
produced not in Canada or the U.S., but in China and India. According
to recent news reports and a GAO report highlighting safety and quality
concerns at foreign drug manufacturing facilities, 80 percent of API
are produced abroad, the majority in China and India; however, the FDA
only inspected one in five registered human drug manufacturing
facilities abroad last year.\1\
---------------------------------------------------------------------------
\1\ Katherine Eban, Americans Need Generic Drugs. But Can They
Trust Them?, The New York Times (May 11, 2019), available at https://
www.nytimes.com/2019/05/11/opinion/sunday/generic-drugs-safety.html.
See also, U.S. Gov't Accountability Off., GAO-17-143, Drug Safety: FDA
Has Improved Its Foreign Drug Inspection Program, but Needs to Assess
the Effectiveness and Staffing of Its Foreign Offices 1 (Dec. 2016).
Didi Martinez, Brenda Breslauer and Stephanie Gosk, Tainted drugs: Ex-
FDA inspector warns of dangers in U.S. meds made in China, India, NBC
News (May 10, 2019, 1:01 PM EDT), available at https://www.nbcnews.com/
health/health-news/tainted-drugs-ex-fda-inspector-warns-dangers-u-s-
meds-n1002971.
This committee has an obligation to ensure that the Food and Drug
Administration (FDA) upholds its responsibility to protect the public's
health by properly overseeing the Nation's drug supply and ensuring
that the drugs Americans use are safe and effective. I am concerned
that the FDA's foreign drug inspection program in China and India is
not sufficient to identify and address key risks to the health and
safety of Americans who rely on these drugs.\2\
---------------------------------------------------------------------------
\2\ Didi Martinez, Brenda Breslauer and Stephanie Gosk, Tainted
drugs: Ex-FDA inspector warns of dangers in U.S. meds made in China,
India, NBC News (May 10, 2019, 1:01 PM EDT), available at https://
www.nbcnews.com/health/health-news/tainted-drugs-ex-fda-inspector-
warns-dangers-u-s-meds-n1002971.
For example, a recent New York Times article published in May of
2019 calls into question the quality, safety and reliability of brand
and generic drugs made overseas.\3\ The article chronicles a former FDA
consumer safety officer's findings while inspecting foreign
manufacturing plants in both China and India from 2012-2018.\4\ During
the course of his 6 years in those countries, he discovered fraud and
deception in 67 of the 86 drug manufacturing plants that he
inspected.\5\ He routinely uncovered hidden laboratories, fake quality-
control, defective sterilization machines and toxic impurities.\6\
Equally alarming, the article outlines how, from 2013-2018, the FDA
downgraded the regulatory sanctions against more than 100 Indian
plants, changing the designation from ``official action indicated'' to
``voluntary action indicated.''7
---------------------------------------------------------------------------
\3\ Katherine Eban, Americans Need Generic Drugs. But Can They
Trust Them?, The New York Times (May 11, 2019), available at https://
www.nytimes.com/2019/05/11/opinion/sunday/generic-drugs-safety.html.
\4\ Id.
\5\ Id.
\6\ Id.
\7\ Id.
An additional news article from NBC News, also published in May of
2019, highlights a different former FDA inspector who also spent time
in China and India inspecting manufacturing facilities.\8\ One plant in
Linhai, China, had numerous issues, including anomalies in testing and
``unknown impurities.'' The inspector recommended a warning letter to
the facility which would bar it from gaining approvals to produce new
drugs at the facility. The FDA reportedly overruled his
recommendation.\9\ After public criticism of how the FDA handled this
case, the FDA said it would have been ``unlikely'' to catch the
impurities at the source of the recall during a routine inspection and
that, ``our inspections did reveal systemic problems of supervision
that could have created the conditions for quality issues to
arise.''\10\
---------------------------------------------------------------------------
\8\ Didi Martinez, Brenda Breslauer and Stephanie Gosk, Tainted
drugs: Ex-FDA inspector warns of dangers in U.S. meds made in China,
India, NBC News (May 10, 2019, 1:01 PM EDT), available at https://
www.nbcnews.com/health/health-news/tainted-drugs-ex-fda-inspector-
warns-dangers-u-s-meds-n1002971.
\9\ Id.
\10\ Id.
A Government Accountability Office (GAO) report in December of 2016
revealed that the number of foreign drug facilities that have never
been inspected by FDA inspectors was ``about 1,000 of the approximately
3,000'' foreign manufacturing facilities.\11\ Moreover, for fiscal year
2017, the report identified 189 of the 572 facilities in India and 243
of the 535 facilities in China that ``may never have been
inspected.''\12\ Lastly, the GAO report detailed, ``to address this
persistent concern, the agency plans to inspect all establishments in
its catalog with no prior surveillance inspection history over the next
3 years (approximately one-third each year), beginning in fiscal year
2017.''\13\
---------------------------------------------------------------------------
\11\ Drug Safety, supra note 1, at 21.
\12\ Id at 45.
\13\ Id at 21.
Despite the serious concerns with manufacturing quality in China
and India, the FDA's data suggests that it does not seem to have
sufficiently enhanced scrutiny of those countries. The FDA/CDER Office
of Pharmaceutical Quality report from May 2019 suggests that the
percentage of inspections in those two countries (22 percent) is on par
with the number of facilities in those countries (23 percent)--not an
outcome that would suggest increased scrutiny given the reported
problems.\14\
---------------------------------------------------------------------------
\14\ U.S. Food and Drug Admin., Report on the State of
Pharmaceutical Quality 4, 6 (2019), available at https://www.fda.gov/
media/125001/download.
The news articles and GAO report are troubling. In order to better
understand the scope and nature these issues, please provide written
---------------------------------------------------------------------------
responses to the following questions no later than July 17, 2019:
1. How many manufacturing plants in China and India currently
manufacture drugs or APIs intended for the U.S. market?
a. For each facility, if the facility produces final dosage
form drugs, please provide a list of drugs and the corresponding NDAs
and ANDAs.
b. For each facility, if the facility produces API, please
provide the name of the API as well as the associated NDAs and ANDAs
for the finished dosage form using that API.
2. Please provide a list of all registered manufacturing
facilities, either for API or final dosage form drugs, located outside
of the United States. In addition, for all drug manufacturing
facilities currently registered with the FDA in the United States,
China, and India, please provide the following information for all
inspections from 2010 to the present:
a. Facility identifier;
b. Whether the facility is an API or final dosage form
facility;
c. The API or final dosage form that is manufactured;
d. Country where the facility is located;
e. The date of each inspection;
f. Inspection type;
g. Whether the inspection was unannounced;
h. Whether the inspection was conducted by an in-country
inspector or an inspector who traveled from the United States or
another country;
i. The initial recommendation of the inspector;\15\
---------------------------------------------------------------------------
\15\ This request would include official action indicated,
voluntary action indicated, and no action indicated results.
---------------------------------------------------------------------------
j. The final FDA recommendation;\16\ and a
---------------------------------------------------------------------------
\16\ Id.
---------------------------------------------------------------------------
k. Description of the resolution to FDA's concerns.
3. If a foreign pharmaceutical manufacturing plant used
subcontractors or imports API or dosage from other plants, does the FDA
inspect these subcontractors or other plants before the primary plant
is approved to export to the United States? If not, why not?
4. What criteria does the FDA use to determine which facilities
to inspect for an initial inspection? In addition, does a change in
ownership trigger a subsequent inspection? Do the criteria differ for
API and finished dosage form facilities? Please explain.
5. After the FDA identifies problems at a facility, what steps
does the FDA take to ensure that problems are corrected? For example,
does the FDA conduct follow-up inspections to ensure that corrective
action has been taken? If so, how often are follow-up inspections made
to ensure compliance with FDA safety standards? Please provide all
records relating to follow-up inspections at manufacturing facilities
in China and India from 2010 to the present to the extent they are not
covered by Question 2.
6. Does the inspection process in China and India differ from
U.S.-based inspections? If so, how and why? In addition, does the
approach differ for API and finished dosage form facilities?
7. Please explain the FDA's review process and grading criteria
in changing a foreign manufacturing plant designation from ``official
action indicated'' to ``voluntary action indicated.'' In addition,
since 2010 to the present, please provide all instances of ``official
action indicated'' being downgraded to ``voluntary action indicated''
and the rationale for those changes.
8. With regards to the 1,000 foreign manufacturing facilities
that the GAO found had not been inspected as of December 2016, how many
have been inspected since then? Please provide all records relating to
the inspection findings for each facility to the extent they are not
covered by Question 2. In addition, has the FDA changed any of its
policies to increase the inspection rate at foreign facilities to
ensure compliance with safety protocols? If so, please explain. If not,
why not?
9. How many FDA personnel and investigative personnel have been
stationed in China and India from 2010 to the present? How does it
compare to FDA's planned staffing levels?
10. What is the average cost for a foreign inspection for fiscal
years 2010-2019?
I anticipate that your written reply and most responsive documents
will be unclassified. Please send all unclassified material directly to
the committee. In keeping with the requirements of Executive Order
13526, if any of the responsive documents do contain classified
information, please segregate all unclassified material within the
classified documents, provide all unclassified information directly to
the committee, and provide a classified addendum to the Office of
Senate Security. Although the committee complies with all laws and
regulations governing the handling of classified information, it is not
bound, absent its prior agreement, by any handling restrictions.
Thank you in advance for your prompt attention to these matters.
Should you have any questions, please contact Joshua Flynn-Brown of my
committee staff at (202) 224-4515.
Sincerely,
Charles E. Grassley
Chairman
Committee on Finance
______
department of health and human services office of the
secretary
_______________________________________________________________________
Assistant Secretary for Legislation
Washington, DC 20201
September 24, 2019
The Honorable Chuck Grassley
Chairman
Committee on Finance
United States Senate
Washington, DC 20515-6115
Dear Chairman Grassley:
I write in response to your June 27, 2019 letter requesting information
related to the Food and Drug Administration's (FDA) and HHS's efforts
to protect the safety of the Nation's drug supply through its foreign
oversight program. This first production includes 808 pages of
documents bearing bates numbers GrasFDI-000001 to GrasFDI-000809.
Your specific requests for which responsive information or documents
are being provided in this production are restated below, in bold type,
followed by a description of the documents provided. We continue to
collect and review documents responsive to your letter.
1. How many manufacturing plants in China and India currently
manufacture drugs or APIs intended for the U.S. market?
a. For each facility, if the facility produces final dosage
form drugs, please provide a list of drugs and the corresponding NDAs
and ANDAs.
b. For each facility, if the facility produces API, please
provide the name of the API as well as the associated NDAs and ANDAs
for the finished dosage form using that API.
This analysis was completed using information from the Center
for Drug Evaluation and Research (CDER) Catalog of
Manufacturing Sites and includes only those facilities involved
in manufacturing approved abbreviated new drug application
(ANDA) and new drug application (N'DA) products as of June 18,
2019. The list excludes: (1) outsourcing facilities (i.e.,
facilities under section 503B of the Federal Food, Drug, and
Cosmetic Act (FD&C Act)), facilities that manufacture only
excipients (inactive ingredients), and facilities that make
drugs for clinical trials only (not subject to routine current
good manufacturing practice (CGMP) inspection); (2) certain
biologicals for human use that are regulated by the Center for
Biologics Evaluation and Research (CBER) (e.g., blood, plasma,
and cells/tissues); and (3) facilities that participate in some
aspect of pharmaceutical manufacturing but do not ship product
to the U.S. (e.g., contracted facilities such as micronizers,
sterilizers, repackers, and analytical labs).
For purposes of this analysis, facilities that manufacture
the finished dosage form (FDF) only, or both the active
pharmaceutical ingredient (API) and the FDF, have been
categorized as FDF manufacturing facilities. Facilities that
manufacture only the API for a given drug product have been
categorized as API manufacturing facilities.
Counts of FDF and API manufacturing facilities in China and
India that are associated with an ANDA or NDA, and counts of
all FDF and API facilities including non-application products,
are included in the table below.
Table 1. Counts of All FDF and API CDER Catalogued Facilities Manufacturing Human Drug for the United States (as
of June 18, 2019)
----------------------------------------------------------------------------------------------------------------
Application-related Facilities (NDA All Facilities (Including Non-
Country and ANDA) Application)
----------------------------------------------------------------------------------------------------------------
China 180 331
----------------------------------------------------------------------------------------------------------------
India 339 436
----------------------------------------------------------------------------------------------------------------
The counts in response to questions 1a and 1b are enclosed.
3. If a foreign pharmaceutical manufacturing plant used
subcontractors or imports API or dosage from other plants, does the FDA
inspect these subcontractors or other plants before the primary plant
is approved to export to the United States? If not, why not?
FDA does not have the authority to license manufacturing
plants and cannot ``approve'' a manufacturing plant for
domestic commerce or for export to the U.S. For manufacturing
plants that are listed in an NDA, ANDA, or a biologics
licensing application (BLA) and that are making an API or FDF,
FDA can and does evaluate the manufacturing plants (facilities)
and their operations as described in the applications by
evaluating the content of the application and in many cases by
reviewing information in our files associated with the facility
(or facilities) named in the application that are associated
with manufacturing. FDA may also inspect a manufacturing plant
identified in the pending application as part of the
application assessment effort prior to a decision on
approvability. For non-application drug products, such as those
that may be legally marketed in conformance with the over-the-
counter (OTC) monograph process, the FD&C Act requires
manufacturers to notify FDA of their manufacturing operation as
it commences to manufacture and distribute a drug in the U.S.
market.\1\ For manufacturers of OTC monograph products, there
is no pre-market assessment of the manufacturing facilities.
FDA strives to inspect such facilities as soon as possible
after the establishment has registered with FDA.
---------------------------------------------------------------------------
\1\ See Section 510 of the FD&C Act on establishment registration
and product listing requirements.
Facilities that are contracted to perform testing and many
other types of operations or controls of the API or FDF in
fulfillment of the CGMP requirement \2\ are also required to
register with FDA and are subject to inspection. FDA expects
such arrangements to be described in NDAs, ANDAs, and BLAs, and
will evaluate the facilities in these arrangements while
assessing the application. The evaluation of a facility may
include an inspection.
---------------------------------------------------------------------------
\2\ See Section 501(a)(2)(B) of the FD&C Act and 21 CFR part 211 or
212 for FDFs.
FDA does not generally know or seek to know the names and
addresses of all the suppliers of raw materials (e.g., solvents
and reagents) used in API manufacturing operations. However,
FDA does expect API manufacturers to identify the names and
addresses of sources of key materials, like API starting
materials and intermediates, because these, by definition, are
key structural fragments of the final API.\3\ FDA may inspect
such facilities and operations as part of the application
assessment. Generally, API starting material and intermediate
producers are exempt from annual establishment registration and
are not routinely inspected.
---------------------------------------------------------------------------
\3\ See Internationally Harmonized Guidance (ICH) Q7, Good
Manufacturing Practice Guidance for Active Pharmaceutical Ingredients
(https://www.fda.gov/media/71518/download) and ICH Q11, Development and
Manufacture of Drug Substances (https://www.fda.gov/media/80909/
download).
For FDFs, FDA does require producers of in-process materials
(i.e., materials that are precursors to the final FDF, such as
granulated powders intended for compression into tablets or for
filling into capsules) to be registered and identified in
applications for marketing approval. FDA inspects such
operations on a risk-based schedule in accordance with section
510(h)(3) of the FD&C Act using the same site selection process
as used for APIs and FDFs. FDA requires FDF repackers,
relabelers, and contract sterilizers to register their
facilities with the agency, and such facilities are subject to
---------------------------------------------------------------------------
inspection on a risk-based schedule like other facilities.
4. What criteria does the FDA use to determine which facilities
to inspect for an initial inspection? In addition, does a change in
ownership trigger a subsequent inspection? Do the criteria differ for
API and finished dosage form facilities? Please explain.
Any facility that registers their establishment in the FDA
electronic drug registration and listing system (eDRLS) is
subject to an inspection as soon as possible following initial
registration. If the establishment is only associated with a
pending NDA, ANDA, or BLA, FDA may conduct a pre-approval
facility inspection as part of the application assessment
process. If the application is approved, all manufacturing
facilities identified in the approved application that are
required to register annually with FDA will be included in
CDER's Catalog of Manufacturing Sites and subject to a
surveillance inspection on a risk-based schedule in accordance
with section 510 of the FD&C Act. FDA has a publicly available
Manual of Policies and Procedures (MAPP) that describes the
agency's risk-based approach to selecting manufacturing sites
for CGMP inspections.\4\ API and FDF facilities are prioritized
for inspection in accordance with the same site selection
model; however, generally, FDF facilities are a higher priority
than API facilities as there are fewer opportunities to
identify a quality problem between the FDF facility's
operations and the patient. FDA CGMP regulations for finished
pharmaceuticals obligate the FDF facility to evaluate API
suppliers and to test each API shipment, and the CGMP
regulations require additional testing of the API during
processing and of the FDF before it can be released for
distribution.
---------------------------------------------------------------------------
\4\ https://www.fda.gov/media/116004/download.
A change in ownership does not itself trigger an inspection,
and certain changes in ownership may not always be known to FDA
or known to FDA on/about the time the ownership change is in
effect. FDA's expectations for the types of changes an
application holder should report are captured in 21 CFR
Sec. Sec. 314.70, 601.12 and further explained in guidance
---------------------------------------------------------------------------
documents.
6. Does the inspection process in China and India differ from
U.S.-based inspections? If so, how and why? In addition, does the
approach differ for API and finished dosage form facilities?
FDA staff performing facility inspections, whether in the
U.S. or abroad, are expected to follow the standard procedures
governing inspections, which are in the Investigations
Operations Manual \5\ and the relevant inspection program, or
Compliance Program, among other procedural and program
documents. Compliance Programs for human drug inspections to
evaluate CGMP compliance do not recommend different types of
coverage based on country or location. What gets evaluated or
covered during an inspection is the same for U.S.- and foreign-
based inspections, and depends primarily on the inspection
assignment (e.g., for surveillance purpose or for pre-approval
purpose), the specific operations at the facility (e.g., API
vs. FDF manufacturing, processing vs. testing, sterile vs. non-
sterile), and the facility's compliance history (e.g., previous
violations or no previous inspection). An inspection team will
adjust the inspection strategy based on findings made while on-
site performing an inspection.
---------------------------------------------------------------------------
\5\ https://www.fda.gov/media/113432/download.
FDA maintains a Compliance Program specific to APIs,\6\ and
there are a variety of Compliance Programs for FDFs.\7\ The
Compliance Program describes very similar approaches to
conducting the inspections, which is to permit either an
abbreviated or full inspection depending on past FDA
inspections, if any, and compliance history and changes to the
facility or operations. API inspections are generally planned
to take less time than an FDF inspection. FDA additionally
maintains a Compliance Program that governs the conduct,
approach, and objectives for Pre-Approval Inspections.\8\
Further information about our Drug Compliance Programs is
available on the FDA website.\9\
---------------------------------------------------------------------------
\6\ https://www.fda.gov/media/75201/download.
\7\ E.g., https://www.fda.gov/media/75167/download (general) and
https://www.fda.gov/media/75174/download (sterile).
\8\ https://www.fda.gov/media/121512/download.
\9\ https://www.fda.gov/drugs/guidance-compliance-regulatory-
information/drug-compliance-programs.
10. What is the average cost for a foreign inspection for fiscal
---------------------------------------------------------------------------
years 2010-2019?
The information below includes the average cost to FDA's
Office of Regulatory Affairs (ORA) per foreign drug inspection,
including travel costs. The inspection costs have been
determined by the average hours per inspection based on
completed inspections from each fiscal year; the average hours
per inspection changes from year to year.
Table 2. Average Cost Per Foreign Drug Inspection
------------------------------------------------------------------------
Fiscal Year Average Cost
------------------------------------------------------------------------
FY 2010 $50,700
------------------------------------------------------------------------
FY 2011 $56,800
------------------------------------------------------------------------
FY 2012 $56,600
------------------------------------------------------------------------
FY 2013 $57,100
------------------------------------------------------------------------
FY 2014 $55,300
------------------------------------------------------------------------
FY 2015 $57,400
------------------------------------------------------------------------
FY 2016 $65,700
------------------------------------------------------------------------
FY 2017 $72,300
------------------------------------------------------------------------
FY 2018 $73,800
------------------------------------------------------------------------
FY 2019 Est. $75,400
------------------------------------------------------------------------
Please note that by releasing the documents with no redactions to the
committee, the Department of Health and Human Services (HHS) is making
an accommodation unique to the facts and circumstances of this
particular matter; it is not a public disclosure, but instead is a good
faith effort to assist the committee in its inquiry. We respectfully
request that the committee not disseminate or otherwise disclose these
documents outside of the committee without prior consultation with HHS.
The production of these materials to the committee does not waive any
applicable privilege. For questions, please contact Traci Vitek, HHS
Senior Counselor, at (202) 620-7194.
Sincerely,
Traci Vitek
Senior Counselor
cc: The Honorable Ron Wyden, Ranking Member
______
United States Senate
committee on finance
Washington, DC 20510-6200
August 6, 2019
The Honorable Alex Azar
Secretary
Department of Health and Human Services
Dr. Norman Sharpless
Acting Commissioner
Food and Drug Administration
Dear Secretary Azar and Acting Commissioner Sharpless:
This committee has an obligation to ensure that the Food and Drug
Administration (FDA) upholds its responsibility to protect the public's
health by properly overseeing the nation's drug supply and ensuring
that the drugs Americans use are safe and effective. I read with
interest your ``Safe Importation Action Plan'' and am pleased that the
administration continues to take steps to address high prescription
drug prices while protecting innovation. As you are aware, I believe
that drug importation will help to reduce drug costs for American
consumers and patients. However, I have also noted that my position is
predicated on the FDA ensuring the safety and efficacy of those drugs.
Accordingly, I want to raise concerns with you that I originally
raised with the FDA in an oversight letter on June 27, 2019, regarding
the FDA's foreign drug inspection program.\1\ Unbeknownst to many
consumers, according to recent news reports and a GAO report
highlighting safety and quality concerns at foreign drug manufacturing
facilities, 80 percent of Active Pharmaceutical Ingredients (API) are
produced abroad, the majority in China and India; however, the FDA only
inspected one in five registered human drug manufacturing facilities
abroad last year.\2\
---------------------------------------------------------------------------
\1\ Didi Martinez, Brenda Breslauer and Stephanie Gosk, Tainted
drugs: Ex-FDA inspector warns of dangers in U.S. meds made in China,
India, NBC News (May 10, 2019, 1:01 PM EDT), available at https://
www.nbcnews.com/health/health-news/tainted-drugs-ex-fda-inspector-
warns-dangers-u-s-meds-n1002971.
\2\ Katherine Eban, Americans Need Generic Drugs. But Can They
Trust Them?, The New York Times (May 11, 2019), available at https://
www.nytimes.com/2019/05/11/opinion/sunday/generic-drugs-safety.html.
See also, U.S. Gov't Accountability Off., GAO-17-143, Drug Safety: FDA
Has Improved Its Foreign Drug Inspection Program, but Needs to Assess
the Effectiveness and Staffing of Its Foreign Offices 1 (Dec. 2016).
Didi Martinez, Brenda Breslauer and Stephanie Gosk, Tainted drugs: Ex-
FDA inspector warns of dangers in U.S. meds made in China, India, NBC
News (May 10, 2019, 1:01 PM EDT), available at https://www.nbcnews.com/
health/health-news/tainted-drugs-ex-fda-inspector-warns-dangers-u-s-
meds-n1002971.
Under the administration's Action Plan, it would draft a Notice of
Proposed Rulemaking (``NPRM'') that would address, in part, the
implementation of section 804(b)-(h) in the Federal Food, Drug, and
Cosmetic Act (Act). The Act allows for drug importation as long as
certain conditions are met including drug quality, record-keeping,
testing, and protections against counterfeiting. The Action Plan notes
the ``NPRM would list those requirements and invite proposals as to how
those conditions would be met by a demonstration project.'' The NPRM
would also allow manufacturers of FDA-approved drugs to import versions
of those drugs sold in foreign countries into the United States.
However, it is not clear how track-and-trace would apply to such
---------------------------------------------------------------------------
products, potentially exacerbating manufacturing quality concerns.
Since my June 2019 letter to the FDA, I have learned that the FDA
does not track in its databases whether a foreign inspection was
subject to an announced or unannounced visit. Further, I have learned
that the FDA generally does not perform unannounced visits of drug
manufacturing facilities in foreign countries but does perform
unannounced visits at facilities based in the United States. Should the
Action Plan be put into effect, the administration must require more
foreign inspections generally and unannounced inspections specifically,
particularly compared to previous administrations.
For example, in 2013 the FDA created a pilot program in India that
eliminated advanced notice and instead used short notice or unannounced
visits.\3\ The pilot program also arranged for FDA inspectors' travel
to be arranged through the U.S. embassies instead of through FDA
offices or manufacturer-arranged travel plans to provide more secrecy
in the lead-up to inspections. According to reports, the new inspection
regime ``exposed widespread malfeasance'' that had otherwise been
hidden because of the advanced warning system.\4\ Among the findings,
the inspections found bird infestations, missing samples, and fake
laboratories, all of which negatively impact drug quality and
safety.\5\ Under the pilot program, the FDA issued a 60 percent
increase in ``Official Action Indicated'' findings.\6\ In 2015, the
pilot program was shut down without explanation.
---------------------------------------------------------------------------
\3\ Katherine Eban, Bottle X: Exposing Impurities in the Generic
Drug Business, Newsweek Magazine (July 2, 2019).
\4\ Id.
\5\ Id.
\6\ Id.
It is unclear why the Obama administration shut the pilot program
down in light of its apparent success. However, because of its reported
successes, I strongly encourage the administration's demonstration
projects to include unannounced inspections in foreign manufacturing
facilities to determine whether they meet the required API and drug
quality and safety standards to include sufficient record-
---------------------------------------------------------------------------
keeping, testing, and protections against counterfeiting.
Sincerely,
Charles E. Grassley
Chairman
Committee on Finance
______
U.S. FOOD AND DRUG ADMINISTRATION
10903 New Hampshire Avenue
Silver Spring, MD 20993
www.fda.gov
February 12, 2020
The Honorable Charles E. Grassley
Chairman
Committee on Finance
U.S. Senate
Washington, DC 20510
Dear Chairman Grassley:
Thank you for your letter regarding the Safe Importation Action Plan
(Action Plan) and your interest in how the U.S. Food and Drug
Administration (FDA or the agency) will ensure the safety and efficacy
of drugs imported under the Action Plan. We appreciate hearing from you
on this important issue.
As you are aware, in July 2019, the Department of Health and Human
Services (HHS) and FDA released the Action Plan to describe steps HHS
and FDA will take to allow the safe importation of certain drugs
originally intended for foreign markets.\1\ The Action Plan describes
two pathways to provide safe and effective drugs to consumers in the
United States at a lower cost. On December 23, 2019, FDA published the
Notice of Proposed Rulemaking (NPRM) and the Notice of Availability for
the Draft Guidance associated with each respective pathway.
---------------------------------------------------------------------------
\1\ See: https://www.fda.gov/about-fda/reports/fda-safe-
importation-action-plan.
Pathway 1 involves an NPRM that would implement an importation program
under section 804 of the Federal Food, Drug, and Cosmetic Act. The
rule, if finalized, would allow importation of certain prescription
drugs from Canada under programs sponsored by States or certain other
non Federal Governmental entities and authorized by FDA. The NPRM
includes requirements to ensure that the importation poses no
additional risk to the public's health and safety and that the program
---------------------------------------------------------------------------
will achieve significant cost savings to the American consumer.
Pathway 2 involves a guidance which would provide recommendations to
manufacturers for importing FDA-approved drug products they
manufactured, and originally intended to sell, in foreign countries. To
use this pathway, the manufacturer, or person authorized by the
manufacturer, would establish with FDA that the foreign version is the
FDA-approved product (e.g., it is manufactured in accordance with the
specifications in the FDA-approved application). FDA would then allow
the drug to be imported and labeled for sale in the United States.
Manufacturers could acquire and use a new National Drug Code for those
products, potentially permitting them to offer a lower price compared
to what their current distribution contracts require.
Toward the goal of lowering prescription drug prices in the United
States, we will be working hard to review comments made to the Federal
Register dockets for the NPRM and draft guidance and to finalize these
documents on an expedited basis.
Your letter also encouraged the use of unannounced inspections and
stated that it was unclear how track-and-trace would apply to products
under the Action Plan. HHS and FDA understand the vital importance of
preserving the drug supply chain's security for continued patient
access to safe and effective medicines. Under both proposed pathways
outlined in the Action Plan, FDA could take action to protect patients
when the agency finds violations of applicable requirements, including
those that pose a significant risk to public health.
The U.S. drug supply chain is among the safest in the world. FDA
prioritizes domestic and foreign inspections based on the facilities
and medicines that have the potential to be the most problematic. The
agency inspects drug manufacturing facilities around the world, and 80
to 90 percent of them--regardless of location--are substantially
compliant with good manufacturing practice requirements. When FDA
identifies manufacturing issues, regardless of whether the facility is
located in the United States or elsewhere in the world, we quickly take
action to address such issues.
Drug manufacturing has become increasingly complex and global,
requiring FDA to remodel its oversight of these tasks to improve the
agency's efficiency and reach. In June 2017, the Center for Drug
Evaluation and Research (CDER) and the Office of Regulatory Affairs
(ORA) entered into an unprecedented concept of operations (ConOps)
agreement to integrate FDA's facility evaluations and inspections for
human drugs.\2\ The agreement, Integration of FDA Facility Evaluation
and Inspection Program for Human Drugs: A Concept of Operations,
outlines the responsibilities and the workflow for pre-approval, post-
approval, surveillance, and for-cause inspections at domestic and
international facilities. ConOps enables CDER and ORA to effectively
manage the growing complexity of the pharmaceutical landscape.
---------------------------------------------------------------------------
\2\ For more information on the ConOps agreement, visit https://
www.fda.gov/drugs/pharmaceutical-quality-resources/integration-fda-
facility-evaluation-and-inspection-program-human-drugs-concept-
operations and https://www.fda.gov/media/107225/download.
Despite FDA's efforts, there may still be ``bad actors'' that fail to
meet the good manufacturing practice obligations. Over the past 4
years, CDER's Office of Compliance has substantially increased the
number of warning letters issued to human drug manufacturers regulated
by FDA. For example, in fiscal year (FY) 2018, the agency issued nearly
five times as many warning letters to human drug manufacturers as in FY
2015. FDA does not believe that the increased number of warning letters
reflects a growing problem in drug quality but instead reflects the
agency's ability to better utilize resources to target problem areas.
The agency uses ``risk-based'' targeting to prevent, uncover, and
combat data and manufacturing problems.\3\
---------------------------------------------------------------------------
\3\ The Office of Pharmaceutical Quality's Manual of Policies and
Procedures (MAPP) 5014.1, Understanding CDER's Risk-Based Site
Selection Model, outlines the policies and procedures for the Site
Selection Model used by CDER staff to prioritize manufacturing sites
for routine quality-related (current good manufacturing practice)
surveillance inspections. This MAPP is available at https://
www.fda.gov/media/116004/download.
FDA conducts both domestic and foreign inspections with comparable
depth and rigor. For both inspections, the agency uses the same highly
trained investigators who conduct each inspection in accordance with
the same compliance programs. In many cases, FDA must announce its
intention to conduct a foreign inspection in advance to be sure the
firm is operational and to avoid wasting inspection resources. However,
when the agency determines the need to do an unannounced inspection,
FDA can and does conduct such operations. For example, over the past
several years, FDA investigators have conducted unannounced inspections
at foreign manufacturing facilities in India and China when needed.
When significant issues are uncovered at a foreign manufacturing
facility, regardless of whether the inspection was announced in
advance, the agency acts expeditiously to protect patients by placing
the facility on an import alert to block its medicines from reaching
---------------------------------------------------------------------------
U.S. patients.
Although it takes only one bad actor to create a health issue for
patients, it is important to note that most facilities and companies
pass FDA's inspections and are manufacturing safe, effective, and high-
quality medicines. FDA' s laboratory testing for drug quality, using
testing standards set by the United States Pharmacopeia or submitted in
marketing applications, has consistently shown that medicines
manufactured in foreign countries meet U.S. market quality standards.
Thank you again for your interest in this important matter. The agency
looks forward to working with you as it executes this plan.
Sincerely,
Stephen M. Hahn, M.D.
Commissioner of Food and Drugs
______
Prepared Statement of Harry M. Lever, M.D., Staff Cardiologist, Sydell
and Arnold Miller Family Heart, Vascular, and Thoracic Institute at
Cleveland Clinic
Thank you, Chairman Grassley and Finance Committee members, for the
opportunity to comment. My name is Harry Lever, and I am a cardiologist
at the Cleveland Clinic. I am one of the country's leading experts in
the treatment of hypertrophic cardiomyopathy, an abnormal thickening of
the heart muscle which affects one in 500 people. It can cause
shortness of breath, chest pain, dizziness, loss of consciousness, and
in a small number of people, sudden death. Many are treated with
medication while some require surgery. Early in my career my concern
for the quality of generic drugs was occasional. With more generics
coming to market and some manufacturing being moved to foreign
factories that do not always follow good manufacturing practices, I now
have concerns.
Many of the patients that I see are quite fragile and dependent on a
combination of medication and surgery. I typically prescribe generic
drugs for my patients because they are much less expensive than their
brand name counterparts. Insurance companies can often rerequire that I
prescribe a generic equivalent as they cost less and are often as just
as effective as brand name medications. But I have found that not all
generic drugs are of the same quality. I have seen inconsistent results
with my patients taking generic drugs in terms of their response to the
medication, particularly generic medications coming from countries with
poor regulation, such as China and India.
1. diuretics to treat congestive heart failure
I have found some diuretics for the treatment of heart failure that do
not work adequately. Some of my patients who become stabilized in the
hospital and then discharged can have a rapid readmission for heart
failure. When I investigated these problems, I found that the patients
were given an alternative generic manufacturer of the diuretic that
doesn't consistently work. I have also had patients stable for a long
period of time on a diuretic and then go into heart failure. Despite my
role as the responsible physician, I am typically not informed that a
generic substitution was made or told the identity of the new generic
medication's manufacturer. The FDA rates generics as interchangeable
and these can be changed at any time at a pharmacy. This works as long
as the medications are of the same quality--but even the FDA
acknowledges that manufacturers need to improve quality.
2. beta blockers to treat hypertrophic cardiomyopathy, coronary artery
disease, and hypertension
Another drug that I have experienced as a problem is the beta blocker,
metoprolol succinate, which is a sustained release drug for the
treatment of patients with hypertrophic cardiomyopathy as well as those
with coronary artery disease or hypertension. I have found for many
patients only the authorized generic or the name brand drug works
consistently. In the treatment of hypertrophic cardiomyopathy, at times
I have had patients symptoms of shortness of breath, chest pain and
dizziness no longer be managed. The question then is am I dealing with
a poor quality drug or a patient whose disease is severe and simply is
no longer responding to medical treatment? Some patients become
symptomatic again for no apparent reason. After checking their drug's
manufacturer, I frequently have found that the drug has been changed to
a poor quality generic without my knowledge.
3. transplant rejection medication
Medications that prevent heart transplant rejections can also be a
problem. Colleagues have seen patients who suddenly begin rejecting a
new heart after their tacrolimus, a drug used to prevent rejection, is
changed to a different manufacturer.
summary
We need solutions to this problem--I suggest quality ratings that are
made public noting which generic products are effective and which
should be avoided. More control is needed over the finished product to
protect patients. To accomplish this, it will require the medical
profession, the drug industry, the insurance companies, and the
government working together as partners.
Thank you.
______
Prepared Statement of David Light,
Founder and CEO, Valisure
Chairman Grassley, Ranking Member Wyden, and distinguished members
of the Senate Finance Committee, thank you for holding this important
hearing. My name is David Light, and I am the founder and CEO of
Valisure.
At Valisure, our mission is to help ensure the safety, quality, and
transparency of medications, and we do this with a very simple but
novel approach: we check. Valisure is an online pharmacy attached to an
analytical laboratory. We are the first and only pharmacy in America
that chemically batch-validates every medication we sell, and we do it
at no additional cost to consumers. Founded in 2015, Valisure is
headquartered at Yale Science Park in New Haven, Connecticut. Valisure
is ISO-17025 accredited by the International Organization for
Standardization (ISO) and is registered with the Drug Enforcement
Administration (Pharmacy: FV7431137, Laboratory: RV0484814) and the
Food and Drug Administration (FDA) (FEI #: 3012063246).
In response to rising concerns about medication quality,
counterfeit medications, and overseas manufacturing, Valisure developed
proprietary analytical technologies that we use in addition to the
FDA's standard assays to test every batch of every medication we
dispense. Valisure tests medications for correct dosage, major inactive
ingredients, proper dissolution, and the presence of carcinogens such
as N-Nitrosodimethylamine (NDMA). Currently, we reject over 10 percent
of on-market medication batches based on these testing standards.
With roughly 80 percent of ingredients in U.S. medications
manufactured in India and China,\1\ medication quality is constantly
called into question. There are roughly three drug recalls in the U.S.
every day and about 100 of those recalls every year are ``Class I,''
which are considered potentially life-threatening. These recalls can be
attributed, at least in part, to the fact that the chemical quality of
medications is primarily checked by manufacturers, which self-report
the results. Most manufacturers are located overseas, where oversight
by the FDA is difficult and fraud is commonplace. These general
difficulties are only made worse by the COVID-19 pandemic.
A useful metaphor for understanding the immense complexity of the
drug supply chain and the critical need for independent analysis is to
think of a bottle of medication like a used car. When you go to pick up
a medication from your local pharmacy, it will often be a year or two
old, have traveled thousands of miles, and touched dozens of hands all
around the world. No one who buys a used car is satisfied to know that
the original manufacturer vouched for its quality. Buyers want a Carfax
report; a 100-point inspection on that specific car, or more. None of
that transparency is available for medications. To ensure quality, we
must do more than just review a manufacturer's paperwork and
facilities: we need independent chemical analysis of the medication
itself.
In a 2015 FDA white paper, the FDA acknowledged that it ``has no
formal means for quality surveillance, except through inspections'' and
conceded that ``inspection findings have not been a reliable predictor
of the state of quality.''\2\ The paper also noted that ``product
recall and defect reporting data demonstrate unacceptably high
occurrences of problems attributed to inherent defects in product and
process design; these data further indicate failures in the
implementation of manufacturing process scale-up as well as routine
production.''
Inspections by FDA at overseas plants are often announced months in
advance and are typically conducted less frequently than the
inspections of U.S. facilities, which are unannounced.\3\ Even these
infrequent overseas inspections have been halted as a result of the
COVID-19 crisis,\4\ making the need for greater oversight and quality
assurance of the drugs coming into our country more imperative than
ever.
Recent drug quality issues have threatened the health and safety of
American consumers, including the widespread contamination of critical
blood pressure medications,\5\ gastroesophageal reflux disease
drugs,\6\ and diabetes medications \7\ tainted with carcinogens.\8\ Not
only do drug quality issues place patients' lives at risk, they also
account for over 60 percent of drug shortages \9\ and generate fear and
mistrust that is a contributing factor to medication non-adherence.\10\
We believe Valisure's work has only scratched the surface of the
troubling drug quality issues in the U.S. supply chain. In less than a
year, Valisure has identified a fourth major carcinogen in valsartan,
discovered the fundamental instability of Zantac/ranitidine leading it
to break down into a carcinogen, detected high levels of NDMA in
roughly 40 percent of analyzed batches of the diabetes drug metformin,
and uncovered many other serious issues. The immense impact of and
critical need for independent chemical testing of medications has
become extremely clear.
the recall of zantac/ranitidine: case study in the
need for independent chemical testing
The idea of independently checking drug products may be new to
industry, but in the academic world, it has been done for decades.
However, warnings from academics have unfortunately largely been
ignored. A grim but perfect example of this relates to the drug Zantac
and its generics, ranitidine.
In 1977, Senators sat in Dirksen Senate Office Building and
listened to testimony from the prominent scholar Dr. William Lijinsky,
Director of the Chemical Carcinogenesis Laboratory at Frederick Cancer
Research Center. Dr. Lijinsky presented strong evidence that certain
drugs are unstable and prone to forming the extremely potent
nitrosamine carcinogen NDMA. In his opening remarks, Dr. Lijinsky
testified:
Methapyrilene, like many similar antihistaminic drugs, is a
tertiary amine. Being a tertiary amine, it reads [reacts] with
nitrites in mildly acid solution to form a nitrosamine,
dimethylnitrosamine [NDMA], which is one of the most potent
carcinogens known, inducing liver cancer in rats.\11\
Like methapyrilene, Zantac is an antihistamine, has a tertiary
amine, and it reacts with nitrites (commonly found in many foods) in
mildly acid solution (like a full stomach) to form NDMA.
A year later, in 1978, the World Health Organization (WHO) and the
United Nations held a global summit on nitrosamine carcinogens \12\
where leading scientists from around the world expressed concern about
NDMA and its formation from some common drugs.
By 1979, methapyrilene, the drug Dr. Lijinsky used as an example in
his testimony, was removed from the market after 25 years of use due to
concerns that it was carcinogenic \13\ and forming
NDMA.\14\, \15\
Despite these multitudes of warnings, Zantac/ranitidine, which had
practically the same, if not worse, chemical instability and NDMA
formation issues, was approved in 1981 in the UK and in 1983 in the
U.S.\16\ The first of many academic studies raising the possibility of
Zantac/ranitidine being carcinogenic were published in 1982 and
1983.\17\, \18\, \19\, \20\ Dozens of
studies in top journals followed, including clinical\21\ and
epidemiological studies.\22\ Another series of studies started in 1982
and investigated the use of ``nitrosatable drugs'' (Zantac/ranitidine
is highly ``nitrosatable'') being used during pregnancy and found links
to childhood tumors,\23\, \24\ birth
defects,\25\, \26\ and other serious negative
effects.\27\, \28\ However, the multitude of studies had
little, if any, practical impact on the pharmaceutical and regulatory
world. Despite the loud warnings from academics, Zantac/ranitidine
became one of the best-selling drugs in history\29\ and among the most
commonly prescribed drugs to treat acid reflux in pregnant women \30\
and infants.\31\
It was not until 2019, 38 years after Zantac/ranitidine was first
approved and 42 years after Dr. Lijinsky delivered his warnings to the
U.S. Senate, that Valisure's analytical pharmacy performed the simple
act of independently checking a bottle of generic Zantac syrup
prescribed to one of our co-founder's infant daughter. The results were
so dramatic that we immediately took the drug off our formulary and
tasked our full scientific staff to investigate.
After we realized the magnitude of the problem, we were not
satisfied by simply publishing our findings in a scientific journal. We
petitioned the FDA directly;\32\ we spoke to press; and we did not back
down from the crystal-clear science that Zantac/ranitidine is
fundamentally unstable, forms a potent carcinogen, and should be taken
off the market. Two months ago, after dozens of countries had already
banned the drug,\33\ the FDA finally granted our petition,\34\ and this
potentially dangerous drug was officially taken off the U.S.
market.\35\
Without independent testing and the drive to make it broadly
transparent and recognized, Zantac/ranitidine could have remained on
the market for many more decades to come.
the prevalence of contaminants in medications in the u.s. supply chain
Valisure's investigation into Zantac/ranitidine's link to NDMA was
a result of our general interest in analyzing medications for
carcinogens, which began as a response to the rampant recalls of the
blood pressure medications valsartan, losartan, and irbesartan. These
recalls, which began in the summer of 2018, eventually expanded to over
1,000 lots of the sartan class of drugs from numerous manufacturers due
to the presence of NDMA and other similar nitrosamines.\36\
While there are an infinite number of possible impurities that a
laboratory could test medications for, some, like NDMA, are obvious.
NDMA has been studied in medications for decades,\37\ and the
technology to detect it down to parts per billion and beyond has been
widely available since at least 1970.\38\, \39\
Other commonplace carcinogens are also logical to investigate, such
as N,N-Dimethylformamide (DMF). DMF is an industrial solvent that was
reclassified in 2018 by the WHO and International Agency for Research
of Cancer (IARC) as a Group 2A ``probable human carcinogen,'' the same
category as NDMA. The FDA classifies DMF as a Class 2 solvent, which
``should be limited in pharmaceutical products because of their
inherent toxicity.''\40\ However, DMF is nonetheless used in the
production of pharmaceutical active ingredients, including valsartan.
Residual solvents are known issues in pharmaceutical processing, and,
because DMF was implicated as a source of NDMA formation in valsartan,
it was one of the first impurities to be added to Valisure's standard
impurities analysis. As soon as we started looking for DMF, we found
it.
Valisure tested over 30 batches of valsartan medications and found
that approximately two-thirds contained high levels of DMF. We included
these findings in a Citizen Petition filed with the FDA on June 13,
2019.\41\ Our analysis suggests that although progress has been made to
reduce NDMA in -sartan medications, even after 2 years of recalls, the
fundamental manufacturing processes have not been significantly
improved. In the absence of independent scrutiny and regulatory action,
manufacturers continue to be motivated to use cheap solvents like DMF
rather than investing in improving drug quality and safety.
Valisure's analysis found DMF not just in medications produced by
generic manufacturers but also in Diovan, the branded version of
valsartan produced by Novartis. This finding illuminates the immense
complexity of the drug supply chain and the difficulty faced even by
manufacturers who are proactive about ensuring quality. A spokesperson
for Novartis provided the following comment to Bloomberg News regarding
the DMF finding:
``Novartis doesn't use DMF in making Diovan and documents
provided by suppliers it purchases ingredients from indicate
that they don't, either,'' said spokesman Althoff. ``But
companies that its suppliers buy from could.''\42\
The vast and incredibly complex web of the pharmaceutical
manufacturing industry has been recognized as a danger for many years,
but it has resisted a slew of new technologies that attempted to
``secure it.''\43\ Therefore, independent, proactive chemical analysis
of medications that is made transparent to all in the health-care
ecosystem is critical,and not just for generic manufacturers in a
handful of overseas countries, but as an overall industry standard.
metformin: a current crisis for roughly 18 million
type 2 diabetics in the u.s.
Metformin is an oral diabetes medication that helps control blood
sugar levels in adults and adolescents with type 2 diabetes. Metformin
is taken by over 18 million Americans and is prescribed over 90 million
times a year, making it the fourth-most prescribed drug in the U.S.\44\
Amid actions by regulators worldwide to step up vigilance on drug
quality, the Ministry of Health of Singapore was the first to publicly
identify NDMA contamination in metformin and issued recalls in early
December 2019.\45\ Switzerland announced recalls weeks later \46\ and,
by February 2020, Canada had followed suit.\47\
The FDA announced it would investigate metformin contamination in
December 2019.\48\ In February 2020, the FDA released a laboratory
method for the analysis of metformin \49\ and published lab
results.\50\ The FDA reported that it had analyzed 16 batches of
metformin from seven companies and found no NDMA beyond acceptable
levels. However, it is important to note that the FDA may have acquired
the medication samples through voluntary submission direct from
manufacturers, which can introduce significant sampling bias and would
not be an independent measure of quality.
To independently evaluate the state of metformin contamination,
Valisure acquired 38 batches of metformin from 22 companies through our
pharmacy's distributors. The results from this analysis were included
in a FDA Citizen Petition filed on March 2, 2020.\51\ In our analysis,
Valisure utilized the FDA's published testing protocol but modified it
to improve sensitivity and, importantly, to add an internal
control.\52\ Our results showed that 42 percent of the batches analyzed
(16 of 38) contained NDMA exceeding the FDA's daily acceptable intake
limit, with the highest detected amount over 16 times the permissible
limit. To further validate this data, Valisure sent samples from a
contaminated batch of metformin to be independently verified by Emery
Pharma, an FDA registered/inspected, cGMP/GLP compliant analytical
laboratory.\53\ Emery's results showed slightly higher NDMA levels than
what Valisure found, confirming the severity of the contamination.
Valisure's analysis of its pharmacy batches significantly widened
the number of sampled products and companies beyond the FDA's original
report and likely reduced the sampling bias but was still limited by
the availability of the drug from Valisure's pharmacy distributors.
Therefore, Valisure conducted a direct-to-
consumer crowdsourcing study in which we called for individuals to send
us samples of metformin for free analysis. This effort resulted in the
evaluation of 128 samples of metformin from individuals located in 30
States. The results of Valisure's analysis of these samples were
detailed in a study co-authored with a researcher at The University of
Maryland School of Pharmacy and posted on medRxiv.org, a pre-
publication server maintained by Yale University.\54\ As summarized in
the study abstract,
42 percent of all medication samples contained detectable
levels of NDMA and, when scaled to maximum daily tablet dose,
36 percent of all medication samples contained NDMA levels
exceeding the FDA daily acceptable intake limit. The highest
NDMA detection from the tested samples was 1565 ng per tablet,
which, when commonly taken four times a day, is 65 times the
United States Food and Drug Administration (FDA) acceptable
daily intake limit. Results underscore the need for immediate
product recalls of tainted medications and an overall
investigation of metformin manufacturing practices.
These results largely mirror the findings from the analysis of
pharmacy samples in Valisure's FDA Citizen Petition, and again
illustrate the importance of independent testing derived from
independently sourced samples.
The FDA recognized the importance of Valisure's Citizen Petition,
and, in response, requested samples from the batches we analyzed. On
April 1, 2020, Valisure voluntarily supplied tablets from each of the
38 identified batches. On May 28, 2020, the FDA announced that it was
in contact with five metformin manufacturers and was urging them to
voluntarily recall their products.\55\ It appears that this action was
spurred in large part by the agency's analysis of the samples provided
by Valisure. Valisure applauds this decision and hopes there will be
future opportunities for collaboration between the FDA and independent
laboratories like ours. However, a disconnect regarding the severity
and breadth of the metformin contamination issue unfortunately persists
due to discord over analytical methodologies.
In the case of metformin, the current FDA statements target only
the extended release (ER) formulations of metformin, which account for
about one quarter of prescriptions,\56\ and not the immediate release
(IR) formulations, which have also been identified by Valisure to
contain unacceptable levels of NDMA. Furthermore, the agency states
that their findings of NDMA in metformin ``were generally lower than
reported by the private laboratory [Valisure].'' Both these
discrepancies are likely explained by the agency's published method for
the analysis of metformin not including an internal control.
Internal controls are considered scientific best practice by the
International Council for Harmonisation of Technical Requirements for
Pharmaceuticals for Human Use (ICH),\57\ and are industry standard for
the analysis of NDMA in complex samples like drinking water,\58\
wastewater,\59\ soil,\60\ food \61\ and beverages,\62\ biological
samples,\63\ and pharmaceutical products \64\ (including Singapore's
published method for NDMA analysis in metformin \65\).
To understand the importance of an internal control more simply, it
is useful to employ the metaphor of taking a picture of a fish to show
its size. To properly portray the size of the fish, one can place a
penny or a dollar bill next to it. The penny is acting as an ``internal
control'' because it is a known size, so now a person can properly
appreciate the size of the fish in the picture.
In Valisure's study of metformin, the internal control was highly
influential to obtain proper quantification of NDMA and the internal
control had the greatest influence on IR tablets.\66\ This implies that
without the use of an internal control, NDMA levels will incorrectly
appear significantly lower overall and, in particular for IR
formulations, potentially to the point that unacceptable levels of
contamination may not be detected at all in IR tablets if the control
is not used.
These details may sound overly technical, but the consequences are
profound. While debate ensues over analytical methodologies, roughly 13
million Americans are currently taking IR formulations of metformin and
are at risk of continued exposure to unacceptable levels of NDMA. This
situation is very similar to what occurred with Zantac/ranitidine
nearly a year ago, in which the product remained on the market for
months while the FDA contested analytical techniques.
Another critical component of the importance of independent
analysis is the flexibility to improve upon regulatory guidance for
analytics which may not always follow the latest best practices.
proposed solutions: certified drugs, drug quality scores,
and regulatory interventions
While the problems with the U.S. supply chain are significant, we
believe there are several straightforward steps that would either stop
these issues before products even leave the manufacturing plant or
enable immediate, real-time action by buyers and payers to avoid
purchasing low-quality products.
Certified Drugs
As aforementioned, Valisure conducts batch-testing of every product
dispensed to our customers before it leaves the pharmacy, and we do so
without adding any cost to patients. We believe this could be
replicated on a larger scale, creating ``certified drugs'' that are
independently chemically analyzed and certified before being sold to a
patient, pharmacy, wholesaler, or health-care system.
Ideally, this independent analysis would be done immediately after
the original manufacturer produces the product, when the full size of
the batch is in one location and before the product is dispensed to
wholesalers and other down-market entities. The results of this
analysis--in the form of a simple certificate--could be a desired,
value-add mark that follows the product through the supply chain and
into the hands of the patient receiving the medication, thus ensuring
transparency and recognition of quality.
This independent analysis is already possible at less than a penny
per pill at Valisure's pharmacy, and the cost could easily be borne by
manufacturers or large entities in the supply chain. Manufacturers
could stand to gain market share for these certified products either by
standard market drivers or through new requirements or incentives by
health systems and large private or government purchasers.
Health systems are constantly plagued by drug quality issues and
are impacted both tangibly (e.g., drug recalls) and intangibly (e.g.,
doctor and pharmacist time dealing with recalls; patient mistrust;
readmissions; poor treatment of patients' conditions). Leading health
centers like the Cleveland Clinic have identified so many issues that
``Cleveland Clinic pharmacists developed a confidential black list of
drugs it would no longer buy.''\67\ Prominent health systems or other
major entities in the drug supply chain that are concerned about
quality and patient safety could demand certified drugs and either
require or incentivize having independent certification in their
purchasing processes.
Certified drugs not only have the advantage of removing potentially
dangerous products from the market but would inject much-needed
transparency into the U.S. drug supply chain. As noted by Professor
John Gray of Ohio State University in a statement submitted for the
record for this hearing:
Unlike many consumer products, consumers/patients generally
cannot know if there is a problem with their drug by looking at
it. Further, even after taking the drug, it is hard to pinpoint
that any side effects are the result of drug quality. This lack
of quality visibility makes testing more critical in the drug
industry than in many other industries. It also increases the
risk that manufacturers, facing cost and delivery pressures,
allow drugs to be shipped that did not meet all process and/or
product specifications.
The opacity of drug quality and the difficulty it can cause
providers is exemplified by the many clinical examples observed by
distinguished doctors at the Cleveland Clinic.\68\ In the book Bottle
of Lies by Katherine Eban, a whole chapter is dedicated to a term
coined by a Cleveland Clinic doctor called ``the X factor'':
visualize each patient's case as an algebraic equation. A new
symptom put an unknown variable, an ``X,'' into the equation .
. . generics seemed to be a new X that threw off the whole
equation.
In other words, potential quality problems resulting from drug
manufacturing present a further ``X factor'' that can frustrate proper
diagnosis and treatment. As such, the visible mark of quality a
certified drug offers would provide immense value to patients, doctors,
payers, and the broader health-care system.
Drug Quality Scores
Although we believe that Valisure's independent chemical analysis
of pharmaceuticals could be replicated on a larger scale, in the near
term, certified drugs are likely only realistic for a handful of high-
volume, high-impact drugs. However, data is available today that
provides valuable insights on practically all drug products in the U.S.
On February 3, 2020, Valisure had the honor to be a plenary speaker
at an event hosted by the Duke Margolis Center for Health Policy in
partnership with FDA, Understanding How the Public Perceives and Values
Pharmaceutical Quality.\69\ At this event, a broad group of leaders
from health-care systems, the pharmaceutical supply industry, payers,
universities, and non-profits strongly agreed there is a troubling lack
of transparency into medication quality, and that the development of
medication ``quality scores'' would be a powerful solution.
The FDA's Task Force on Drug Shortages has endorsed the creation of
a voluntary ``rating system. . . . to inform purchasers, group
purchasing organizations (GPOs) for health-care systems, and even
consumers, about the quality management maturity of the facilities
making the drugs.''\70\ We believe that this would be an important
first step. However, data on quality management maturity--in other
words, a manufacturer's paperwork--falls far short of the transparency
on drug quality demanded by supply chain stakeholders.
Independent quality rating systems should be developed through a
process that includes robust stakeholder feedback, including patients,
providers, academic institutions, and health systems. These ratings
systems should rely on objective, science-based data that is not solely
voluntarily provided by manufacturers but generated by independent
third parties. To accomplish this, results from independent chemical
analysis of drug products could be combined with publicly available
regulatory data and turned into drug quality scores that could be as
simple as a ``red/yellow/green'' rating for each drug made by each
manufacturer. Any buyer or payer could simply strive to buy green,
occasionally yellow, and just avoid red.
A recent paper, Evidence-Based Quality Scores for Rating Drug Products
and Their Utility in Health Systems,\71\ (Attachment B) written by
authors from NYU Langone Health, Columbia University, Defense Health
Agency, University of Utah Health Care, Cleveland Clinic, Yale School
of Public Health, and University of Connecticut School of Pharmacy,
illustrates how such an independent system of quality ratings could
work. Valisure contributed data and expertise to this paper. As
explained in the extract:
The quality of drug products in the United States, which are
largely produced overseas, has been a matter of growing
concern. Buyers and payers of pharmaceuticals, whether they are
health-systems, insurers, PBMs, pharmacies, physicians, or
patients, have little to no visibility into any quality metrics
for the manufacturers of drug products or the products
themselves. A system of ``quality scores'' is proposed to
enable health-
systems and other purchasers and payers of medication to
differentiate among drug products according to evidence-based
metrics. Metrics influencing the quality scores described
herein include both broadly applicable regulatory information
and more drug-specific, third-party chemical analysis
information. The aggregation of these metrics through a
proposed set of rules results in numerical values on a 0-100
scale that may be further simplified into a red/yellow/green
designation. The simplicity of such scores enables seamless
integration into existing healthcare systems and an integration
scheme is proposed. Using real-world data from currently on-
market valsartan drug products, this proposed system generated
a variety of quality scores for six major manufacturers. These
scores were further evaluated according to their current market
price showing no significant correlation between quality score
and price. The implementation of drug quality scores at
healthcare institutions in the United States and their
potential utilization by regulators, could create a much-
needed, market-driven incentive for pharmaceutical
manufacturers to produce quality medications that would reduce
drug shortages and improve public health.
This landmark paper is attached to this testimony and offers the
first real blueprint of how independently generated, evidence-based
drug quality scores can be built and utilized by healthcare systems
throughout the U.S.
Regulatory Interventions
Finally, we believe there are a number of actions that the FDA and
Congress could take that would bolster the effectiveness of the
solutions above and further strengthen Federal oversight of drug
quality.
First, the proposed industry-driven solutions of certified drugs
and drug quality scores could be significantly strengthened by
incentives or requirements put in place by government payers. For
example, the Department of Defense (DoD), which purchases its own
medications, could require independent certification prior to purchase
or provide incentives for manufacturers to do so. These concepts could
also be included in legislation currently proposed to reform government
purchasing of drugs (including for DoD) to incentivize sourcing from
the U.S. and move pharmaceutical manufacturing to America.\72\
Second, legislation could fill critical voids in the FDA's current
ability to enforce appropriate measures for ensuring the safety and
quality of the Nation's drug supply. In the aforementioned Duke
Margolis Center event, representatives from the FDA presented data from
a survey of physicians. When asked, ``Which, if any, of the following
are functions of the FDA in terms of regulating drug quality?'' the top
answer was, ``Remove a drug from market if unexpected risks are
detected.''\73\ It is a sad irony that this is one power that the FDA
does not have.
Congresswoman Rosa DeLauro (D-CT) has introduced H.R. 1108, the
Recall Unsafe Drugs Act,\74\ which would remedy this situation by
providing the FDA with the authority it lacks to conduct the mandatory
recalls of drugs. The bill was reintroduced in January 2020, along with
a call from the Congresswoman to recall all ranitidine products.\75\
Valisure strongly supports this legislation, which would mirror the
mandatory recall authority FDA already has over medical devices, food,
and biological products, but lacks for drugs.
Finally, another avenue where independent batch-level validation of
drugs could easily be applied is drug importation. Drug importation is
a unique opportunity to reimagine the drug supply chain and rebuild it
in a way that helps ensure drug quality by incorporating independent
chemical analysis of all imported products--essentially making all
imported drugs certified drugs. We believe that drug importation is not
only an important opportunity to provide lower-cost drugs to American
consumers, but to enable even higher quality assurance than is
presently possible in the current domestic drug supply.
In general, Valisure supports the framework set forth in the
administration's Importation of Prescription Drugs Proposed Rule,
particularly the proposed batch-level testing of all imported products.
However, it is critical that the rule is revised to ensure that this
testing is performed by independent laboratories rather than requiring
further cGMP testing conducted by manufacturers that would be subject
to the same conflicts of interest and errors as under our current
system.\76\ (Attachment A)
Valisure is greatly honored by the engagement it has received from
government agencies and legislators and is open to exploring any
avenues in which it can help to increase quality assurance and
transparency in medications.
covid-19 and the impact on medication quality
In addition to its devastating toll on global health and economies,
the COVID-19 pandemic has had significant impacts on the drug supply
chain. Although finding treatments and vaccines for the virus and
caring for the sick are the immediate first-order problems to address,
it is becoming increasingly clear that one of the biggest second-order
issues will be serious disturbances to the U.S. pharmaceutical supply
chain. Drug shortages are already affecting Americans prescribed
medications being repurposed for COVID-19 treatment,\77\ and the
shutdown of overseas manufacturing will likely create dozens of
widespread shortages in the months to come--many of which we have
little visibility into today.
In addition to the challenge of drug shortages, existing
pharmaceutical quality problems may be exacerbated by the COVID-19
crisis. Many safety and quality issues stem from overseas manufacturers
cutting corners, and it is certainly possible that many more corners
will be cut in the scramble to ramp back up production and fill
backorders. The potential for the market to be flooded with
counterfeit, substandard, and tainted products is a serious concern,
particularly in light of the suspension of routine FDA inspections,\78\
the approval of previously banned manufacturers, and dramatically
increased demand for specific drugs.
Through Emergency Use Authorization Act (EUA) authority, the FDA
has chosen to make decisions now for the good of public health that
will undoubtedly impact public safety in the future. For example, in
its efforts to authorize production of large quantities of several
drugs, the FDA has lifted its ban on one overseas manufacturer, Ipca
Laboratories. The FDA had previously banned products from three Ipca
manufacturing facilities because of rampant data manipulation and what
the FDA in a warning letter called a ``cascade of failure'' at its
plant in Silvassa.\79\ One potential solution could be a mandate that
any drugs produced under an EUA should be independently tested and
certified before entering the U.S. market.
We are also concerned about quality problems resulting from
escalated production of products used to treat COVID-19. Many of these
drugs are also used broadly for the treatment of other medical issues
by non-COVID patients. In the race to produce large amounts of these
drugs, quality may be sacrificed for quantity, thereby exposing a large
population to substandard products. Further, when new COVID treatments,
preventives, and vaccines are developed, manufacturers will face
enormous pressure to produce large volumes quickly. Without careful
regulatory oversight and independent analysis, this could result in
quality problems from rushed manufacturing.
It is important to note that manufacturing problems that arise from
the escalated production of drugs and a lack of FDA inspectors on the
ground at foreign plants could produce a domino effect for years to
come. The lifecycle of a drug in the supply chain is many years and it
could be many more before significant and serious issues are found, let
alone addressed.
conclusion
Since Valisure's founding, our mission has been to bring quality
assurance and increased transparency into the opaque world of the
nearly $2 trillion global pharmaceutical industry. While we initially
brought these benefits directly to patients through our online
pharmacy, we are encouraged by the growing awareness of these problems
by public and private stakeholders and increased opportunities for
collaboration. By working together, we strongly believe that we can
bring critically needed quality and transparency in medications to all
Americans.
We are grateful to the Senate Finance Committee's commitment to
ensuring the safety and quality of the U.S. drug supply chain and hope
to continue working with you towards this critical goal.
_______________________________________________________________________
End Notes
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[76] See Valisure's comments to the proposed rule, Importation of
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www.regulations.gov/document?D=FDA-2019-N-5711-1247). See Attachment A.
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(COVID-19) Update: Foreign Inspections. March 10, 2020. https://
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[79] FDA Warning Letters on Ipca Laboratories Limited. January 29,
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01292016.
______
ATTACHMENT A
Valisure
March 9, 2020
VIA ELECTRONIC FILING TO:
www.regulations.gov
Stephen M. Hahn, M.D.
Commissioner
Food and Drug Administration
Department of Health and Human Services
5630 Fishers Lane, Room 1061
Rockville, MD 20852
RE: Importation of Prescription Drugs Proposed Rule, Docket No. FDA-
2019-N-5711
Dear Dr. Hahn,
On behalf of Valisure, the Nation's first and only analytical
pharmacy, I appreciate the opportunity to comment on the FDA's proposed
rule on the importation of prescription drugs. We commend the FDA's
thoughtful approach to the rule, particularly the focus on batch-level
testing of imported products. Drug importation is not only an important
opportunity to provide lower-cost drugs for American consumers, but to
enable even higher quality assurance than is presently possible with
the domestic drug supply. We urge speedy implementation of the rule to
allow States and stakeholders the opportunity to assemble Section 804
Implementation Programs (SIPs) as quickly as possible.
i. background on valisure
Valisure is an online pharmacy attached to an analytical
laboratory, and is the first and only pharmacy in America that
chemically batch-validates every medication it sells at no additional
cost to consumers. Founded in 2015, Valisure is headquartered at Yale
Science Park in New Haven, Connecticut. Valisure is ISO-17025
accredited by the International Organization for Standardization (ISO)
and is registered with the Drug Enforcement Administration (Pharmacy:
FV7431137, Laboratory: RV0484814) and the FDA (FEI #: 3012063246).
Valisure's mission is to help ensure the safety, quality, and
consistency of medications and supplements in the market. In response
to rising concerns about counterfeit medications, the quality of
generics, and overseas manufacturing, Valisure developed proprietary
analytical technologies that it uses in addition to FDA standard assays
to test every batch of every medication it dispenses. Valisure tests
medications for correct dosage, major inactive ingredients, proper
dissolution, and for the presence of carcinogens such as N-
Nitrosodimethylamine (NDMA). Valisure currently rejects over 10 percent
of medication batches based on these testing standards.
Over the past year, Valisure identified a fourth major carcinogen
in valsartan and discovered the presence of NDMA in Zantac/ranitidine,
which led to recalls of the drug throughout the United States and the
world. Most recently, Valisure detected high levels of NDMA in specific
lots of the drug metformin.
In an August 7, 2018 inspection of Valisure's facilities by the
FDA, the FDA determined that since Valisure's unique testing facility
is not a part of the pharmaceutical manufacturing system and does not
perform release testing, stability testing, or any related services for
pharmaceutical manufacturers, Valisure did not require FDA
registration. However, Valisure has elected to maintain voluntary
registration status with the FDA. Valisure also received guidance that
since it operates outside of the manufacturing industry using the
appropriate ISO guidelines as opposed to Good Manufacturing Practices
(GMPs), any product failures or concerns that Valisure identifies
should be reported back to the pharmaceutical industry. Valisure has
complied with this guidance and regularly provides reports to
applicable parties in the pharmaceutical industry.
ii. comments on the proposed rule
Valisure supports the importation framework proposed by the rule.
In particular, we support the rule's proposed batch-level testing of
all imported products, which will help ensure the integrity and safety
of the medication. Below, we offer specific comments on several key
provisions of the rule, including suggestions to help ensure that
importation can be done both efficiently and cost-effectively.
A. SIP Sponsors
Valisure supports the proposal to allow pharmacies and wholesalers
to co-sponsor SIPs. Pharmacies, in particular, have significant
expertise acquiring and distributing prescription drugs, as well as
ensuring the quality of these products; this makes pharmacies uniquely
well-suited to partner with State SIP sponsors. We also believe that a
pharmacy could safely serve as both a co-sponsor and an Importer within
an SIP. To help safeguard these arrangements, we recommend requiring
States to establish sufficient oversight mechanisms to ensure that this
dual role does not present a conflict of interest.
Valisure also supports the proposal to allow pharmacies and
wholesalers to sponsor a SIP independent of a State (``Option 2'' under
Sec. 251.2). We recommend limiting this option to pharmacies that can
demonstrate the ability to manage the administrative aspects of the
program, develop sustainable partnerships with reputable Foreign
Sellers, and administer the required Statutory Testing with high-
quality independent laboratories.
Finally, Valisure supports the proposal to allow pharmacies and
wholesalers to serve as Importers, for all the reasons enumerated
above. We agree that part of Importers' responsibilities should include
an initial screening of imported products. In addition to a visual
comparison of each product to the HPFB-approved drug, on-site laser
spectroscopy-based techniques could be used to quickly screen products
as a first-pass screening using handheld advices. This would require a
relatively minimal investment by the Importer, but would add an
additional level of security. However, this would not replace the need
for significantly more detailed analysis by a qualified laboratory.
B. Covered Products
Valisure believes that the rule's restrictions on covered products
would still allow the importation of many commonly used medications
that not only provide significant opportunities for price savings, but
have already been subject to critical quality and safety issues (for
example, valsartan, losartan, and metformin). The proposed Statutory
Testing for imported products could result in even safer products than
are currently available for sale in the United States.
In particular, Valisure supports the FDA's decision not to exclude
modified-release drugs and narrow-therapeutic index drugs from the
definition of covered products. These are precisely the types of
products that Valisure often hears quality complaints about from
doctors and patients. Batch-to-batch variation in drug dissolution and
dosage in narrow-therapeutic index drugs can translate into significant
adverse events and negatively impact patients' clinical outcomes.
Valisure's testing has revealed substantial quality and safety issues
with many of these products: for example, products with significantly
different dissolution rates across batches, and batches of narrow-
therapeutic drugs, like anticonvulsants, that fall outside the
manufacturers' stated ranges. As noted above, we believe this rule is
an opportunity to add an additional layer of testing that can actually
improve the quality and safety of imported products versus the current
domestic supply.
C. Statutory Testing
Valisure believes that the Statutory Testing is a critical
component of the proposed rule that will help ensure that imported
products are safe and high quality. In particular, Valisure supports
batch-level testing of all imported drugs, which will provide an
important safeguard that goes beyond the requirements for domestically
marketed drugs. However, Valisure has several suggestions to ensure
that this testing is additive and not redundant and is conducted by
independent third-party laboratories.
a. Qualifying Laboratories
Valisure strongly agrees with the proposal that all qualifying
laboratories should have an inspection history and must have
satisfactorily addressed any objectionable conditions or practices
identified during its most recent inspection. Valisure agrees that
qualifying laboratories should be held to rigorous standards, namely
ISO 17025 accreditation.
However, Valisure disagrees that qualifying laboratories should be
required to hold Current Good Manufacturing Practice (CGMP)
certification. CGMP laboratories, by definition, contract with
pharmaceutical manufacturers. This raises a potential conflict of
interest that could lead CGMP laboratories to compromise the integrity
of their testing. Moreover, CGMP testing follows manufacturer
specifications rather than scientific and physiological best practice.
In the past year alone, academics and independent laboratories like
Valisure have discovered serious drug quality issues that were missed
by CGMP testing, including potent carcinogens found in losartan,
valsartan, ranitidine, and metformin. In some cases, these carcinogens
were found because FDA testing guidelines had not yet been updated; in
other cases, carcinogen contamination was widespread but apparently
missed during CGMP testing.\1\ Regardless, these lapses have profound
consequences for patient health.
---------------------------------------------------------------------------
\1\ See Valisure, Valisure Citizen Petition, June 19, 2019 (finding
high levels of the carcinogen DMF in lots of valsartan); Valisure,
Valisure Citizen Petition on Ranitidine, Sept. 9, 2019 (finding
extremely high levels of NDMA in ranitidine); Valisure, Request that
the FDA recall of identified batches of metformin on the basis that,
due to contamination with a probable human human carcinogen, these
drugs are adulterated under Section 501 of the FDCA (21 U.S.C.
Sec. 351) and misbranded under Section 502 of the FDCA, March 2, 2020
(finding high levels of the carcinogen NDMA in lots of metformin).
In addition to raising a potential conflict of interest and
possibly neglecting critical testing that is not prescribed by
manufacturers, pharmaceutical companies placing their products for sale
in the U.S. are already required to conduct a GMP analysis, making the
testing in the proposed rule redundant in many cases. GMP testing is
also particularly expensive; most contract research organizations
(CROs) will charge more for a GMP test than a non-GMP test, even though
the only substantive difference is the paperwork. As such, requiring
qualifying laboratories to hold CGMP certification will unnecessarily
raise the cost of the Statutory Testing and lower cost savings to
---------------------------------------------------------------------------
American consumers.
ISO-17025 accreditation is rigorous, and actually goes beyond GMP
by not only setting standards for laboratory and analytical
methodology, but also governing quality systems company-wide including
business practices. As such, Valisure urges the FDA to eliminate the
requirement that qualifying laboratories hold CGMP certification in
order to ensure that the sponsors of SIPs have the option of
contracting with truly independent and unbiased laboratories.
b. Laboratory Testing Requirements
Valisure recognizes that 21 U.S.C. Sec. 384 permits laboratory
testing to be done by the Importer or by the manufacturer. However,
Valisure remains concerned that permitting the testing to be conducted
by the manufacturer significantly increases the risk of inadequate
scrutiny (at best) and fraud (at worst). As discussed above, this is
especially true if the testing is conducted by a CGMP laboratory that
routinely contracts with the pharmaceutical industry or is itself owned
or controlled by the manufacturer selling the product.
To lower the risk that manufacturer testing might allow low-quality
products to be imported into the U.S., Valisure reiterates its
recommendation that testing should be permitted to be conducted by ISO-
17025 certified labs rather than restricted only to labs that hold CGMP
certification. This would allow SIP sponsors the option of requiring
any imported products to be tested by independent laboratories free of
potential conflicts of interest. Additionally, Valisure urges that the
rule clarify that manufacturers cannot satisfy the Statutory Testing
requirements through pre-existing release or conformance testing. To
the extent products have already undergone release or conformance
testing at a qualifying laboratory in the U.S., the FDA should
stipulate that the Statutory Testing should be conducted at a separate,
independent laboratory to ensure thorough analysis before the products
enter the United States market. Valisure also strongly supports the
requirement in the proposed Sec. 251.16(e) that if testing is done by
manufacturers, detailed data should be provided to the FDA.
D. Product Labeling
Finally, Valisure supports labeling imported products appropriately
to allow pharmacists to be able to distinguish them on a shelf.
However, Valisure suggests that the required language on each box
include the stipulation that each product was batch-tested to help
ensure safety and quality.
* * *
Valisure appreciates the opportunity to provide comments on the
proposed rule and looks forward to working with the FDA and States to
help implement the safe and affordable importation of drugs from
Canada. If you have any questions or if we can provide any further
information that would be useful, please do not hesitate to contact me
at [email protected] or 833-497-7370.
Sincerely,
David Light
Founder and CEO
Valisure
______
ATTACHMENT B
evidence-based quality scores for rating drug products
and their utility in health systems
Arash Dabestani, Pharm.D., MHA, FASHP,\1\ Carl W. Bazil, M.D.,
Ph.D.,\2\ Ryan C. Costantino, MS, Pharm.D., BCPS, BCGP,\3\ Erin Fox,
Pharm.D., BCPS, FASHP,\4\ Joe Graedon MS,\5\ Harry Lever, M.D.,\6\
Robert Makuch, Ph.D.,\7\ C. Michael White, Pharm.D., FCP, FCCP \8\
[1] Department of Pharmacy, NYU Langone Health, New York, NY
[2] Columbia University Medical Center, New York, NY
[3] USA MEDCOM Pharmacy Service Line, Defense Health Agency, San
Antonio, TX
[4] Department of Pharmacy, University of Utah Health Care, Salt
Lake City, UT
[5] People's Pharmacy, Durham, NC
[6] Hypertrophic Cardiomyopathy Center, Heart and Vascular
Institute, Cleveland Clinic, Cleveland, OH
[7] Department of Biostatistics, Yale School of Public Health, Yale
School of Medicine, New Haven, CT
[8] University of Connecticut School of Pharmacy, Storrs, CT
abstract
The quality of drug products in the United States, which are largely
produced overseas, has been a matter of growing concern.\1\ Buyers and
payers of pharmaceuticals, whether they are health-systems, insurers,
PBMs, pharmacies, physicians, or patients, have little to no visibility
into any quality metrics for the manufacturers of drug products or the
products themselves. A system of ``quality scores'' is proposed to
enable health-systems and other purchasers and payers of medication to
differentiate among drug products according to evidence-based metrics.
Metrics influencing the quality scores described herein include both
broadly applicable regulatory information and more drug-specific,
third-party chemical analysis information. The aggregation of these
metrics through a proposed set of rules results in numerical values on
a 0-100 scale that may be further simplified into a red/yellow/green
designation. The simplicity of such scores enables seamless integration
into existing healthcare systems and an integration scheme is proposed.
Using real-world data from currently on-market valsartan drug products,
this proposed system generated a variety of quality scores for six
major manufacturers. These scores were further evaluated according to
their current market price showing no significant correlation between
quality score and price. The implementation of drug quality scores at
healthcare institutions in the United States and their potential
utilization by regulators, could create a much-needed, market-driven
incentive for pharmaceutical manufacturers to produce quality
medications that would reduce drug shortages and improve public health.
---------------------------------------------------------------------------
\1\ Conti RM, Berndt ER, Kaygisiz NM, Shivdasani Y. ``We Still
Don't Know Who Makes This Drug,'' Health Affairs Blog, February 7,
2020. (https://www.healthaffairs.org/do/10.1377/hblog20200203.83247/
full/).
---------------------------------------------------------------------------
introduction
As most of the United States' complex drug supply chain has moved
overseas, especially to countries such as India and China, quality and
safety concerns have become more pressing. Eighty percent of active
pharmaceutical ingredients (``API'') for products sold in the U.S. now
come from outside the country, the vast majority from China.\2\ As Dr.
Janet Woodcock, Director of the Food and Drug Administration (``FDA'')
Center for Drug Evaluation and Research (``CDER''), has noted, this
``use of foreign-sourced materials creates vulnerabilities in the U.S.
drug supply.''\3\ Recent drug quality issues have threatened the health
and safety of American consumers, including the widespread
contamination of critical blood pressure medications,\4\
gastroesophageal reflux disease drugs,\5\ and diabetes medications \6\
with carcinogens.\7\ Not only do drug quality issues place patients'
lives at risk, they also account for over 60 percent of drug shortages
\8\ and generate fear and mistrust that is an important cause of
medication non-adherence.\9\
---------------------------------------------------------------------------
\2\ U.S.-China Economic and Security Review Commission, 2019 Report
to Congress 250 (2019).
\3\ Statement of Janet Woodcock, M.D., Director, Center for Drug
Evaluation and Research, FDA, before the Subcommittee on Health,
Committee on Energy and Commerce, U.S. House of Representatives,
``Safeguarding Pharmaceutical Supply Chains in a Global Economy'' 2
(Oct. 30, 2019), available at https://bit.ly/2SYjqqy.
\4\ FDA Updates and Press Announcements on Angiotensin II Receptor
Blocker (ARB) Recalls (Valsartan, Losartan, and Irbesartan). https://
bit.ly/38MRM6C.
\5\ FDA Updates and Press Announcements on NDMA in Zantac
(ranitidine) (February, 27, 2020). http://bit.ly/3b92dlP.
\6\ Reuters. (March 2, 2020). ``Online Pharmacy Valisure Says Tests
Show Carcinogen in Diabetes Drug Metformin.'' The New York Times.
(https://nyti.ms/2UhtwDw).
\7\ Edney A, Berfield S, Yu E. (September 12, 2019). ``Carcinogens
Have Infiltrated the Generic Drug Supply in the U.S.'' Bloomberg
Businessweek. (https://bloom.bg/2x7P11z).
\8\ See Dr. Patrizia Cavazzoni, FDA, ``The Importance of
Pharmaceutical Quality'' 11 (2020), at https://bit.ly/37LwrJB.
\9\ Brown MT, Bussell J, Dutta S, Davis K, Strong S, Mathew S.
``Medication Adherence: Truth and Consequences.'' Am J Med Sci.
2016;351(4):387-399. doi:10.1016/j.amjms.2016.01.010. (https://
www.ncbi.nlm.nih.gov/pubmed/27079345).
Certain manufacturers have exhibited substantive quality issues and
even engaged in data manipulation. This issue is highlighted by the
record $500 million fine imposed on the generics manufacturer, Ranbaxy,
after it pleaded guilty to failing to report its drugs did not meet
specifications. The firm also made false statements to the FDA. Ranbaxy
knowingly manufactured drugs that tested out-of-specification, had
unknown impurities, and would not maintain their expected shelf
life.\10\
---------------------------------------------------------------------------
\10\ White CM. ``Generic Drugs Not as Safe as FDA Wants You to
Believe.'' Annals Pharmacotherapy 2020;54(3):283-286. (https://
journals.sagepub.com/doi/full/10.1177/1060028019881692).
Although significant attention is given to overseas manufacturers,
American companies are not immune from quality issues. Numerous cases
exist of serious quality problems affecting American consumers caused
by poor manufacturing practices at facilities in the United States.\11\
---------------------------------------------------------------------------
\11\ FDA Updates on Multistate Outbreak of Burkholderia cepacia
Infections.'' (August 2, 2017). (http://bit.ly/33pjhkK).
For these reasons, we applaud the FDA's recent recognition of the
need for more transparency with regard to drug manufacturing.\12\
Recalls and FDA investigations have made clear that not all
manufacturers are alike in their capacity to reliably produce high-
quality pharmaceutical products. However, purchasers of pharmaceutical
products--including drug distributors, pharmacies, and health systems--
often have no reliable way to distinguish between high- and low-quality
manufacturers or their drug products.
---------------------------------------------------------------------------
\12\ Woodcock J. FDA. To Help Reduce Drug Shortages, We Need
Manufacturers to Sell Quality--Not Just Medicine. Oct. 24, 2019, at
https://bit.ly/2SOEy3P.
The FDA's Task Force on Drug Shortages has endorsed the creation of
a voluntary ``rating system . . . to inform purchasers, group
purchasing organizations (GPOs) for health care systems, and even
consumers, about the quality management maturity of the facilities
making the drugs.''\13\ This underscores the importance of the
fundamental principle of having a quality score that can differentiate
between manufacturers. However, since the FDA proposal is voluntary, it
may not achieve broad implementation. Furthermore, it is important that
the criteria used be evidence-based. Announcements have also been made
by private industry for the creation of a commercially available drug
quality scores platform intended for use by health systems.\14\
---------------------------------------------------------------------------
\13\ Id.
\14\ Press release. (January 8, 2020). ``Valisure and Govzilla
Announce a Collaboration Focused on Creating a Platform for Evidence-
Based Quality Scores for Drug Products.'' PR Newswire. (https://prn.to/
2xAuZgw).
Any reliable rating system should draw upon objective, science-
based, independently generated data that is not voluntarily provided by
manufacturers but collected by independent parties. Although a quality
score system may include voluntarily furnished data, it must be
primarily based on independent data to be broadly applicable and thus
optimally useful to healthcare systems. The American College of
Cardiology stressed the need for ``independent testing and verification
of the chemical content of batches of pharmaceuticals'' in a recent
resolution \15\ that emphasizes the necessity to rely on more than just
the manufacturer's self-reported data.
---------------------------------------------------------------------------
\15\ American College of Cardiology resolution to the American
Medical Association. (May, 9, 2019).
These independent quality rating systems should be developed
through a process that incorporates robust stakeholder feedback,
including patients, providers, academic institutions, regulatory
agencies and health systems. In order to spur such discussion and make
meaningful progress towards establishing a viable system for use among
an array of healthcare providers, the authors propose criteria for the
creation of evidence-based quality scores, examples of use on existing
drug products, and a mechanism for utilization exemplified by a
proposed workflow for health systems.
methods
Quality Score Overview
Evidence collected in this proposed system originates from both
broad manufacturer-level data and from specific product information.
The combination of this data is intended to influence scores for
specific drug products of a particular drug from a specific
manufacturer. Although the evidence can be aggregated to evaluate a
given manufacturer as a whole, the greatest utility to healthcare
purchasers and payers is likely achieved by focusing on specific
products. This is due to the immense complexity and opacity of the
pharmaceutical supply chain. The source of ingredients used in any one
drug product is considered proprietary and is therefore not easily
accessible.
The specificity down to a drug product is not intended to directly
describe a given National Drug Code (``NDC''), which further defines a
drug product's dosage form and packaging. It is assumed that evidence
gathered on a specific drug product will be applicable to all NDCs
related to that drug product from the specific manufacturer, regardless
of dosage level or packaging. As an illustrative example, if negative
information is gathered for ``manufacturer X's'' valsartan 160mg
tablets packaged in 100 count bottles, this will influence quality
scores on NDCs for all valsartan tablets in all package sizes for
manufacturer X. When substantially more data is available, future
iterations of quality scores may directly describe individual NDCs or
individual dosage forms.
The proposed system would generate a quality score on a numerical
scale from 0 to 100, with 100 being the most desirable and highest
achievable score and 0 being the lowest and least desirable score.
Since all drug products legally sold in the United States are FDA-
approved and produced at registered facilities certified as conforming
to Current Good Manufacturing Practices (``CGMP''), the default
assumption is that, absent evidence to the contrary, all products
receive a default score of 100.
Criteria proposed herein are all based on information that is
negative in nature and thus produces evidence for reducing a starting
score of 100. Future iterations of such quality scores may also include
criteria based on positive information that generates evidence for
raising a score. The default value of such scores may be subsequently
lowered to add opportunity for particularly well-performing
manufacturers or products to outperform the default. It is also
contemplated that temporal considerations be given to modify the impact
of negative information and to eventually remove or significantly
reduce its influence. The intention for a reliable quality score system
would be to continuously incorporate new regulatory and chemical
analysis data to enable optimal, real-time, guidance of drug product
quality.
Quality Score Criteria
Proposed below are detailed criteria and their influence on a
default score. These are based on independently gathered evidence from
regulatory information and chemical analysis of on-market drug products
obtained from a licensed pharmacy.
----------------------------------------------------------------------------------------------------------------
Score
Category Criteria Qualifiers Influence
----------------------------------------------------------------------------------------------------------------
Warning Letter ratio to total >1.5 3-yr industry average -10
inspections >2 3-yr industry average -30
--------------------------------------------------------------------------------------
Form 483 ratio to total inspections >10% 3-yr industry average -10
>20% 3-yr industry average -30
--------------------------------------------------------------------------------------
Regulatory Information GMP related Consent Decree/CIA in -50
place
--------------------------------------------------------------------------------------
Public Product Quality complaints e.g., % ``bad odor'' >2 -10
competitors -30
e.g., % ``bad odor'' >4
competitors
--------------------------------------------------------------------------------------
Serious adverse event e.g., % ``death'' >2 competitors -10
e.g., % ``death'' >4 competitors -30
----------------------------------------------------------------------------------------------------------------
Dosage failure Single batch -10
>33% of batches -30
All batches -61
--------------------------------------------------------------------------------------
Dissolution failure of USP Single batch -10
>33% of batches -30
All batches -61
--------------------------------------------------------------------------------------
Dissolution failure of >33% of batches -10
Physiological Conditions All batches -30
--------------------------------------------------------------------------------------
Carcinogen failure of FDA levels Single batch -30
>33% of batches -61
--------------------------------------------------------------------------------------
Chemical Analysis Carcinogen failure at evidence- Single batch -10
based, stricter levels >33% of batches -30
All batches -61
--------------------------------------------------------------------------------------
Heavy metals failure of FDA levels Single batch -30
>33% of batches -61
--------------------------------------------------------------------------------------
Microbial detection failure by FDA Single batch -30
method >33% of batches -61
--------------------------------------------------------------------------------------
Microbial detection failure by PCR Single batch -10
method >33% of batches -30
All batches -61
--------------------------------------------------------------------------------------
Ingredients ID failure, API Single batch -30
>33% of batches -61
--------------------------------------------------------------------------------------
Ingredients ID failure, excipient Single batch -10
>33% of batches -30
All batches -61
----------------------------------------------------------------------------------------------------------------
Table 1. Proposed quality score criteria are categorized by
information derived from regulatory data and chemical analysis
data. For most criteria, the severity of negative influence on
the score is dependent on qualifiers on the information
gathered.
The specific criteria proposed above are primarily self-
explanatory. Criteria requiring clarification are discussed below.
Form 483 and Warning Letter Ratio of Inspections--The 3-year
average of total drug industry inspections, Form 483 letters and
warning letters is aggregated and the ratios of Form 483 letters to
total inspections and warning letters to total inspections is
calculated. These same values are also calculated for an individual
manufacturer and if the ratios for the manufacturer are higher than the
global average by a set qualifier, a negative score influence is
triggered. Future iterations may utilize total drug industry
inspections within geographic regions as opposed to a global average.
This could be an important refinement given the differences in
inspection practices within the United States and overseas; such as
domestic inspections are unannounced whereas foreign inspections often
come with months of advanced warning.\16\
---------------------------------------------------------------------------
\16\ Government Accountability Office. (2019). ``Preliminary
Findings Indicate Persistent Challenges With FDA Foreign Inspections.''
(https://www.gao.gov/assets/710/703077.pdf).
Public Product Quality Complaints or Serious Adverse Events--The
ratio of this complaint or event to all others for this product is
compared to other manufacturers of the same product. If the ratio for a
concerning complaint or serious event is significantly higher than the
average ratio of its competitors, a negative score influence is
---------------------------------------------------------------------------
triggered.
Dissolution Failure of Physiological Conditions--This differs from
dissolution failure of USP conditions for a variety of products where
the registered USP monograph for dissolution testing does not conform
to industry standard physiologically relevant conditions. For example,
industry standard simulated gastric fluid is often used for 2 hours and
has a pH of 1.2 and simulated intestinal fluid is often used for the
remainder of dissolution testing thereafter and has a pH of 6.8.
However, USP dissolution media for ibuprofen tablets prescribes using
only one solution with a pH of 7.2 without any exposure to acid.
Although testing ibuprofen tablets in USP solution may yield a passing
test, performing dissolution testing in physiologically relevant media
has been shown to yield certain specific products taking over 24 hours
to dissolve whereas others dissolve quickly, as expected.\17\
---------------------------------------------------------------------------
\17\ ``Your Medication May Not Be Dissolving Properly.'' (2018).
The Valisure Notebook. http://bit.ly/38XVDNm (accessed March 15, 2020).
Carcinogen Failure at Evidence-based, Stricter Levels--FDA
regulations for acceptable daily exposures or intakes of various
carcinogen compounds generally follow internationally accepted
guidelines. However, there are cases where organizations such as the
World Health Organization (``WHO'') and the International Agency for
Research on Cancer (``IARC'') will provide guidance which differs from
that listed by the FDA. This is currently the case with N,N-
Dimethylformamide \18\ (``DMF'') which is classified by WHO and IARC as
a Group 2A probable human carcinogen.\19\ For the purposes of this
proposed quality score system, a negative score influence is triggered
when DMF levels exceed 96 nanogram but are less than 1,000 nanograms
and a more severe negative score influence is triggered when DMF levels
exceed 1,000 nanograms.
---------------------------------------------------------------------------
\18\ Light D, Kucera K. (June, 13, 2019). ``Request that the FDA
issue a regulation, revise industry guidance, and take such other
actions.'' FDA Citizen Petition filed by Valisure, LLC. (https://
www.regulations.gov/docket?D=FDA-2019-P-2869).
\19\ International Agency for Research on Cancer and World Health
Organization. IARC Monographs on the Identification of Carcinogenic
Hazards to Humans. Volume 47, 71, 115 (2018). (https://
monographs.iarc.fr/list-of-classifications-volumes/).
----------------------------------------------------------------------------------------------------------------
Score
Category Criteria Qualifiers Influence
----------------------------------------------------------------------------------------------------------------
Chemical PAnalysis Carcinogen failure: DMF >96 ng, >33% of batches -10
<1,000ng All batches -30
--------------------------------------------------------------------------------------
Carcinogen failure: DMF >1,000 ng Single batch -10
>33% of batches -30
All batches -61
----------------------------------------------------------------------------------------------------------------
Table 2. Quality score criteria definitions for ``Carcinogen
failure at evidence-based, stricter levels'' specific for DMF.
Notably absent from the proposed quality score criteria is
information regarding recalls. Although the existence of high volumes
of recalls for a particular manufacturer of a drug product may
intuitively induce a negative score influence, this may, in fact, be an
indication of responsible quality surveillance. Furthermore, a lack of
recalls may be indicative of overly lax quality assurance measures for
a given manufacturer as opposed to a truly quality product. In the
United States, drug product recalls are almost all voluntary and
performed at the discretion of pharmaceutical manufacturers.\20\ This
conundrum warrants a deeper investigation. A retroactive review of
chemical data compared with recall data could potentially better inform
the correct view of product recalls. While such insights are yet to be
elucidated, it was deemed best to leave such information out of the
currently proposed quality score system.
---------------------------------------------------------------------------
\20\ Newkirk M, Berfield S. (December 13, 2019). ``The FDA Drug
Recall System Is Voluntary, Haphazard, and Broken.'' Bloomberg
Businessweek. (https://www.bloomberg.com/graphics/2019-voluntary-drug-
recalls-zantac/).
Also absent from the quality score criteria is the FDA-proposed
concept of quality management maturity. Indicators of quality
management maturity have been proposed but appear to primarily rely on
manufacturers' proprietary information.\21\ To the authors' knowledge,
there is no existing metric that uses publicly available inputs other
than recalls which are discussed above. The lack of available
information to assess the merits of quality management maturity for use
in an independently derived and broadly applicable, evidence-based
quality score system precludes it from inclusion in this proposal;
however, future iterations may add such criteria when the information
required for evaluation is made available or new indicators are
elucidated.
---------------------------------------------------------------------------
\21\ ISPE Drug Shortages Prevention Plan. (October 2014). http://
www.ispe.org/Drug
ShortagesPreventionPlan.
It is envisioned that a drug quality score system or platform could
include a mechanism for health system users to report potential drug
quality issues, adverse events or send suspect medication samples for
chemical analysis. This could create a much broader net to identify
quality issues and if broadly utilized, such information could be
valuable for the creation of new criteria to influence quality scores.
Quality Score Mechanics
To enable further ease of use and straightforward implementation
within established healthcare systems, the proposed numerical quality
score output can be categorized in a red/yellow/green fashion according
to the following table:
----------------------------------------------------------------------------------------------------------------
Color Designation Quality Score Range
----------------------------------------------------------------------------------------------------------------
Green 80-100
----------------------------------------------------------------------------------------------------------------
Yellow 40-79
----------------------------------------------------------------------------------------------------------------
Red 0-39
----------------------------------------------------------------------------------------------------------------
Table 3. Quality scores receive a color designation dependent
on their numerical value.
Recognizing that a drug product receiving a red designation could
induce significant impact within a healthcare system; special
consideration was given to criteria which can trigger a red. In this
proposal, only the quality score criteria within the category of
Chemical Analysis is allowed to trigger a red designation. Even if the
sum of Regulatory Information criteria resulted in a score influence of
-61 or below, the reported quality score would be a minimum of 40,
yielding a yellow designation. The logic for this is rooted in the
assumption that regulatory findings and public reporting can be
influenced by many factors and do not have a well-established
correlation to product quality, which is defined by its chemical
composition. Supporting this is an excerpt from a 2015 White Paper from
the FDA Office of Pharmaceutical Quality:\22\
---------------------------------------------------------------------------
\22\ Food and Drug Administration. (2015). ``FDA Pharmaceutical
Quality Oversight: One Quality Voice.'' (https://www.fda.gov/media/
91721/download).
FDA has only limited information about the current state of
pharmaceutical quality. FDA has no formal means for quality
surveillance, except through inspections. . . . Furthermore,
inspection findings have not been a reliable predictor of the
state of quality.
Proposed Implementation for Health Systems
The intended use of the proposed quality scores system in an
established health-
care system would be to inform and enable pharmacy procurement teams so
that decision trees could be enacted. Decision trees could be
implemented through healthcare IT systems that standalone or are
integrated into the health systems' existing vender or purchasing
system. A proposal of a decision tree utilizing such quality scores in
order to purchase primarily green, occasionally yellow after manager
review and completely avoid red is proposed for a health system where a
robust process exists for managing drug shortages. Such drug shortage
processes may include identification of substitute products,
determination of alternative drugs or treatments and other remedies for
mitigating or minimizing the impact of a drug shortage. In extreme
cases that are reviewed by management, a poorly scoring medication
product where there is no alternative could be treated by the health
system as a drug shortage instead of purchasing a product designated
red. Depending on the healthcare system, it may require a different
decision tree and may elect to utilize different criteria, or adopt the
same criteria with different degrees of influence on the quality score
values.
[GRAPHIC] [TIFF OMITTED] T6220.005
Figure 1. Proposed decision tree implementing red/yellow/green
quality score designations. The first column describes the
color designation of a drug product that is the default
selection for the health system, which then triggers the
decision tree.
results
The angiotensin receptor blocker drug, valsartan, has been subject
to heavy scrutiny over quality due to a multitude of recalls after
carcinogenic impurities were found.\23\ This drug has been selected
here for analysis using available data to generate a limited number of
quality score criteria which give illustrative examples of how such
quality scores can be derived. Regulatory information was gathered by
Govzilla and chemical analysis information was acquired from Valisure's
analytical laboratory that is attached to a licensed pharmacy.
---------------------------------------------------------------------------
\23\ See Food and Drug Administration, Search List of Recalled
Angiotensin II Receptor Blockers (ARBs) Including Valsartan, Losartan
and Irbesartan. (http://bit.ly/3aUIbLF).
----------------------------------------------------------------------------------------------------------------
Table 4A Regulatory Information (2017-2020)
----------------------------------------------------------------------------------------------------------------
Form 483
Form Warning Form Warning % Above Warning Letter
Inspections 483 Letter 483 Letter Global % Above Global
Ratio Ratio Ratio Ratio
----------------------------------------------------------------------------------------------------------------
Company A 38 20 0 0.526 0.000
----------------------------------------------------------------------------------------------------------------
Company B 6 1 0 0.167 0.000
----------------------------------------------------------------------------------------------------------------
Company C 36 24 1 0.667 0.028 26%
----------------------------------------------------------------------------------------------------------------
Company D 15 9 1 0.600 0.067 13% 181%
----------------------------------------------------------------------------------------------------------------
Company E 10 3 0 0.300 0.000
----------------------------------------------------------------------------------------------------------------
Company F 53 27 0 0.509 0.000
----------------------------------------------------------------------------------------------------------------
Global 3-year 6,967 3,691 257 0.530 0.037
----------------------------------------------------------------------------------------------------------------
----------------------------------------------------------------------------------------------------------------
Table 4B Chemical Analysis
----------------------------------------------------------------------------------------------------------------
DMF
Batches >96ng, DMF NDMA Dosage Dissolution Ingredients
Analyzed <1000ng >1000ng >96ng
----------------------------------------------------------------------------------------------------------------
Company A 6 1 0 1 0 0 0
----------------------------------------------------------------------------------------------------------------
Company B 2 2 0 0 0 0 0
----------------------------------------------------------------------------------------------------------------
Company C 9 9 0 0 0 0 0
----------------------------------------------------------------------------------------------------------------
Company D 7 0 0 0 0 0 0
----------------------------------------------------------------------------------------------------------------
Company E 7 0 7 0 0 0 0
----------------------------------------------------------------------------------------------------------------
Company F 2 2 0 0 0 0 0
----------------------------------------------------------------------------------------------------------------
Table 4. Detailed regulatory information (Table 4A) and
chemical analysis information (Table 4B) on available
manufacturers of valsartan. Although the names have been
deidentified, the data describes real manufacturers of
valsartan drug products being currently sold in the United
States.
----------------------------------------------------------------------------------------------------------------
Table 5 Quality Scores Impactful Criteria Findings (Score Influence)
----------------------------------------------------------------------------------------------------------------
% of
Batches % of % of Warning
Quality Score DMF Batches Batches Form 483 Form 483 Letters
>96, DMF NDMA >10% >20% >1.5
<1000ng >1000ng >96ng
----------------------------------------------------------------------------------------------------------------
Company A 70 17% (-
30)
----------------------------------------------------------------------------------------------------------------
Company B 70 100% (-
30)
----------------------------------------------------------------------------------------------------------------
Company C 40 100% (- 26% (-
30) 30)
----------------------------------------------------------------------------------------------------------------
Company D 80 13% (-10) 1.8 (-
10)
----------------------------------------------------------------------------------------------------------------
Company E 39 100% (-
61)
----------------------------------------------------------------------------------------------------------------
Company F 70 100% (-
30)
----------------------------------------------------------------------------------------------------------------
Table 5. Data output for criteria triggering an influence on
quality scores and the corresponding numerical influence on the
scores denoted in parentheses, regarding current, on-market
valsartan drug products from specific manufacturers. The final
calculated quality scores are displayed and given their
corresponding color designation.
Even with a drug such as valsartan that has had many quality
issues, some of which appear to persist, the use of the proposed
quality score system is able to identify a supplier that scores a
green. Even among potentially mediocre product quality choices, those
that appear to perform particularly poorly are identified by a red and
can be reasonably avoided.
To further evaluate the impact on pricing by using the proposed
quality score system, the relative costs of the valsartan drug products
were analyzed across the six companies. Four dosage forms (40mg, 80mg,
160mg and 320mg) were evaluated using pricing from three different
distributors and ensuring packaging size was consistent among all
companies.
[GRAPHIC] [TIFF OMITTED] T6220.006
Figure 2. Relative pricing of drug products from companies A--F
(denoted in parenthesis) plotted against their quality scores
and given their respective red/yellow/green designation.
Although the decision tree in Figure 1 proposes the option of
paying more for a higher scoring drug product, the pricing comparison
illustrated above suggests that higher quality drug products do not
necessarily cost more. Despite continued quality issues with valsartan,
the least expensive option had the second-highest quality score, the
highest quality score option was only 2 percent more expensive and the
lowest scoring option was 67 percent more expensive.
discussion and conclusion
When originally conceived, generic drug products were assumed to be
equal in quality to each other and to the innovator product so the only
differentiating feature would be the price paid. This has led to
automatic generic substitution laws across the country where patients
receive the generic selected by the pharmacy and this could change
several times over the patient's course of therapy. The premise that
every innovator and generic product is of equal quality is demonstrably
false.\8\
With the changing market dynamics that drove pharmaceutical
manufacturing offshore and made it very difficult to warrant acceptable
quality, a new strategy is needed to ensure patient safety. The use of
drugs that are improperly dosed as well as products that don't dissolve
properly can put patients at risk of clinical failure or adverse
events. The use of products with bacterial contamination, unacceptably
high amounts of carcinogens or heavy metals may lead to unintended
health problems as a result.\24\
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\24\ Mathes RW et al. (2008). ``Relationship between histamine2-
receptor antagonist medications and risk of invasive breast cancer.''
Cancer Epidemiology Biomarkers and Prevention, a publication of the
American Association for Cancer Research. Vol. 17(1): p. 67-72.
(https://www.ncbi.nlm.nih.gov/pubmed/18199712#).
We hope this will be a useful overview and baseline proposal for
the use of quality scores for drug products. This is critical for
adding much-needed transparency into the American drug supply chain and
enabling health system purchasers and payers of medications to avoid
low-quality drug products. As the data demonstrates with valsartan,
high quality drug products do not necessarily cost more. Thus, even if
a health system is unable or uninterested to add any additional
purchasing cost or add any potential drug shortage burden, it is highly
likely that the use of the proposed quality score system will provide a
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significant benefit in avoiding low-quality drug products.
Such action taken by established healthcare systems could help
protect them from recalls and drug shortages while serving as a
significant market driver to incentivize the manufacturing industry to
produce quality products. Furthermore, the proposed quality score
system could provide regulatory agencies with transparent and rational
metrics with which to reward high-scoring manufacturers (e.g., faster
ANDA approvals) and/or penalize low-scoring manufacturers (e.g., slower
and more scrutinized drug approvals).
Overall, drug quality scores have the potential to improve public
health; therefore, their continued development and implementation is
highly encouraged.
acknowledgement
The authors would like to thank Michelle Call and Michael de la
Torre from Govzilla, Martin Van Trieste from Civica Rx and Amber
Jessop, Kaury Kucera and David Light from Valisure, for their
assistance in providing data and expertise for this paper.
______
Questions Submitted for the Record to David Light
Questions Submitted by Hon. Chuck Grassley
Question. What is the role of new analytical technology in the
evaluation of drug quality, and is there anything the FDA should be
doing to ensure it incorporates the latest scientific best practices?
Answer. Apart from occasional improvements in efficiency, overall
analytical technology for drug quality has remained largely unchanged
over the past 5 decades. For example, analysis of well-studied
carcinogenic impurities like N-Nitrosodimethylamine (NDMA) has been
fairly consistent for roughly 50 years. Scientific studies describing
the analysis of NDMA down to parts per billion and even parts per
trillion \1\ were published as early as 1970, and Senate hearings \2\
were held specifically about NDMA in medications in 1977. Even specific
drugs like Zantac/ranitidine have been flagged by academics for many
years for serious quality issues using standard scientific methods.
Since Zantac/ranitidine's first approval in 1981, a Google Scholar
search for ``ranitidine NDMA'' reveals over 500 scientific studies that
reference this problem that took regulators 39 years to address, only
after Valisure's independent analysis and drive for action brought
global recalls.
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\1\ Sen NP. (1970). ``Gas-liquid chromatographic determination of
dimethylnitrosamine as dimethylnitramine at picogram levels.'' Journal
of Chromatography. Vol. 51, pp. 301-304. (https://
www.sciencedirect.com/science/article/abs/pii/S0021967301968682).
\2\ Senate hearings before the Subcommittee on Monopoly and
Anticompetitive Activities of the Select Committee on Small Business on
``Effect of Promotion and Advertising of Over-the-Counter Drugs on
Competition, Small Business, and the Health and Welfare of the
Public.'' June 1977. (https://drive.google.com/file/d/
1dTw6mwdMVFmoGAM1tQvHieohLiuzicgn/view).
The most critical ``new'' element of analysis that is having a
dramatic impact today is analysis that is independent from the
traditional pharma/regulatory world. At its essence, this means that
the testing strives to independently answer the fundamental question of
``is this a quality medication,'' as opposed to adhering only to a set
of rules largely dictated by manufacturers that can have many
limitations or biases. Whether it's using updated international
standards, following scientific/
academic best practices, or acquiring samples without significant bias,
all these components summarized by the term ``independent testing''
have immense value and have already caught serious drug quality issues
when they were otherwise missed or ignored. Most clearly illustrating
this is the fact that every major drug that has had potentially life-
threatening quality problems and recalls in the past 2 years
(specifically, metformin, Zantac/ranitidine, nizatidine, valsartan,
losartan and irbesartan) have all been flagged and tested by the FDA in
their ``Drug Sampling and Monitoring'' program \3\ since 2013 and all
of these drugs have passed FDA testing. Many of these major drugs
(metformin, Zantac/ranitidine, nizatidine) had serious issues that were
first identified at Valisure.
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\3\ Food and Drug Administration. ``Drug Quality Sampling and
Testing Programs.'' February 3, 2020. (https://www.fda.gov/drugs/
science-and-research-drugs/drug-quality-sampling-and-testing-programs).
In Valisure's opinion, FDA should work more closely with
independent laboratories and academics to create a robust system of
independent testing in addition to the prescribed industry and
regulatory oversight currently in place. Such a collaboration would
certainly help update FDA's methodologies to help safeguard the
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American public and our critical drug supply.
Question. From Valisure's perspective, what are the biggest gaps in
the FDA's current regulatory oversight framework, and is there any
current or proposed legislation to address these gaps?
Answer. One of the biggest gaps in FDA oversight is the agency's
inability to conduct mandatory recalls of drugs. At a Duke Margolis
Center event held in conjunction with the FDA in February 2020,
representatives from the FDA presented data from a survey of
physicians.\4\ When asked, ``Which, if any, of the following are
functions of the FDA in terms of regulating drug quality,'' the top
answer was ``Remove a drug from market if unexpected risks are
detected.'' It is likely that the American public would similarly be
surprised by the fact that the FDA lacks the authority to force the
removal of dangerous drugs from the market.
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\4\ Fisher A. (February 3, 2020). ``Patient and Provider
Perceptions of Pharmaceutical Quality.'' Food and Drug Administration,
Duke Margolis Center for Health Policy. Page 64. (https://
healthpolicy.duke.edu/sites/default/files/atoms/files/
pharmaceutical_quality_slides_final.pdf).
Valisure supports recent legislation introduced by Rep. DeLauro (D-
CT) to provide the FDA with this critical mandatory recall
authority,\5\ which the agency already possesses over medical devices,
food, and biological products.
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\5\ H.R. 1108, the Recall Unsafe Drugs Act (116th Congress).
Question. Does Valisure observe more quality issues from overseas
manufacturers, specifically manufacturers in China and India, than from
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domestic manufacturers?
Answer. As most of the United States' complex drug supply chain has
moved overseas, quality and safety concerns have become more pressing.
Roughly 80 percent of the volume of active pharmaceutical ingredients
(API) for products sold in the U.S. now come from outside the country,
the majority from China.\6\ This is an important clarification from Dr.
Throckmorton's oral statement during the hearing that ``the U.S.
provides about 28 percent, China about 13 percent'' of API given that
this ``13 percent'' figure references the percentage of registered
facilities, not the volume produced at those facilities.
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\6\ Edney A. ``FDA Misled Senators on China's Role as Vital U.S.
Drug Supplier.'' Bloomberg News. June 9, 2020. (https://
www.bloomberg.com/news/articles/2020-06-09/fda-misled-senators-on-
china-s-role-as-key-u-s-drug-supplier).
Although it is apparent we have a significant reliance on overseas
drug manufacturers, the lack of transparency regarding where all the
ingredients of a drug originate can make it difficult or almost
impossible to determine country of origin for a specific drug product.
The National Drug Code only tracks the final labeler of the drug and
not the dose manufacturer, the producer of the API, or the producer of
the fine chemicals that are used to manufacture the API. These labelers
can also be re-packagers, adding another layer that keeps regulatory
agencies and consumers from knowing the true provenance of the
pharmaceuticals coming into the U.S. Furthermore, many manufacturers
have multiple facilities around the world, and even though a final drug
product may State that it was manufactured in a specific country, the
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reality is that this may not be an accurate representation.
In summary, due to the immense lack of transparency into origin of
manufacturing, it is not currently possible for Valisure to determine
which regions or specific manufacturers have the greatest incidence of
quality issues. However, we do see widespread drug quality problems
throughout this complex supply chain and believe more must be done to
safeguard the hundreds of millions of Americans that rely on
medications.
Question. On May 26, 2020, a consortium of leaders from eight
health care institutions, including the Defense Health Agency,
published a paper that advocates for an independently generated,
evidence-based quality score system for drug products that could be
used by private and public sector entities and regulators. Under this
concept, what criteria would be used to determine the scores? What role
does the FDA's proposed ``quality management maturity'' play in these
scores?
Answer. The May 2020 paper \7\ makes the argument that the criteria
for determining drug quality scores should be science- and evidence-
based and should be derived from independent sources and not only from
manufacturers' reports. Results from independent chemical analysis of
drug products could be combined with publicly available regulatory data
and turned into simple red/yellow/green drug quality scores. Ideally,
these scores would be continually updated with new regulatory and
chemical analysis data to provide real-time, evidence-based guidance on
drug product quality.
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\7\ Dabestani A et al. (May 26, 2020). ``Evidence-Based Quality
Scores for Rating Drug Products and Their Utility in Health Systems.''
MedRxiv. (https://www.medrxiv.org/content/10.1101/
2020.05.22.20110775v1).
The FDA's ``quality management maturity'' ratings could
theoretically be a useful input for drug quality scores, although this
is difficult to gauge as the information and specific criteria is not
currently available or finalized. Using only quality management
maturity to generate drug scores would likely fall short of providing
the science-based transparency into drug quality and safety that
healthcare leaders are advocating for. Valisure strongly supports a
collaborative approach between the FDA and healthcare industry
stakeholders to finalize details of quality management maturity ratings
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and potentially incorporate them into drug quality scores.
______
Questions Submitted by Hon. John Cornyn
pharmaceutical product testing
Question. Valisure conducts batch testing of every product that is
dispensed. How does this process differ from the testing criteria FDA
applies when they test pharmaceutical products? Would applying this
standard to drugs with foreign sourced API prevent lower-quality,
adulterated, or counterfeit medications from making it to the market?
Answer. Important background to this question is the fact that the
FDA very rarely tests pharmaceutical products. Rather, the overwhelming
majority of drug quality testing is conducted by the pharmaceutical
manufacturers, who then self-
report this data to the FDA. This presents a potential conflict of
interest, as well as a significant opportunity for data manipulation
and fraud, especially from foreign manufacturers where inspection
processes differs from domestic manufacturers. In fact, of the over 4
billion prescriptions written in the U.S. annually, typically only a
few dozen drug products are tested per year by the FDA.\8\
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\8\ Food and Drug Administration. ``Drug Quality Sampling and
Testing Programs.'' February 3, 2020. (https://www.fda.gov/drugs/
science-and-research-drugs/drug-quality-sampling-and-testing-programs).
Valisure's testing follows a combination of FDA/industry guidance
and adherence to scientific/academic best practice, which are not
always perfectly aligned. The differences can be nuanced and complex,
though essentially Valisure's testing strives to independently answer
the fundamental question of ``is this a quality medication'' as opposed
to adhering only to a set of analytical rules largely dictated by
manufacturers that can have many limitations or biases. There are three
primary components of Valisure's independent testing that occasionally
differ from that of the FDA: criteria set by manufacturers, criteria
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set by regulators, and sourcing of samples.
Criteria for what to test for in a specific medication and how to
test for it are usually determined by the manufacturer of that specific
drug product. Testing for dissolution, or how a pill dissolves, is one
example of methodologies registered by manufacturers that do not always
follow scientific best practice and are not always indicative of
conditions in a human body. For example, the registered testing
condition for ibuprofen tablets uses a solution with a pH of 7.2 (water
is pH of 7). The commonly accepted scientific standard conditions are
to use ``simulated gastric fluid'' with a pH of 1.2 for 2 hours and
then ``simulated intestinal fluid'' with a pH of 6.8, thereby
simulating exposure to the stomach and intestines. Using this
scientific standard protocol, Valisure identified batches of ibuprofen
that do not dissolve for over 24 hours; however, when using the
manufacturer-registered test, they dissolve in under 30 minutes.\9\
Valisure uses the scientifically accepted dissolution conditions that
represent the human body and therefore rejects some medication batches
that are not able to dissolve in such an environment.
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\9\ ``Your Medication May Not Be Dissolving Properly.'' (2018). The
Valisure Notebook. http://bit.ly/38XVDNm (accessed June 22, 2020).
For criteria that is set by the FDA and not by drug manufacturers,
like the limits for certain carcinogens, the agency does not always
promptly incorporate independent scientific research, techniques, and
guidance. For example, the carcinogen DMF (N,N-Dimethylformamide), is
in the same ``group 2A'' carcinogenic risk class as NDMA (N-
Nitrosodimethylamine) according to the World Health Organization (WHO).
NDMA is the carcinogen responsible for recalls of major drug products
over the last 2 years including blood pressure drugs valsartan,
losartan and irbesartan, heartburn drugs ranitidine and nizatidine, and
the diabetes drug metformin. Valisure filed an FDA Citizen Petition in
June 2019 on the alarmingly high abundance of DMF in the drug
valsartan.\10\ The petition underscored that the WHO and International
Agency for Research on Cancer (IARC) had reclassified DMF as a Group 2A
carcinogen in 2018, but the FDA's last assessment was from 2017 when
DMF was not yet considered at high risk of causing cancer in humans.
Likely because of this outdated understanding, the FDA allows over
90,000 times more DMF to contaminate a medication than it allows for
NDMA even though these two probable human carcinogens are now in the
same, high-risk class. At Valisure, medications with excessively high
DMF contamination (some have been found with over 1,000 times the
current NDMA limit) are rejected even if they pass the FDA's current
limit for DMF.
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\10\ Light D, Kucera K. Valisure FDA Citizen Petition on DMF.
Regulations.gov. June 16, 2019. (https://www.regulations.gov/
docket?D=FDA-2019-P-2869).
Lastly, the source of what is being tested can have a significant
impact, even if the criteria are the same at the FDA and Valisure. The
FDA will often request voluntary samples of a suspect medication direct
from a manufacturer, which again presents a potential conflict of
interest. At Valisure, we independently source the medication to
minimize any potential bias. A critical example of this is the diabetes
drug metformin where international regulators initiated recalls in
December 2019 due to the presence of NDMA. On February 3, 2020, the FDA
posted lab results from its testing of metformin from seven companies
and 16 batches, finding that all passed the FDA's daily acceptable
intake limit for NDMA.\11\ However, Valisure independently acquired 38
batches of metformin from 22 companies through its pharmacy's
distributors and found failures from 11 companies.\12\ When the FDA
acquired and tested samples provided by Valisure, the agency requested
recalls from a number of these companies, including ones the FDA had
previously passed.\13\
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\11\ Food and Drug Administration. Statement. ``FDA posts
laboratory testing results for NDMA levels in metformin.'' February 3,
2020. (https://www.fda.gov/drugs/drug-safety-and-availability/fda-
updates-and-press-announcements-ndma-metformin).
\12\ Light D, Kucera K, Wu Q. Valisure FDA Citizen Petition on
Metformin. Regulations.gov. March 2, 2020. https://www.regulations.gov/
document?D=FDA-2020-P-0978-0001.
\13\ Food and Drug Administration. Update. ``FDA names companies
recalling ER metformin.'' June 11, 2020. (https://www.fda.gov/drugs/
drug-safety-and-availability/fda-updates-and-press-announcements-ndma-
metformin)
Whether it's using updated international standards, following
scientific best practices, or acquiring samples without significant
bias, all these components summarized by the term ``independent
testing'' have immense value and have already identified serious drug
quality issues that were otherwise missed. Illustrating this is the
fact that every major drug that has had potentially life-threatening
quality issues and recalls in the past 2 years (specifically metformin,
Zantac/ranitidine, nizatidine, valsartan, losartan and irbesartan) have
all been flagged and tested by the FDA in their ``Drug Sampling and
Monitoring'' program since 2013 and all of these drugs have passed FDA
testing.\14\ These serious problems in metformin, Zantac/ranitidine,
and nizatidine were first identified by Valisure.
---------------------------------------------------------------------------
\14\ Food and Drug Administration. ``Drug Quality Sampling and
Testing Programs.'' February 3, 2020. (https://www.fda.gov/drugs/
science-and-research-drugs/drug-quality-sampling-and-testing-programs).
Valisure strongly believes that independent batch-testing of all
products, regardless of country of origin, would help safeguard against
lower-quality, adulterated, or counterfeit medications from entering
the U.S. market. Beginning with certain high-risk products, such as
metformin, would be a good start that will already affect tens of
millions of Americans, and can eventually be scaled to thousands of
drug products. Creating a new category of ``certified drugs'' would
inject much-needed transparency and security into the U.S. drug supply.
Valisure is proof of concept that this testing can be done at no
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additional cost to consumers.
Regarding foreign-sourced API, it is important to note that when
Dr. Throckmorton responded to Senator Cornyn's query about the
percentage of active API for drugs in America sourced from China, his
response that ``the U.S. provides about 28 percent, China about 13
percent'' does not paint the full picture. While China has 13 percent
of the API facilities in the world, those are very large plants and
supply roughly 60 percent or more of our API total
volume.\15\, \16\, \17\ The vast majority of the
volume of our medications rely on foreign manufacturers, primarily
China.
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\15\ Edney A, Berfield S, Yu E. ``Carcinogens Have Infiltrated the
Generic Drug Supply in the U.S.'' Bloomberg Businessweek. Sept. 12,
2019. (https://www.bloomberg.com/news/features/2019-09-12/how-
carcinogen-tainted-generic-drug-valsartan-got-past-the-fda).
\16\ Harper M. ``Sanofi to start pharmaceutical ingredients
company, which it says may avert future shortages.'' STAT News. Feb.
24, 2020. (https://www.statnews.com/2020/02/24/sanofi-to-start-
pharmaceutical-ingredients-company-which-it-says-may-avert-future-
shortages/).
\17\ U.S.-China Economic and Security Review Commission, 2019
Report to Congress 248 (2019).
______
Questions Submitted by Hon. Tim Scott
Question. We must do more to proactively address drug shortages and
shortage risks, as well as to promote the production of medical
products in the U.S. With that in mind, I recently released a proposal
called the MADE in America Act, which would: (a) identify barriers to
domestic manufacturing and recommendations for removing those barriers;
(b) enhance efficiency and transparency when it comes to detecting and
resolving drug shortages and shortage risks; and (c) create targeted
tax credits for manufacturing critical medical products in Opportunity
Zones. This proposal would also us to leverage incentives in a way that
accelerates our economic recovery and bolsters our supply chain
security at the same time.
For the two CEOs on Panel II, as we work to identify legislative
and regulatory solutions, what do you see as some of the principal
barriers to manufacturing medications domestically while keeping
costs--and by extension consumer prices--low?
How does the United States' tax and regulatory environment for drug
manufacturing and manufacturing more broadly compare with those of some
of our competitors?
What types of job opportunities can domestic API, excipient, and
finished drug form manufacturing and packaging create for lower-income
and working-class Americans, along with middle-class Americans?
What do you see as the potential for advanced manufacturing
technologies to accelerate drug development and bolster drug quality,
as well as to address shortage risks? What are some of the hurdle's
manufacturers are experiencing when looking to adopt technologies that
could expedite production and improve drug quality, and how can
Congress and the administration act to facilitate this type of
innovation?
Answer. Valisure is not a manufacturer of drug products, nor do we
provide any FDA-mandated Current Good Manufacturing Practice (cGMP)
testing of drug products for pharmaceutical manufacturers. Valisure's
core business is to analyze medications that have already been produced
in order to screen out poor quality batches and manufacturers. By doing
so, we help ensure that patients, doctors, and health systems can
benefit from independently certified drugs. Given that the current
regulatory framework for pharmaceutical manufacturing is largely
dependent on the self-regulation of the pharmaceutical industry,
including self-reporting of testing of manufacturers' own products,
there is tremendous value to independent scientific analysis. This is
particularly important given Senator Scott's concern about overseas
manufacturing and the heavy reliance specifically on China, which
supplies roughly 60 percent of the volume of active pharmaceutical
ingredients (API) used in drugs sold in the U.S.\18\
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\18\ Edney A. ``FDA Misled Senators on China's Role as Vital U.S.
Drug Supplier.'' Bloomberg News. June 9, 2020. (https://
www.bloomberg.com/news/articles/2020-06-09/fda-misled-senators-on-
china-s-role-as-key-u-s-drug-supplier).
Valisure is not an expert in the business considerations around
drug manufacturing in the United States. However, Valisure supports
incentivizing American pharmaceutical production of finished drugs,
APIs, and the fine chemicals used to make APIs, especially for drugs
that are considered essential for national security like antibiotics.
Importantly, Valisure believes that independent analysis should be a
part of the standard manufacturing process regardless of where a drug
is made, and that any new legislation proposed for the production of
medications in the U.S. should consider incorporating this critical
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safeguard.
______
Questions Submitted by Hon. Sherrod Brown
Question. Recent examples of adulterated products include the
recalls of multiple drugs containing the API valsartan, and the over
the counter drug known as ranitidine. Valsartan is found in several
drugs that are used to treat high cholesterol and heart failure. The
United States and 22 other countries issued a recall of valsartan after
it was found to contain a cancer-causing chemical known as N-
nitrosodimethylamine (NDMA). Because the FDA does not engage in the
regular testing of imported products to check for quality and purity,
regulators have been unable to ascertain how long this impurity has
existed. Shortly after the valsartan recall, your company, Valisure,
notified the FDA that it had detected NDMA in multiple batches of
ranitidine in October 2019. Regulators are also unaware of how long we
have been importing adulterated ranitidine.
Describe the process Valisure went through to notify the FDA of the
adulterated ranitidine. Do you have recommendations to improve the
process with which individuals are able to report suspected
adulterations in products?
Answer. First, as additional background on valsartan, while the FDA
very rarely tests drug products (only a few dozen tests are conducted a
year out of the billions of bottles that are dispensed), valsartan was
indeed tested by FDA in 2015 due to customer complaints, as was
similarly contaminated losartan in 2013 and 2017, and irbesartan in
2017. Industry estimates suggest the contamination issue for valsartan
began in 2011.\19\ While the FDA reported that it tested multiple lots
and manufacturers of valsartan and these other drugs, all the tested
samples passed the FDA's testing standards.
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\19\ Edney A, Berfield S, Yu E. ``Carcinogens Have Infiltrated the
Generic Drug Supply in the U.S.'' Bloomberg Businessweek, Sept. 12,
2019. (https://www.bloomberg.com/news/features/2019-09-12/how-
carcinogen-tainted-generic-drug-valsartan-got-past-the-fda).
Regarding ranitidine, Valisure presented extensive data to the FDA
through an FDA Citizen Petition filed on September 13, 2019 on the
inherent instability of the drug and its ability to easily form high
amounts of the carcinogen N-Nitrosodimethylamine (NDMA).\20\ Apart from
Citizen Petitions, Valisure is not aware of an effective mechanism for
an independent laboratory like Valisure to raise drug quality or safety
concerns to the agency.
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\20\ Valisure FDA Citizen Petition Requesting Recall of Ranitidine
and Other Actions. September 9, 2019. Regulations.gov. (https://
www.regulations.gov/docket?D=FDA-2019-P-4281).
Currently, there are two primary paths for a drug quality complaint
to be filed. First, non-GMP (Good Manufacturing Practices) entities
like Valisure can report an ``adverse event'' to manufacturers or the
FDA, which are typically filed with thousands of individuals'
complaints and generally receive very limited follow up, if any.
Second, GMP entities registered with the FDA can make a GMP report of a
quality violation to the FDA or the responsible manufacturer which
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triggers mandated follow ups and corrective actions.
Because Valisure does not itself manufacture products or conduct
release testing for pharmaceutical companies, we are not a GMP
laboratory. As such, following guidance from the FDA, Valisure submits
dozens of drug quality problem findings directly to pharmaceutical
companies. We believe these reports are most often ignored or filed
away in the ``adverse events'' category which requires little to no
follow-up. This means that many products that fail Valisure's testing
are likely distributed to American consumers through other pharmacies.
To improve this process, FDA could issue guidance to industry that
a report submitted to a pharmaceutical company from a ``qualified
laboratory'' must go through a more rigorous follow-up process than are
typically afforded the standard ``adverse event'' complaints. A
``qualified laboratory'' could be defined as one that has accreditation
from an internationally recognized organization such as the
International Organization for Standardization (ISO).
Question. Please describe the technology Valisure utilizes to test
products before distribution. You mentioned in your testimony this
service takes place at no cost to patients, and in your response to
Chairman Grassley that it results in small additional costs. Please
clarify what the cost of this service is, who pays for this testing,
and what the financial impact on the patient is?
Answer. Valisure has developed proprietary, laser-based analytical
technology that we use in combination with industry-standard approaches
to analyze a variety of critical chemical components of medications.
This includes analyzing for dosage/potency, dissolution (how a pill
dissolves in a patient's body), identifying inactive ingredients, and
detecting a range of impurities and carcinogens. Importantly,
analytical technology specifically for the detection of well-studied
carcinogenic impurities like NDMA has been largely unchanged over the
past five decades.
Regarding costs, Valisure's optimized analytical workflows are
themselves very cost-effective and the cost is amortized over large
batches of a medication. This often translates to less than a penny per
pill of additional quality assurance cost, which Valisure pays for from
a portion of our retail pharmacy margin. As such, we are able to
dispense medications at no additional cost to patients and still remain
profitable.
If the Valisure model were to be expanded significantly--such as in
the creation of what we term ``certified drugs'' in which independent
analysis is performed at the same time as the FDA-required, standard
analysis--the analysis would add minimal cost, which we believe could
be borne by manufacturers without impacting patients. Health systems
and government programs could help facilitate this concept by
incentivizing or requiring independent analysis as part of their
sourcing and bidding processes for drugs.
Question. What steps would you suggest Congress, regulators such as
the FDA, and other organizations across the drug supply chain take to
ascertain the extent of the purity problems that are possibly
afflicting our supply chain, and address these problems?
Answer. To accurately ascertain the extent of drug quality problems
in the U.S., Valisure recommends a broad analytical survey conducted by
independent entities (in other words, entities operating outside the
regulatory and pharmaceutical GMP system). Currently, the FDA conducts
very limited surveillance testing (a few dozen products a year) of drug
products based on perceived risks and customer complaints.\21\
Troublingly, this surveillance testing included each major drug that
has had highly publicized drug recalls due to serious quality problems
in recent years, including metformin, Zantac/ranitidine, nizatidine,
valsartan, losartan and irbesartan, and all passed the FDA's testing.
With this in mind, we believe that a properly funded survey of U.S.
pharmaceutical products could be very impactful if conducted by
qualified independent entities.
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\21\ Food and Drug Administration. ``Drug Quality Sampling and
Testing Programs.'' February 3, 2020. (https://www.fda.gov/drugs/
science-and-research-drugs/drug-quality-sampling-and-testing-programs).
Regular, independent surveillance of drug quality is an approach
that can be implemented immediately and is already being performed at
Valisure on a small scale with tremendous impact. Such surveillance
would likely identify specific quality issues, and the overall data it
produces on all analyzed drug products could be used as guidance for
buyers and payers in the form of drug quality scores. In a May 26, 2020
paper entitled ``Evidence-Based Quality Scores for Rating Drug Products
and Their Utility in Health Systems,'' a consortium of leaders from
eight health-care institutions proposed a system of drug quality scores
to provide transparency into America's drug products.\22\ These scores
could be used by drug purchasers and payers to avoid low-quality
products. Further, if used by regulators to incentivize or penalize
manufacturers, these scores could be a powerful driver to produce high-
quality pharmaceutical products.
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\22\ Dabestani A et al. (May 26, 2020). ``Evidence-Based Quality
Scores for Rating Drug Products and Their Utility in Health Systems.''
MedRxiv. (https://www.medrxiv.org/content/10.1101/
2020.05.22.20110775v1).
A more definitive solution is what Valisure terms ``certified
drugs'' that are independently chemically analyzed at the batch level
and certified before being sold to a patient, pharmacy, wholesaler, or
health care system. This added layer of quality assurance would improve
public health and likely offer overall cost savings by mitigating drug
recalls and increased hospitalizations that can arise from low-quality
drugs. Such a system is very reasonable to quickly implement on a few
high-volume and high-risk drugs, like metformin, and later scale up to
many thousands of drug products. As a proof of principal, Valisure
currently offers over 2,000 certified drug products in its pharmacy at
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no additional cost to patients.
Question. Are there other companies on the market that are able to
do testing similar to what Valisure offers its customers?
Answer. There are many contract research laboratories in the U.S.
that possess similar analytical capabilities as Valisure. However, most
of these labs are GMP facilities and thus primarily, if not entirely,
work for pharmaceutical manufacturers and follow very prescriptive
analytical procedures that, like those performed at the FDA, have
missed drug quality problems for decades. The largest source of
independent analytical testing in the U.S. is in academia and
universities. However, these analyses and research have historically
been almost entirely ignored by regulators and the pharmaceutical
industry as evidenced by hundreds of studies published in the past 4
decades on the carcinogenic and unstable nature of ranitidine. Valisure
believes there is already very strong evidence and multiple examples
that underscore the position that impactful improvements to
safeguarding drug quality in the U.S. need to come from industry-led,
independent analysis.
______
Prepared Statement of Martin VanTrieste, RPh,
President and CEO, Civica, Inc.
Chairman Grassley, Ranking Member Wyden, and members of the
committee, my name is Martin VanTrieste. I am the president and CEO of
Civica, Inc. I am also a 35-year veteran of the pharmaceutical
industry.
It is an honor to appear before you today, and an honor to follow a
group of dedicated public servants. My dealings with the FDA and BARDA
over the past few months have reminded me how tirelessly these
officials work to serve the American people.
In my testimony today, I will:
Introduce you to Civica and our non-profit model;
Discuss several policy options to help the United States
ensure a robust supply of drugs; and
Share some background on a recently announced agreement with
the Federal Government to enhance U.S. manufacturing capacity for
essential medicines.
about civica
Civica is a non-profit 501(c)(4) social welfare organization
established by U.S. health systems and philanthropies to reduce chronic
drug shortages and ensure a safe and stable supply of essential
medicines to U.S. patients.
That is our mission: to serve patients by making quality
medications available and affordable.
Today, more than 50 health systems have joined Civica (Figure I).
They represent approximately 1,200 hospitals and over 30 percent of all
U.S. hospital beds. Civica also supplies the Veteran's Administration,
the Department of Defense and ``340B'' hospitals, which care for
vulnerable patients in some of the most underserved areas of the
country.
[GRAPHIC] [TIFF OMITTED] T6220.015
The Supply Chain
Civica was primarily created to improve the resiliency of the
supply of essential medicines used in hospitals daily, often for
critical care. The drugs we make are not those with the highest return
on investment. Rather, they are the ones that are identified and
prioritized by our health systems--by doctors and pharmacists on the
front lines--as the medications most important for high-quality patient
care. Civica's members have also identified generic medications that
are excessively priced, such as daptomycin, where Civica lowered
significantly the market price.
Civica is implementing, simultaneously, a three-pronged product
supply strategy to reduce chronic drug shortages and secure the supply
of essential generic medicines for patients:
Working with multiple generic drug manufacturers that have the
U.S. Food and Drug Administration (FDA) approved manufacturing
facilities and capacity to produce generic drugs under Civica's
National Drug Code,\1\ allowing manufacturers to re-enter the market or
increase existing capacity. Civica is currently working with five
supplier partners and is in negotiations with several more.
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\1\ A unique numerical identifier indicating the labeler
(manufacturer, repackager, or distributer), strength, and dosage form
of each drug.
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Developing Abbreviated New Drug Applications \2\ (ANDAs) to
produce Civica medications using contract manufacturers.
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\2\ The approval pathway for generic drugs.
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Building Civica manufacturing capability using Civica's ANDAs.
Civica is fully committed to stabilizing the supply of antibiotics,
anesthetics, cardiac medications, pain management medications, and
other essential sterile injectable medicines. To date, and in just over
a year, Civica has launched 24 sterile injectable medications for use
in hospitals across the country (see Table I). Civica is on track to
deliver approximately 20 more medications in 2020, building toward 100
medications (in hundreds of dosage forms) by 2023.
Many of our drugs are used in the management of patients with
COVID-19 (see Table I). And during this pandemic, Civica has
contributed 1.6 million containers of medicine to the Strategic
National Stockpile.
TABLE I. CURRENT CIVICA MEDICATIONS
------------------------------------------------------------------------
Source of
Drug finished API COVID-19 Surge SNS
drug Source
------------------------------------------------------------------------
Aminocaproic acid USA Japan
Calcium chloride USA Germany
Ceftriaxone Portugal Italy *
Daptomycin India Hungary
Dexamethasone USA France
Diazepam Italy Italy
Fentanyl USA USA Y 5mL - 224%
Glycopyrrolate USA Finland Y
Heparin USA USA Y
Hydralazine USA Japan
Ketamine Portugal Germany Y 5mL - 367% Y
10mL - 265%
Labetalol Portugal Italy Y Y
Lidocaine Portugal Spain Y Y
Metoprolol Portugal Spain/
India
Midazolam USA Israel/ Y 5mL - 324% Y
India
Morphine USA USA Y
Naloxone USA USA
Neostigmine USA/India Austria Y
Nicardipine USA Italy
Ondansetron USA Spain/
India
Prochlorperazine USA Italy
Sodium bicarbonate USA USA Y
Tranexamic acid USA Italy
Vancomycin Denmark/ Denmark Y Y
USA *
------------------------------------------------------------------------
Source of finished drug refers to the country of manufacture of the
sterile vial or prefilled syringe.
API Source refers to the country of origin of the active pharmaceutical
ingredient.
COVID-19 identifies those drugs used in the management of patients with
COVID-19, including management of patients on ventilators and
treatment of secondary pneumonia.
Surge represents the increase in demand over anticipated volume for
select drugs during the initial weeks of the COVID-19 pandemic. Note
that some health systems had no increased demand; others ranged as
high as 800 percent for select drugs. These data illustrate the
ability of the ``Civica model'' to cope with a demand surge, but can't
be used to extrapolate to national increase in demand or predict
future demand.
SNS indicates that the initial set of identified drugs contributed to
the Strategic National Stockpile.
* China is backup API source.
The Civica model brings together hospital systems and drug
manufacturers to work collaboratively, ensuring both stable and fairly
priced generic drugs for hospitals and predictable volumes for
manufacturers. Key elements of the model include:
Hospital systems join Civica, allowing them to purchase drugs
in predetermined volumes at transparent and stable prices. Member
health systems prioritize the medications needed to reduce shortages
for patients and identify the volume requirements for their hospitals.
Civica conveys this information to its manufacturing team or
trusted manufacturing partners--those with a history of producing high-
quality products. Manufacturers commit their production capacity based
on long-term projected volumes of medications identified by the health
systems.
As a result, patient care improves as hospitals receive a
reliable supply of the essential generic medications.
Because its specific mission is to create a robust, high-quality
supply of essential medicines, several features of the Civica supply
chain model may have lessons for the larger U.S. system, including:
Long-term purchase take-or-pay commitments allow Civica, and
our suppliers, to invest in quality systems;
Use of backup suppliers and maintenance of a reserve stock
averaging at least six months' supply;
A preference to purchase medicines made in the U.S. where
possible, followed by other highly regulated markets, followed by India
and avoiding Chinese ingredients where possible in our drugs due to
quality concerns; and
Entrusting those on the front lines--hospital physicians and
pharmacists--to prioritize the medications Civica makes, based on their
experiences day-to-day or in times of crisis like the pandemic.
the importance of a robust supply chain
The global coronavirus pandemic has highlighted weaknesses in the
U.S. supply chain for essential medicines and other medical supplies.
Key products required to manage the epidemic have been unavailable or
in short supply. Increased demand, both within the United States and
among our trading partners, are important factors but have largely
served to exacerbate supply chain shortcomings that are pre-existing
and longstanding.
It is important to note that many of the medicines used to manage
COVID-19, including the sedatives and neuromuscular blocking agents
essential for patients on ventilators, were already in short supply
prior to the pandemic. They represent a longstanding weakness in our
supply chain that is explained, in part, by the relentless pursuit of
ever-lower costs.
The desire for low-cost drugs--the race to the bottom in
manufacturer pricing in order to get market share--is understandable,
but it creates unintended consequences. Facing low margins and
uncertain sales, companies are discouraged from investing in quality
and incentivized to move production out of the U.S. to economies with
lower labor costs, lower regulatory compliance costs and where they may
receive direct or indirect support from foreign governments for to
build new facilities.
Reliance on a sole source of supply, whether that is a single
manufacturer or a supply from a single country, increases the risk of
supply disruption. No purchaser should source essential drugs or other
products from a single supplier.
Indeed, Civica's policy is not to supply all of any health system's
needs for a given drug. If we were the sole supplier, we would be
increasing rather than reducing vulnerabilities in the supply chain.
Longer supply chains and just-in-time inventory systems are
especially vulnerable to disruption, whether due to quality problems
or, as we've recently witnessed, export restrictions by foreign
governments who understandably put their domestic needs ahead of those
of their trading partners.
No single policy caused the exodus of pharmaceutical companies from
the U.S., and it will take a multi-faceted approach--and a sustained
commitment--to further diversify the supply chain and rebuild our
domestic manufacturing capacity.
policy tools
Nevertheless, the U.S. Government has a range of tools that can
help rebuild capacity as well as protect against supply interruptions
and keep the cost of medications in check. These include:
Creating an essential medicines list to set priorities for
investments, policy and regulatory reviews;
Improving transparency in sourcing, pricing and drug quality;
Utilizing incentives to encourage U.S. investment;
Committing government programs to prioritize purchase of U.S.-
made goods;
Enhancing the Strategic National Stockpile;
Directly supporting U.S. manufacturing; and
Focusing on advanced manufacturing.
Target Essential Medicines
Civica selects medicines to manufacture based on the needs of
patients, as prioritized by those on the front lines of the health care
system. The U.S. government could benefit from a similar priority list
to guide policy.
For these essential drugs, policymakers should incentivize
contingency planning or redundant production lines for manufacturers to
use in the event of a shortage, particularly for medicines that already
have too few manufacturers.
To encourage investments in critical drugs, policymakers should
consider waiving FDA user fees for drugs on the drug shortage list and
when there is minimal competition.
Congress may also want to reconsider policies that turn generic
drugs into sole-source products without competition. Specifically, the
Drug Efficacy Study Implementation (DESI) program provides market
exclusivity to companies in exchange for filing a New Drug Application
on very old products. While intended to create an incentive for
companies to submit efficacy and safety data to the FDA, this can
result in unintended consequences, including reduced supply chain
resiliency and dramatic price hikes.\3\
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\3\ Civica letter to Congress, February 6, 2020. https://
civicarx.org/letter-closing-loopholes-that-lead-to-unreasonable-price-
increases-for-decades-old-drugs/. Accessed May 24, 2020.
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Transparency in Sourcing and Quality
Civica provides not only complete transparency on the source of its
finished drugs, but also on the source of the active pharmaceutical
ingredients (APIs) (Table I). But such transparency is not required by
law. Any purchaser wishing to avoid active ingredients from high-risk
countries is currently constrained by a lack of information. Congress
could require country of origin labeling for both finished drug and
API.
Similarly, Congress should consider steps to increase publicly
available manufacturer quality information. It is a well-known quality
principle that quality cannot be tested or inspected into a product.
For example, if five tablets are tested from a batch of one million and
they all pass, then all that is known is that those five tablets
passed. In contrast, a mature quality system requires protocols,
standard operating procedures, appropriate oversight and a culture of
compliance. These are the ingredients of a quality system that are
essential to producing quality pharmaceuticals. The supply chain itself
must be considered a part of a quality assessment: A drug that does not
reach patients cannot be considered high quality, whatever its other
attributes.
There are tools that can be used to measure the maturity of a
pharmaceutical quality system, such as those used for the Malcomb
Baldrige National Quality Award and Parenteral Drug Association Quality
System Maturity Model.
Making robust quality data available to health systems would help
purchaser to take quality into account when buying medications.
Congress could consider requiring the FDA to validate its quality
metrics program \4\ with a limited number of manufacturers within 1
year.
---------------------------------------------------------------------------
\4\ Geok Yan Loo, U.S. Food and Drug Administration. https://
static1.squarespace.com/static/58d0113a3e00bef537b02b70/t/
5e726c5316537f1aa5309d79/1584557142149/2P0410_Loo_CDE
RsApproach.pdf. Accessed May 24, 2020.
Manufacturers could be incentivized to participate. When the
metrics have been sufficiently validated, manufacturer participation
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should be required.
We also commend Congress and the FDA for recently adding
requirements for manufacturers to notify the FDA of discontinuance or
interruption in active pharmaceutical ingredient supply and in the
event of a demand surge or other factors that could interrupt
supply.\5\
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\5\ Food and Drug Administration Guidance for Industry: Notifying
FDA of a Permanent Discontinuance or Interruption in Manufacturing
Under Section 506C of the FD&C Act (March 2020). https://www.fda.gov/
media/136486/download.
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Tax Incentives
As a non-profit organization, Civica does not benefit directly from
tax incentives to encourage U.S. manufacturing, but other manufacturers
may, including some of our suppliers. For example, one recent proposal
would allow 100 percent expensing for any new U.S. pharmaceutical
manufacturing facility placed in service before 2026.\6\
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\6\ For example, S. 3537, the ``Protecting Our Pharmaceutical
Supply Chain from China Act of 2020,'' introduced by Senators Cotton,
Blackburn, and Cruz.
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Priority Purchase of U.S.-Made Goods
One change Congress could make, as proposed in recent
legislation,\7\ would be to amend the Trade Agreements Act of 1979 to
clarify that pharmaceutical products would not be considered to have
originated in a country if the API originated in a different country.
Updating this definition would reverse a recent court decision, Acetris
Health, LLC v. United States, that precludes U.S. government purchasers
from giving preference, under the Buy American Act, to pharmaceutical
products that originated entirely within the United States or our
preferred trading partners.
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\7\ For example, S. 3538, ``The Strengthening America's Supply
Chain and National Security Act,'' introduced by Senators Rubio and
Warren.
Congress could also consider recognizing the real cost differences
between U.S. drug production and manufacturing in low-wage countries,
by increasing the incremental additional cost the government will pay
in order to purchase U.S.-made goods from the current level of 6
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percent.
Given that it will take time to rebuild U.S. manufacturing, it may
be inadvisable to set a firm short-term deadline to exclude Chinese
suppliers completely, but the government should have a goal of having
at least one U.S. supplier for every U.S. essential drug, with annual
targets and progress tracking.
Enhanced Strategic National Stockpile
The U.S. essential medicines list identified above can be used to
guide an enhanced national stockpile. The Federal Government currently
maintains an emergency stockpile of drugs and medical equipment in
warehouses around the country. While some supplies are inexpensive and/
or can effectively be warehoused for long periods, the cost of
stockpiling more expensive products with limited shelf lives, such as
drugs, could be reduced with a commercially managed ``flow through''
inventory so that drugs are distributed and used prior to expiry, with
the stockpile being continually replenished with newer product.
Direct Government Support of U.S. Manufacturing
Recently, the Biomedical Advanced Research and Development
Authority (BARDA) announced a new partnership that will help build more
U.S. advanced manufacturing capacity for essential drugs.\8\
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\8\ Health and Human Services, May 19, 2020. https://www.hhs.gov/
about/news/2020/05/19/hhs-industry-partners-expand-us-based-
pharmaceutical-manufacturing-covid-19-response.html. Accessed May 24,
2020.
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the barda partnership
Under this agreement, BARDA will fund Phlow Corporation, a newly
formed
public-benefit pharmaceutical manufacturing company in Richmond, VA, to
build a new state-of-the art continuous manufacturing facility to
produce API.
On the same site, Civica will build a facility capable of producing
finished sterile injectable medicines for U.S. patients on an ongoing
basis and to meet the needs of the national stockpile. Civica will use
API from Phlow and from Ampac Fine Chemicals, an API maker on the same
site.
This partnership will create a 100 percent U.S.-owned and -operated
end-to-end domestic drug manufacturing infrastructure to secure
essential medicines and prevent shortages of these vital medicines in
the future.
Advanced manufacturing
Advanced manufacturing is a term for newer technologies that will
help improve the speed and flexibility of drug manufacturing. In the
case of the BARDA agreement, Phlow will commercialize continuous
manufacturing technology developed at Virginia Commonwealth
University's College of Engineering. In contrast with traditional batch
manufacturing, this approach offers several advantages, including:\9\
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\9\ Statement of Janet Woodcock, M.D., U.S. Food and Drug
Administration, October 30, 2019. https://energycommerce.house.gov/
sites/democrats.energycommerce.house.gov/files/documents/Testimony-
Woodcock-API_103019.pdf. Accessed May 20, 2020.
Precise control of product quality;
Ability to rapidly respond to changes in demand;
Lower cost of production; and
Reduced environmental impact.
As set forth in recent proposed legislation,\10\ Congress could
further support the development of advanced manufacturing by supporting
the creation of Centers of Excellence and providing expedited review if
a technology is likely to prevent or resolve a drug shortage,
maintaining an adequate supply of critical medications for national
emergencies, or promote the adoption of innovative approaches to drug
product design and manufacturing.
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\10\ For example, S. 3532, the ``Securing America's Medicine
Cabinet Act of 2020,'' introduced by Senators Blackburn and Menendez,
and S. 3780, the ``Help Onshore Manufacturing Efficiencies for Drugs
and Devices Act,'' introduced by Senator Peters.
Thank you again for your attention to this important topic. Civica
looks forward to working with this committee as it considers how best
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to protect the interest of American patients.
______
Questions Submitted for the Record to Martin VanTrieste, RPh
Questions Submitted by Hon. John Cornyn
Question. The COVID-19 pandemic has shown us that there are
vulnerabilities in our supply chain. As demand has surged for
medications for patients on ventilators, manufacturers have been unable
to meet the needs. Your testimony outlines policy tools to better
prepare against supply chain interruptions.
Can you expand on how we can incentivize production of essential
medicines?
Answer. To incentivize production of essential medicines, the
United States should first identify those drugs in order to guide
policy and target incentives. Criteria could include: likely need in
the event of a demand surge due to pandemic or other public health
emergency; current U.S. sources of finished drug, API and, where
relevant, key precursors; redundancy and resiliency of supply across
the entire supply chain, U.S. and OUS, with particular attention to
single- or geographically-concentrated sourcing. For these essential
drugs, policymakers should incentivize contingency planning or
redundant production lines for manufacturers to use in the event of a
shortage, particularly for medicines that already have too few
manufacturers. To encourage investments in critical drugs, policymakers
should consider waiving FDA user fees for drugs on the drug shortage
list and when there is minimal competition.
To incentivize U.S. manufacturing, Congress could consider allowing
100-percent expensing for any new U.S. pharmaceutical manufacturing
facility placed in service before 2026 and waiving supplemental ANDA
fees for manufacturers modifying an existing ANDA to create a new U.S.
source of API or finished drug.
Congress could also ensure that the purchasing power of the U.S.
Government is used to support a resilient drug supply chain, including
sufficient U.S.-based manufacturing. For example, Congress could amend
the Trade Agreements Act of 1979 to clarify that pharmaceutical
products would not be considered to have originated in a country if the
API originated in a different country, reversing Acetris Health, LLC v.
United States, a recent decision that precludes U.S. Government
purchasers from giving preference, under the Buy American Act, to
pharmaceutical products that originated entirely within the United
States or our preferred trading partners.
Congress could also increase the ``Buy American'' price
differential from the current 6 percent to 20 percent to recognize the
real cost differences between U.S. drug production and manufacturing in
low-wage countries.
Congress could also consider requiring the FDA to provide expedited
review if a technology is likely to prevent or resolve a drug shortage,
maintain an adequate supply of critical medications for national
emergencies, and/or promote the adoption of innovative approaches to
drug product design and manufacturing.
Question. How can we reform the Drug Efficiency Study
Implementation to allow for more manufacturers but also maintain
incentives for manufacturers to go through the approval process for
those ``grandfathered'' drugs?
Answer. The Drug Efficacy Study Implementation (DESI) program was
begun by the U.S. Food and Drug Administration (FDA) in the 1960s after
the Kefauver-
Harris Amendment, to classify all pre-1962 drugs that were already on
the market as either effective, ineffective, or needing further study.
By 1984, final action had been completed on 3,443 products, of which
2,225 were found to be effective, 1,051 were found not effective, and
167 were pending.
In 2006, the FDA introduced the ``Unapproved Drugs Initiative''
with the aim of removing unapproved drugs from the market, including
DESI drugs and new drugs that were marketed without FDA approval. The
Initiative required NDA (New Drug Application) approval for DESI or
``grandfathered'' drugs. Once the FDA approves an NDA for a DESI drug,
the existing unapproved drugs are removed from the market, until the
pharmaceutical company obtains an ANDA (Abbreviated New Drug
Application) approval from the FDA.
There are numerous benefits to NDA approval for DESI or
``grandfathered'' drugs. NDA approval demonstrates to physicians,
health-care providers, and patients that a drug is safe and effective.
The Sponsor of an NDA must demonstrate how the entire end-to-end
manufacturing process is reliable and reproducible, and consistently
meets standards of identity, strength, quality and purity. This is
particularly important for the prevention of drug shortages and ensures
that patients receive quality products with greater certainty of safety
and efficacy.
However, the exclusivity period awarded to the NDA sponsor and
resulting lack of competition has resulted in substantial price
increases to consumers, health systems and plans, including Medicare
and Medicaid, and was associated with more frequent drug shortages. An
analysis by Gupta et al. found that between 2006 and 2015, 34
previously unapproved prescription drugs were addressed by the UDI.
Nearly 90 percent of those with a drug product that received
FDA approval were supported by literature reviews or
bioequivalence studies, not new clinical trial evidence. Among
the 26 drugs with available pricing data, average wholesale
price during the 2 years before and after voluntary approval or
UDI action increased by a median of 37 percent (interquartile
range (IQR) = 23% 204%; P < 0.001). The number of drugs in
shortage increased from 17 (50.0%) to 25 (73.5%) during the 2
years before and after, respectively (P = 0.046). The median
shortage duration in the 2 years before and after voluntary
approval or UDI action increased from 31 days (IQR = 0 - 339)
to 217 days (IQR = 0 - 406; P = 0.053). (J Manag Care Spec
Pharm, 2017, 23(10):1066-1076)
To reintroduce competition to the market following the end of the
exclusivity period, generic manufacturers must invest substantial sums
to bring their products through the ANDA development and approval
process. While the NDA process benefits patients (as noted above),
Congress could consider several avenues to promote competition and
reduce the cost of this program to taxpayers:
Allow FDA to end the exclusivity period if the NDA holder
enters into business practices to create an artificial monopoly, like
exclusive contracts with all viable API manufacturers or a restricted
distribution channel (unless mandated by FDA) that prevents competitors
from obtaining reference product.
Require the NDA holder to provide reference product to
potential competitors at no charge.
Waive the ANDA fees for manufacturers of previously unapproved
drugs seeking to re-enter the market and for new ANDA applicants.
Require the NDA holder to submit confidential information to
the government regarding its expenses to obtain an NDA approval, and
terminate exclusivity if an analysis of Medicare spending data or
national pricing and utilization patterns indicate that cost to the
taxpayer has exceeded those expenses by more than a defined factor.
Directly fund NDA development through an RFP process, allowing
ANDA approvals to begin without any defined exclusivity period.
______
Questions Submitted by Hon. Tim Scott
Question. We must do more to proactively address drug shortages and
shortage risks, as well as to promote the production of medical
products in the U.S. With that in mind, I recently released a proposal
called the MADE in America Act, which would identify barriers to
domestic manufacturing and recommendations for removing those barriers;
enhance efficiency and transparency when it comes to detecting and
resolving drug shortages and shortage risks; and create targeted tax
credits for manufacturing critical medical products in Opportunity
Zones. This proposal would also us to leverage incentives in a way that
accelerates our economic recovery and bolsters our supply chain
security at the same time.
As we work to identify legislative and regulatory solutions, what
do you see as some of the principal barriers to manufacturing
medications domestically while keeping costs--and by extension consumer
prices--low?
Answer. Barriers to U.S. manufacturing include higher labor costs
and additional regulatory costs, particularly associated with
environmental and occupational health and safety approvals, in the
United States compared with lower-cost economies.
Question. How does the United States' tax and regulatory
environment for drug manufacturing and manufacturing more broadly
compare with those of some of our competitors?
Answer. Civica is committed to manufacturing in the United States
and, moreover, as a non-profit would not benefit directly from tax
incentives (though some of our manufacturing partners might).
Nevertheless, the examples of Ireland, Singapore, and, previously,
Puerto Rico illustrate the potential of favorable tax treatment to
attract pharmaceutical manufacturing.
Question. What types of job opportunities can domestic API,
excipient, and finished drug form manufacturing and packaging create
for lower-income and working-class Americans, along with middle-class
Americans?
Answer. Pharmaceutical manufacturing creates direct employment for
hundreds of thousands of Americans. These jobs include roles for
chemical engineers, materials scientists, biological scientists,
laboratory technicians, line operators, quality managers, compliance
personnel, as well as all the associated ancillary management and
support personnel. For example, the recently announced BARDA
partnership with Phlow and Civica is expected to create hundreds of new
jobs. Some of those will be filled by individuals with professional
qualifications and experience in the industry, but others will be
filled by training and growth opportunities within the local workforce.
Question. What do you see as the potential for advanced
manufacturing technologies to accelerate drug development and bolster
drug quality, as well as to address shortage risks? What are some of
the hurdles manufacturers are experiencing when looking to adopt
technologies that could expedite production and improve drug quality,
and how can Congress and the administration act to facilitate this type
of innovation?
Answer. Compared with traditional batch manufacturing, advanced
pharmaceutical manufacturing has the potential to reduce production
costs, improve flexibility and speed of production and reduce waste. As
a more nimble manufacturing process, continuous manufacturing will help
mitigate drug shortages caused by lack of access to API. Hurdles to
advanced manufacturing include the cost of new capital investment and
the regulatory cost associated with modifying the supply chain for
currently approved drugs. In the generic market, these costs may be
prohibitive, and companies are unlikely to invest to change the
production of existing drugs without substantial support. To facilitate
this type of innovation, Congress and the administration may wish to
consider lowering the costs of new investments in U.S.-based advanced
pharmaceutical manufacturing through tax incentives, direct grants or
contracts; by waiving the FDA user fees associated with new or
supplemental drug applications that use advanced manufacturing
technology, and by supporting innovation and workforce development
through the establishment of academic centers of excellence, provided
they are directly and closely associated with commercial manufacturing
enterprises. Congress and FDA should also evaluate the potential of
system-based regulatory oversight that enables simpler and faster
regulatory approval for manufacturing provided appropriate quality
systems and protocols are in place.
______
Questions Submitted by Hon. Benjamin L. Cardin
Question. Prescription drug shortages have been a persistent and
troubling occurrence. Many of the drugs in shortage are generic and
have been off patent for years, which should lead to a market with
reasonable prices and reliable manufacturing.
Instead, patients and providers in Maryland and nationwide struggle
to afford and obtain many of these critical medications.
CivicaRx and its member hospitals look to address the issue of drug
shortages by making their own generic drugs. I am excited that CivicaRx
is focusing on generic drugs susceptible to shortages, and am curious
to learn more about your company's drug shortage prevention practices.
How are the drug shortage prevention practices of CivicaRx
different from those of other drug companies?
Answer. Civica differs from other drug companies in several
important ways. First, Civica is a non-profit, non-stock social welfare
organization established by U.S. health systems and philanthropies for
the express purpose of reducing chronic drug shortages and ensuring a
safe and stable supply of essential medicines to U.S. patients at a
fair price. The drugs Civica makes are not those with the highest
return on investment. Rather, they are the ones that are identified and
prioritized by our health systems--by doctors and pharmacists on the
front lines--as the medications most important for high-quality patient
care. Civica's members have also identified generic medications that
are excessively priced, such as the antibiotic daptomycin, where Civica
lowered significantly the market price.
Additionally, Civica's member health systems sign long-term ``take-
or-pay'' purchase agreements that allow Civica, and its suppliers, to
invest in quality systems. The organization establishes backup
suppliers for all drugs and maintains a physical reserve stock
averaging at least 6 months' supply. This contrasts with a more typical
30-day supply distributed across the entire supply chain. Civica also
sources medicines made in the U.S. where possible, followed by other
highly regulated markets, followed by India, and avoiding Chinese
ingredients where possible in our drugs due to quality concerns.
Question. Based on your experience, what recommendations for FDA,
or Congress, would you suggest to better prevent drug and medical
supply shortages?
Answer. To better prevent drug shortages, the FDA and/or Congress
should give consideration to creating an essential medicines list to
set priorities for investments, policy, and regulatory reviews. An
essential medicines list can be used to guide policy and target
incentives. For these drugs, policymakers could incentivize contingency
planning or redundant production lines for manufacturers to use in the
event of a shortage, particularly for medicines that already have too
few manufacturers. To encourage investments in critical drugs,
policymakers could also consider waiving FDA user fees for drugs on the
drug shortage list and when there is minimal competition.
Improved transparency in sourcing and quality can better enable
purchasers to choose products that are less likely to experience supply
interruptions. To achieve this, Congress could consider country of
origin labeling for both finished drug and API. In addition, increasing
publicly available manufacturer quality information could be supported
by establishing a timeline for FDA to finalize its quality metrics
program and requiring manufacturer participation by date certain and/or
incentives for manufacturers to participate.
Congress could also consider directing major Federal purchasers to
establish a goal of having at least one U.S. supplier for every U.S.
essential drug, with annual targets and progress tracking that take
into account market share and ability to scale up production on a
defined timeline.
Question. In May, the administration announced a 4-year, $354-
million contract with a newly formed company, Phlow, to produce both
drug ingredients and generic medicines in the U.S. that are in short
supply and used to treat COVID-19 patients. Phlow has partnered with
CivicaRx, and plans to make medicines and ingredients at CivicaRx
plants and will open its own facility in Virginia in 2021.
Based on recent press articles, Phlow is partnering with CivicaRx
to ramp up domestic production of certain pharmaceutical ingredients
and medications. Part of this strategy will include building
manufacturing facilities.
How long will this take?
What drugs is Phlow manufacturing?
I understand that Phlow is working with CivicaRx's existing
contractors, but as I understand it none of the existing contractors
are domestic. Can you elaborate on how you will build up domestic
production?
Answer. A typical timeline for establishing a new pharmaceutical
manufacturing facility, from the beginning of construction to
commercialization, would be as soon as 36 months. That could be
considerably shortened by expediting regulatory approvals. The timeline
for Phlow to produce active pharmaceutical ingredient is shorter. In
the meantime, Civica and Phlow are contributing to the strategic
national stockpile through Civica's existing network of contract
manufacturers, which prioritizes U.S. manufacturing where possible. Of
the 26 drugs we've contracted to date, we manufacture 17 in the U.S.
and 8 in Europe. The primary source of the API is in the United States
or Europe for 21 of 26 products.
Civica and Phlow will create new U.S. capacity through the
construction of new API and finished drug manufacturing facilities. In
addition, the Phlow facility will manufacture key precursor compounds
used to make APIs. These facilities will make drugs prioritized by the
U.S. Government.
______
Questions Submitted by Hon. Sherrod Brown
Question. One of your policy recommendations to rebuild capacity
and protect against supply chain interruptions is for the U.S. to
establish an essential medicines list to set priorities for
investments, policy and regulatory reviews.
Can you please elaborate on this policy recommendation? Which
Federal agency would you suggest take the lead on developing this list?
What considerations should be taken into account in building out this
list of essential medicines?
What priorities should follow the development of an essential
medicines list?
Answer. In establishing a list of essential medicines, the
Secretary of Health and Human Services could draw on the expertise of
multiple agencies. The U.S. Food and Drug Administration (FDA) has
comprehensive information on approved drugs and their uses and
countries of origin, as well as ongoing communication with sponsors and
agency staff actively engaged in addressing drug shortages. The Public
Health Emergency Medical Countermeasures Enterprise (PHEMCE)
coordinates Federal efforts to enhance chemical, biological,
radiological and nuclear threats (CBRN) and emerging infectious
diseases (EID) preparedness from a medical countermeasure (MCM)
perspective. The PHEMCE is led by the HHS Office of the Assistant
Secretary for Preparedness and Response (ASPR) and includes three
primary HHS internal agency partners: the Centers for Disease Control
and Prevention (CDC), the FDA and the National Institutes of Health
(NIH), as well as several interagency partners: the Department of
Defense (DoD), the U.S. Department of Veterans Affairs (VA), the
Department of Homeland Security (DHS), and the U.S. Department of
Agriculture (USDA). The Strategic National Stockpile (SNS) is designed
to supplement and resupply State and local public health agencies in
the event of a national emergency anywhere and at any time within the
United States or its territories. In 2018, oversight of the SNS was
transferred to HHS/ASPR from HHS/CDC.
An essential medicines list should include drugs essential for
routine clinical care. Civica relies on pharmacy and medical trends
advisory committees from a cross section of U.S. health systems to
identify the drugs most needed, and most vulnerable, on the front lines
of care. A similar process may inform establishment of a U.S. list.
Other factors for consideration should include a recent history of
shortages, the number of suppliers in the market (including whether
they, in turn, rely on common upstream suppliers of active
ingredients), the potential for supply interruptions due to demand
surges (such as during a pandemic or other public health emergency) and
the likelihood of supply interruptions, taking into account
geographical concentration of manufacture and country of origin,
including the potential that supplies could be interrupted as other
countries seek to ensure supply for their own populations or limit
exports for strategic advantage.
______
Prepared Statement of Hon. Ron Wyden,
a U.S. Senator From Oregon
This afternoon the Finance Committee is holding its first meeting
since March, focusing on the FDA's failure to adequately inspect
foreign drug manufacturers for safety. In my view, the head of the FDA
ought to face tough questions in any hearing on this topic. But FDA
Commissioner Hahn is not with the committee today because the Trump
administration blocked his testimony. They did this to prevent the
committee from holding the FDA's point person accountable. I'd also
asked for the committee to invite the journalist Katherine Eban here to
testify, because she literally wrote the book on this issue. That did
not happen either. In lieu of that, I'll ask consent to enter into the
record testimony and articles from Ms. Eban on this subject.
While the committee meets for this hearing, COVID-19 is ripping
through nursing homes and killing thousands of Americans every week.
Unemployment is at near-Depression levels. The kindling laid down over
centuries of racial injustice was reignited by the murder of George
Floyd. The President is agitating for more violence and more
escalation. Our Nation is suffering.
The injustice driving peaceful protestors to the streets over the
last few days is woven throughout society. Since the committee is
dealing with health care in today's hearing, I'm going to start with an
immediate piece of urgently needed health-care reform. COVID-19 has hit
the African American community harder than virtually any other group of
Americans, and the status quo is immoral.
There is a long and terrible history of our health-care system
working against black people in this country, from simply not listening
when they report symptoms right up to performing cruel experiments on
black human beings. That's part of why COVID-19 is having such an
outsized impact on the African American community today. There's a risk
that when a COVID-19 vaccine becomes available, vaccination rates in
the African American community may be lower than elsewhere--because
many in that community, for understandable reasons, do not believe that
American health care is really looking out for them.
So I want to make something clear: this committee has muscle when
it comes to health-care policy--$2 trillion in spending and
jurisdiction over flagship programs like Medicare, Medicaid, the
Affordable Care Act, and more. Today I'm calling on this committee to
come together in the weeks and months ahead and use all that power to
right the wrongs of the past.
As for the subject of this afternoon's hearing, I want to focus on
one specific example of the FDA and the President teaming up to put
Americans in danger. Let's talk about hydroxychloroquine.
Back in March, with the pandemic exploding nationwide, far-right
media began talking about using this old malaria drug to treat COVID-
19. The President glommed onto those reports, and without any valid
evidence, he spent weeks declaring it the ultimate game-changer in the
fight against the pandemic.
The FDA, in my view, bowed to the pressure and issued what's called
an ``emergency use authorization'' for the drug. Doing so threw open
the door to tens of millions of pills, including some, directly related
to this hearing, manufactured inside facilities in Pakistan and India
that have either failed FDA's inspection or never been inspected by the
FDA at all. Studies have now shown that the drug has no benefit for
COVID-19 patients. In fact, it is linked to higher rates of COVID-19
mortality.
Finally on April 24th, the FDA warned against using the drug in
COVID-19 treatments, citing ``serious and potentially life-threatening
heart rhythm problems,'' but the FDA still says it can be imported from
unapproved manufacturing facilities.
A recent article in The New England Journal of Medicine said the
episode posed, quote, ``fundamental threats to the U.S. drug evaluation
process.'' Mr. Chairman, without objection, I'd like to have that
article inserted into the hearing record.
The fact is, lots of Americans take this medication to treat other
diseases, including lupus and rheumatoid arthritis. It's prescribed by
their doctors, part of a valid treatment. They're counting on having a
safe supply of their medication, and Donald Trump took that away from
them. He repeated a bunch of far-right pundits touting junk science,
and now the U.S. market is polluted with tens of millions of
hydroxychloroquine doses that may or may not be safe. It's not clear
there's a system in place to distinguish them from other stockpiles
that came from approved sources. So if you're talking about FDA
failures leading to greater risk for Americans, hydroxychloroquine is
the case in point.
There's also the botched rollout of COVID-19 antibody tests.
There's the emergency use authorization for faulty KN95 masks that pose
a danger to health-care workers and first responders. There's the fact
that the number of FDA inspections of foreign drug manufacturing
facilities was already down under the Trump administration.
On this committee, there's bipartisan interest in seeing
improvements at the FDA, and it makes sense to look for ways to build
up our drug manufacturing capacity in the U.S. However, the Trump
administration just handed a big contract for COVID-19 drug
manufacturing to a company with no experience manufacturing drugs and
no facilities in which to manufacture them.
That's not a good enough plan to help COVID-19 patients who are
suffering right now. It also raises serious questions about how this
administration would handle a COVID-19 vaccine, if and when a vaccine
becomes available.
There's a lot to account for on this issue. It's unfortunate that
the Trump administration is continuing to stonewall our oversight by
blocking Commissioner Hahn from answering our questions today. Still, I
thank our witnesses for joining us today, and I look forward to their
testimony.
______
From: Katherine Eban
Author, Bottle of Lies: The Inside Story of the Generic Drug Boom
Vanity Fair Contributor
To: Senate Committee on Finance
Attn. Editorial and Document Section
Rm. SD-219
Dirksen Senate Office Bldg.
Washington, DC 20510-6200
Re: Statement for the Record
``COVID-19 and Beyond: Oversight of the FDA's Foreign Drug
Manufacturing Inspection Process''
Date: June 1, 2020
_______________________________________________________________________
Introduction
I spent a decade investigating the overseas manufacturing plants that
supply a majority of generic drugs to the U.S. market, and the FDA's
system for regulating those plants. That effort culminated in the
publication of my New York Times best-selling book, Bottle of Lies: The
Inside Story of the Generic Drug Boom (Ecco/Harper Collins, May 2019).
The book takes readers into the overseas manufacturing plants where the
majority of our low-cost generic medicine is made. It reveals endemic
fraud and dire conditions in an industry where companies routinely
falsify data and circumvent principles of safe manufacturing to
minimize cost and maximize profit. To report the book, I traveled to
four continents, interviewed hundreds of sources and obtained over
20,000 pages of confidential FDA documents.
The U.S. drug supply is 90 percent generic, with a majority of those
drugs coming from overseas, principally India and China. As well, 80
percent of the active ingredients in all our drugs, whether brand or
generic, come from overseas, the bulk of those from China and India.
It is crucial to the health and safety of the American public that
these drug products are effectively regulated. No substandard drug
product should be permitted to enter the U.S. market. And yet, as my
book uncovers, low-cost drug plants overseas routinely falsify their
quality data in order to gain market approval. In a bid to cut costs
and speed time to market, they use low-quality ingredients and take
manufacturing shortcuts. The FDA, in numerous instances, has chosen to
overlook these problems in its drive to approve a greater volume of
low-cost medicine. The result is that generic drugs with toxic
impurities, unapproved ingredients, dangerous particulates, or that are
non-bioequivalent, have reached American patients.
The COVID-19 pandemic--which has increased drug shortages and snarled
global supply chains--has intensified these problems. It has deepened
our dependence on overseas drug manufacturers that produce low-quality
medicine and has diminished the FDA's ability and inclination to police
those manufacturers.\1\
---------------------------------------------------------------------------
\1\ Katherine Eban, ``The Coronavirus Pandemic Is Creating a Drug
Supply Crisis Just When We Most Need Medicine,'' Time Magazine, March
26, 2020.
After extensive reporting on this topic, it is my conclusion that: the
FDA is not effectively regulating the overseas manufacturing plants
that export to the U.S. market. The FDA is granting exceptions to these
plants and allowing substandard drug products into the U.S. for reasons
that include: concern over drug shortages; confusion about its own
authority; reliance on drug companies' promises of reforms. The FDA's
investigators are spread too thin, with depleted staff in overseas
offices, anemic recruiting efforts, and a relatively small cadre of
---------------------------------------------------------------------------
U.S.-based investigators willing to perform inspections overseas.
In conclusion, I believe the FDA must overhaul its foreign inspection
system, more strictly enforce its own regulations, and create a
transparent and verifiable system to ensure the integrity of our
medicine and the safety of the American public.
1. The Widespread Problem of Data Fraud
Extensive data fraud at generic drug companies overseas first came to
light in 2005, when a brave whistleblower, Dinesh Thakur, alerted the
FDA to egregious fraud at India's largest drug company, Ranbaxy. In May
2013, after an 8-year investigation by the FDA, Ranbaxy pled guilty to
seven felonies connected to its widespread falsification of quality
data.\2\ But Ranbaxy was hardly an outlier, as Bottle of Lies exposes.
Dozens of overseas drug manufacturing plants have misrepresented their
drug-quality data in order to gain market approval.
---------------------------------------------------------------------------
\2\ Katherine Eban, ``Dirty Medicine.'' Fortune Magazine, May 15,
2013. Available at: https://fortune.com/2013/05/15/dirty-medicine/.
One FDA investigator Peter Baker, who I feature in my book, inspected
86 drug plants in India and China from 2012 to 2016, and found evidence
of serious data-integrity violations in 67 of them. He uncovered this
fraud and data manipulation by looking inside the computer systems of
the manufacturing plants he inspected. There, he found widespread
evidence that plants were engaged in hidden testing to pre-screen their
drugs. This allowed them to figure out if the drugs would meet
specifications, and then alter the parameters on the official tests
which they showed to the FDA.\3\
---------------------------------------------------------------------------
\3\ Eban, Katherine. ``Americans Need Generic Drugs. But Can They
Trust Them?'' The New York Times, May 11, 2019.
Additional evidence supports the view that fraud and manipulation of
quality data is endemic in overseas drug plants. In 2016, an
investigation by China's own State Food and Drug Administration (SFDA)
found that 80 percent of clinical trial data submitted by Chinese
companies to regulators to gain approval for new drugs was
fabricated.\4\
---------------------------------------------------------------------------
\4\ Fiona Macdonald, ``80% of Data in Chinese Clinical Trials Have
Been Fabricated,'' Science Alert, October 1, 2016, https://
www.sciencealert.com/80-of-the-data-in-chinese-clinical-trial-is-
fabricated (accessed September 30, 2018).
The generic drug industry has claimed that fraudulent practices have
largely been corrected. But in October 2019, for an article in STAT
News, co-author Sony Salzman and I analyzed the FDA's own records,
which revealed that violations of data integrity are not only
persistent and ongoing in overseas drug manufacturing plants, but are
happening with greater frequency than in U.S. plants.\5\ With the help
of FDAzilla, a leading data analytics company, we analyzed 5\1/2\ years
of FDA inspection records, from 2014 to 2019, for four major markets:
China, India, Europe, and the United States.
---------------------------------------------------------------------------
\5\ Eban, Katherine, and Sony Salzman. ``In Generic Drug Plants in
China and India, Data Falsification Is Still a Problem.'' STAT News,
October 29, 2019. https://www.statnews.com/2019/10/29/data-
falsification-still-problematic-china-india-generic-drug-plants/.
The data showed significantly greater falsification or manipulation of
manufacturing data in Indian and Chinese drug plants. For example, a
January 2019 FDA inspection at Indoco Remedies in Goa, India, uncovered
that the manufacturing plant had faked the data in its batch production
records to justify the release to market of its diabetes drug
glimepiride.\6\ By contrast, the raw testing data showed that the drug
did not meet quality standards and therefore should not have been
released to patients.
---------------------------------------------------------------------------
\6\ Food and Drug Administration. Warning Letter, Indoco Remedies
Ltd., July 16, 2019.
While data integrity violations may sound minor and technical, for
patients they can mean the difference between a safe, effective generic
drug that functions just like the brand and a drug that is not
equivalent to the brand, or that may contain toxic impurities or
foreign particulate matter. In short, a difference between life and
death.
2. Essential Difference Between U.S. and Foreign Inspections
In the United States, in order to inspect drug plants, FDA
investigators simply show up unannounced and stay as long as is needed.
But for overseas inspections--due to the complex logistics of getting
visas and ensuring access to the plant--the FDA has chosen to announce
its inspections in advance, despite there being no requirement to do
so.
Overseas drug plants typically ``invite'' the FDA to inspect and the
agency accepts. Plant officials serve as hosts to the visiting FDA
investigators, who become their guests. It is not unusual for
manufacturing plants to arrange local travel for FDA investigators.
This system has allowed manufacturing plants to ``stage'' inspections,
as one FDA investigator put it, and conceal evidence of data
fabrication. Some companies have even sent in teams of data fabricators
in advance of FDA inspections, to alter, shred, or backdate documents
to create a facade of compliance.
This system of advance notification has also harmed the integrity and
independence of FDA investigators. It has allowed companies to organize
shopping trips, golf outings, and tourist excursions for them, leaving
them ``captive and compromised,'' as a former head of the FDA's India
office, Altaf Lal, described it.
In January 2014, with the FDA's permission, Lal launched what came to
be known as the India pilot program.\7\ He eliminated the months-long
advance notice and company-arranged travel plans. Instead, the FDA gave
only short notice--or no notice--of investigators' arrival for all
inspections in India.
---------------------------------------------------------------------------
\7\ Eban, Katherine. ``Bottle X: Exposing Impurities in the Generic
Drug Business.'' Newsweek, July 2, 2019.
The FDA's new inspection program exposed widespread malfeasance that
had previously been hidden. By showing up unannounced, the
investigators uncovered an entire machinery that had existed for years:
one dedicated not to producing perfect drugs, but to producing perfect
results. The investigators found a bird infestation at one sterile
manufacturing site. At another, they found a facility's paperwork for
its sterility testing in perfect order, ensuring that the plant's air,
water and surfaces were free of microbial contamination. Yet the
samples didn't exist. They were testing nothing. The entire laboratory
---------------------------------------------------------------------------
was a fake.
Under the India pilot program, the rate of inspections resulting in the
FDA's most serious finding, Official Action Indicated, increased by
almost 60 percent. The program succeeded in exposing endemic fraud and
dire conditions in India's drug manufacturing plants. But in July 2015,
the FDA abruptly ended the pilot program without explanation, and
resumed pre-announced inspections. This raises the crucial question of
how the FDA deals with the problems that it finds.
3. How the FDA Responds to Findings
It is striking that the FDA has all too frequently chosen to downgrade
the findings of its own investigators.
In May 2017, in Linhai, China, an FDA investigator inspected Zhejiang
Huahai Pharmaceuticals, the world's largest manufacturer of the active
ingredient for valsartan, a generic version of the blood pressure drug
Diovan. He found evidence at the plant that the company was failing to
investigate potential impurities in its own drugs, which showed up as
aberrant peaks in its test results. The investigator recommended the
inspection be categorized as Official Action Indicated, which would
have forced the manufacturing plant to urgently make changes or face
further sanctions.
But in a September 7, 2017 memo, the agency downgraded the recommended
classification to Voluntary Action Indicated, which allowed the company
to make non-
urgent corrections. The memo \8\ concluded:
---------------------------------------------------------------------------
\8\ Tamara Felton Clark, Branch Chief, Global Compliance Branch 4,
``Reclassification of Surveillance Inspection: VAI as Inspection
Classification,'' CMS File--Work Activity 161861, Zheijiang Huahai
Pharmaceutical.
The firm's response is mostly adequate including as it
concerned the observation pertaining to their investigation of
aberrant peaks on HPLC chromatograms. The firm provided data
and information to demonstrate the peaks did not impact product
and timeframes for improving their method and revising their
---------------------------------------------------------------------------
investigation procedure.
In fact, the peaks were a clue to a compromised product. Less than a
year later, the company wound up in the middle of a worldwide quality
scandal. In July 2018, European regulators announced a harrowing
discovery: the active ingredient made by Zhejiang Huahai contained a
cancer-causing toxin known as NDMA.
The FDA's decision to overrule its own investigator and downgrade the
Zhejiang Huahai inspection was not unique. According to the FDA's own
data, which I obtained, from 2013 to 2018, out of 864 inspections in
China of drug manufacturing plants that FDA investigators recommended
as Official Action Indicated, FDA officials downgraded 78 of those. Of
1,514 inspections in India in the same time period, FDA officials
downgraded 109. By contrast, in the same time period, out of 11,642
inspections that FDA investigators conducted in the U.S. and
recommended as Official Action Indicated, only one inspection was
downgraded.
These downgrades reflect the FDA's willingness to give foreign plants
the opportunity to continue operations without sanctions.
4. COVID-19 Compromises
The coronavirus pandemic has intensified our dependence on potentially
dangerous sources of foreign drugs, and the FDA's willingness to grant
exceptions to source those drugs.
Most glaringly, in its efforts to source hydroxychloroquine, a
treatment of unproven utility for COVID-19, in late March the FDA
lifted restrictions on the Indian drug company Ipca Laboratories, which
had previously been caught manipulating and deleting quality data, so
that the U.S. could import the company's hydroxychloroquine sulphate
and chloroquine phosphate active ingredients and hydroxychloroquine
sulphate tablets.\9\
---------------------------------------------------------------------------
\9\ Altstedter, Ari, and Anna Edney. ``Censured Indian Plant Gets
USFDA Nod to Supply Trump-Touted Drug.'' Bloomberg, March 23, 2020.
https://www.bloomberg.com/news/articles/2020-03-23/fda-lifts-import-
curbs-on-maker-of-unproven-virus-drug-in-india.
Even more concerning was the emergency use authorization the FDA issued
on March 28th, which for the first time allowed the U.S. to import a
version of chloroquine phosphate called Resochin, donated by Bayer AG,
that had been made in plants in India and Pakistan that had never been
registered with, or inspected by, the FDA.\10\
---------------------------------------------------------------------------
\10\ Eban, Katherine. ``Exclusive: FDA May Have Dropped Standards
Too Far in Hunt for Chloroquine to Fight Coronavirus--Sources.''
Reuters, April 16, 2020. https://www.reuters.com/article/us-health-
coronavirus-bayer-chloroquine/exclusive-bayers-chloroquine-donation-to-
u-s-raises-concern-about-fda-standards-in-pandemic-idUSKBN21Y2LO.
At the same time, the FDA has been forced to suspend foreign
inspections, and is relying on information provided by drug companies,
a number of which have previously been caught supplying falsified
data.\11\
---------------------------------------------------------------------------
\11\ FDA Statement, ``Coronavirus Disease 2019 (COVID-19) Update:
Foreign Inspections.'' https://bit.ly/3gL6O19, March 10, 2020.
As well, plants that are facing regulatory restrictions, based on
previous inspection findings of Official Action Indicated, are
increasingly getting accelerated approvals to market their drugs, based
on the Agency's regulatory discretion. The committee should request
that data.
5. Suggested Reforms to Safeguard the U.S. Drug Supply
The FDA needs to overhaul its foreign drug inspection program
The FDA's overseas offices are poorly staffed, and its cadre of U.S.-
based investigators willing to perform inspections overseas is
relatively small and demoralized. The FDA needs a specialized and
highly trained workforce that can make a years-long commitment to serve
overseas and become a ``go to'' group for emergency assignments. This
would remedy the problem behind the FDA's anemic recruitment to foreign
posts: a lack of clear career progression and promotion opportunities.
Unannounced inspections should be the norm
The FDA's current regimen of pre-announced overseas inspections is
counter-productive and ineffective, and allows companies to stage-
manage inspections. Short notice, or no notice inspections, should be
the norm.
Downgrades should be rare
Too often, FDA officials at the agency's headquarters in Maryland
overrule the judgment of investigators in the field, and downgrade
recommended findings.
In the course of my reporting, an FDA spokesperson justified these
downgrades as follows:
The FDA can and does change assessments of a plant's
compliance. After the initial data gathered by the investigator
is reviewed by both the Office of Regulatory Affairs and the
Center for Drug Evaluation, additional information can be taken
into account. Oftentimes, a firm is not able to provide
paperwork at the time of an inspection but can produce
documents later on that provide more insight into the matter.
Assessments can also change based on how willing a firm is to
cooperate and fix issues that are found.
This system allows manufacturing plants to fabricate documents and
generate excuses for submission to the FDA.
Drugs should be systematically tested
The FDA has largely used an honor system to verify the quality of drugs
made overseas: it reviews data provided by the companies and conducts
pre-announced inspections. Actual testing of drugs is rare.
The FDA should either institute a system of testing, or commission
outside labs to do this testing, to serve as independent corroboration
of quality.
Country-of-origin labeling on drugs and drug ingredients
Consumers want to know where their drugs are made. There is no reason
to conceal that information. The food we eat and the clothes we wear
come with country-of-origin labeling. Yet when it comes to our
prescription drugs, that information is deemed proprietary. It
shouldn't be. Required country-of-origin labeling would likely
underscore our dependence on foreign drug sources and accelerate the
current push to return drug manufacturing to the United States.
Notify doctors of medication manufacturer switches
Doctors are struggling to stabilize patients who are often being
switched, month to month, between different manufacturers' versions of
their monthly prescriptions. Those versions can vary widely in quality,
absorption, and bio-availability. Doctors, particularly those that
prescribe drugs where dosing is critical, should have the option to be
notified about any medication switches that result in a change of
manufacturers.
______
From Time, March 26, 2020
The Coronavirus Pandemic Is Creating a Drug Supply Crisis
Just When We Most Need Medicine
By Katherine Eban
As the world scrambles for a magic pharmaceutical bullet to stop the
coronavirus, drugs perceived as cures--despite reed-thin evidence--have
vanished from pharmacy shelves. Just last Friday, after President Trump
touted the still unproven remedy of a malaria drug, hydroxychloroquine,
the Food and Drug Administration lifted a restriction it had imposed on
a Indian drug manufacturer with a record of manipulating its quality
data, to allow it to make the active ingredient now suddenly in hot
demand. With the United States long dependent on foreign drug
manufacturers for low-cost medicine and key drug ingredients, it is
little wonder that we have arrived at this frightening moment, with the
FDA allowing companies that it didn't even trust enough last month to
make any drug for the American public, to now churn out unproven drug
ingredients for a largely untested off-label use.
Coronavirus has now done what years of U.S. Government Accountability
Office (GAO) reports and congressional hearings could not achieve. It
has laid bare the full perils of our dependence on an overseas drug
supply. Not only has this pandemic intensified already serious drug
shortages. But question marks loom over the safety of the drugs we are
able to procure. Experts have long warned this day would come.
Last July, a Pentagon official testified before the U.S.-China Economic
and Security Review Commission that U.S. dependence on Chinese-made
prescription-drug ingredients constituted a national security threat.
This was an understatement, even then. Over eighty percent of the
manufacturing plants that make active ingredients for all U.S. drugs
are located overseas, concentrated particularly in China. Furthermore,
a majority of our finished generic drugs, which constitute ninety
percent of the U.S. drug market, are made overseas, with a full forty
percent coming from India, which in turn is also dependent on China for
active drug ingredients.
Fast forward to the coronavirus pandemic, and that national security
threat has turned into a full-blown national security disaster, with
dangerous dominoes falling in the American drug supply, pointing to
deeper trouble ahead.
India recently announced that it would curb the export of 26 drugs and
drug ingredients, as it consolidates pharmaceutical supplies to treat
its own population. The FDA announced, in light of travel bans, that it
would halt all inspections at overseas drug plants. And the Chinese
government recently threatened to impose restrictions on pharmaceutical
exports to the U.S.
Even before the onset of coronavirus, serious questions loomed about
the integrity of much of our low-cost foreign-made medicine. The FDA's
foreign drug inspection program has been frighteningly threadbare for
years: woefully understaffed and poorly organized, with long-standing
vacancies, as a December report by the GAO confirmed. But it also
operates on an honor system, where the FDA gives foreign plants months
of advance notice, does not systematically test drugs and instead,
relies on reviewing company data.
This has allowed overseas plants to refine elaborate techniques for
duping the FDA, a dangerous cat-and-mouse game that I first exposed in
my book Bottle of Lies: The Inside Story of the Generic Drug Boom.
The overseas plants use hidden laboratories, secret testing machines,
altered test results--and even clandestine drug samples taken from
brand-name drug competitors--all to create pristine quality data to
gain approvals from regulators and pass inspections. The result is that
much of the quality data emanating from certain overseas plants is not
``worth the paper it's written on,'' as one FDA investigator told me.
Ipca Laboratories, the Indian drug company that just got the FDA's
permission to make hydroxychloroquine, was found by FDA investigators
to be manipulating and deleting quality data.
When the FDA announced it would suspend all foreign inspections, the
FDA offered this to reassure the public: it would be ``requesting
records'' from plants ``in advance of or in lieu of'' on-site drug
inspections. In other words, the issue is not just the
hydroxychloroquine made by one dubious company. Neither the FDA nor
American consumers will have any idea whether the majority of our drugs
on the market will be safe or work as intended, and will be relying
entirely on information provided by drug companies, a number of which
have previously been caught supplying falsified data.
Facing looming drug shortages, the U.S. finds itself at the mercy of
China, which has threatened to cut active drug ingredients. India,
which has already put an export hold on 26 vital drugs and drug
ingredients. And Italy, another vital supplier of active drug
ingredients, is under siege with almost 69,000 COVID-19 cases, and
close to 7,000 deaths.
The generic drug market, responsible for ninety percent of the drugs
Americans consume, operates on a ``30/30/30 supply chain,'' said Martin
VanTrieste, president of Civica Rx, a nonprofit drug maker aiming to
ramp up U.S. manufacturing of generic drugs in short supply. At any
given time, Trieste explained, there's a 30-day supply of active drug
ingredients, a 30-day supply of drugs moving through the wholesale
market and a 30-day supply of drugs on pharmacy shelves. That gives the
U.S. government about ``30 [days]'' to avert major drug shortages. ``My
biggest fear is the shipping lanes close off,'' said Trieste, though it
hasn't happened yet. ``That would be setting off a disaster.''
Within the last few weeks, lawmakers have introduced legislation that
would incentivize innovation and advanced pharmaceutical manufacturing
in the U.S., and require drug makers to more clearly disclose the
origin of ingredients and the amount of stock on hand. The White House
is pushing ``Buy American'' policies that would require the Federal
government to prioritize the purchase of U.S.-made drugs and medical
supplies.
But the flurry of proposals cannot make up for years of a broken drug
supply, in which so many drug manufacturers looked for the cheapest way
to make lifesaving drugs as far from vigilant regulators as possible.
Facing a far-flung drug supply, the FDA failed to implement real
verification systems--such as unannounced inspections and systematic
drug testing--to safeguard the quality of foreign-made drugs. It was
under this porous review system that millions of Americans wound up
getting blood pressure medicine that contained a dangerous carcinogen.
If and when the COVID-19 pandemic subsides, our drug supply will
require major reforms. The FDA must make unannounced inspections the
norm for every plant it inspects, anywhere in the world. It must
implement a system for routine testing of drugs. The big pharmacy
chains, such as CVS and Walgreens, should also test the drugs they
dispense.
And consumers should get country-of-origin labeling that discloses
where their drugs and drug ingredients are actually made. That kind of
information--available on our cereal boxes and clothing--is somehow
deemed proprietary when it comes to lifesaving medications. These
disclosures would probably shock most patients--and would go a long way
to helping restore America's lost medicine manufacturing base.
In all likelihood, says VanTrieste, bringing drug manufacturing home
will require an ``all-out Manhattan project [style] initiative to get
infrastructure back to the U.S. market.'' After all, it was just such a
U.S. government effort--in the midst of World War II--that led to one
of the great breakthroughs in modern science, the commercial
development of penicillin.
______
From Rueters, April 16, 2020
Exclusive: FDA May Have Dropped Standards Too Far in Hunt for
Chloroquine to Fight Coronavirus--Sources
By Katherine Eban
On March 21, two days after President Donald Trump first touted
chloroquine drugs as a ``gamechanger'' in the fight against COVID-19,
administration officials privately described what they felt was a
``win'' in the president's efforts to build an emergency stockpile of
the drugs: a hefty donation of pills from Bayer AG.
In an exchange of enthusiastic emails among federal health officials
reviewed by Reuters, Keagan Lenihan, chief of staff of the U.S. Food
and Drug Administration (FDA), cautioned that ``3-4 days'' of testing
would be needed.
``Potentially serious issues with product so let's be careful when we
take that win,'' she wrote.
Bayer has since donated three million tablets of the drug, called
Resochin, to the U.S. national stockpile for treatment of COVID-19, the
disease caused by the coronavirus. After a brief period of testing, its
use in the United States was approved on an emergency basis.
But three U.S. government sources familiar with the matter told Reuters
that there is reason to be concerned about the quality of Resochin and
its makers, located in India and Pakistan.
Although some rules can be waived in an emergency, the FDA dropped its
quality-control standards too far as it scoured the world for scarce
supplies of chloroquine drugs, according to the sources, who spoke on
condition of anonymity.
The plants that make Resochin ingredients and finished doses in India
and Pakistan have never been registered with, or inspected by, the FDA,
according to the three government sources, as well as FDA documents
compiled in the private online database FDAzilla.com. Some chloroquine
drugs were already approved by the FDA before the pandemic as
antimalarial medications, a process that required plant inspections.
Resochin was not approved.
Pakistani regulators, who inspected Bayer's Resochin plant in Karachi
in 2015, found a ``gross failure'' in manufacturing processes there,
according to documents from the Drugs Regulatory Authority of Pakistan,
reviewed by Reuters. And though the FDA has never screened the Indore,
India plant that supplies ingredients for Resochin, the U.S. agency has
inspected other Indian plants run by the same Indian supplier and found
serious deficiencies, including falsification of records, inspection
documents spanning 2014 through 2019 show.
Responding to questions from Reuters about Resochin, FDA spokesman
Michael Felberbaum said that the agency ``sampled and tested the
donated drugs to evaluate acceptability for importation'' and they met
appropriate standards.
Asked about Lenihan's March 21 email, the FDA spokesman said the agency
``does not comment on alleged, leaked emails.''
In a statement to Reuters, Bayer said that the FDA had tested Resochin
``and found it to be of appropriate quality for release to the
(stockpile) for emergency use. We are proud to make this donation to
the U.S. government in the fight against COVID-19.''
Resochin is part of a class of medications containing one of two active
ingredients--chloroquine or hydroxychloroquine--that the Trump
administration has praised as a potentially lifesaving treatment. But
the effectiveness of chloroquine drugs against coronavirus has not been
proven. Though in use for years in the United States as a treatment for
malaria and autoimmune conditions such as lupus, the medicines can have
serious side effects, including heart arrhythmias.
The three U.S. sources who spoke with Reuters, as well as an
independent expert, said spot-testing is not always sufficient to
ensure a drug's safety and effectiveness, and plant inspections
normally done by the FDA are crucial to ensuring overall quality.
``If you're talking about millions of doses, you can't test every
product,'' said Stephen Payne, who for years chaired a practice group
specializing in the FDA and health care at a global law firm. ``You
have no idea what you don't know.''
A PHOTO OPPORTUNITY
Trump first endorsed chloroquine drugs to treat COVID-19 from the White
House podium on March 19, citing ``very, very encouraging early
results'' and downplaying any risks. ``If things don't go as planned,
it's not going to kill anyone,'' he said.
The statements came as the administration was being hammered for its
slow response to the growing coronavirus crisis, which to date has
infected more than 637,000 people in the United States, killing almost
31,000. His comments set high public expectations for the drugs, which
are now being snapped up all over the globe.
In emails two days later, federal health officials greeted the Bayer
donation of chloroquine phosphate, or Resochin, with eagerness.
Cicely Waters, director of external affairs for the U.S. Department of
Health and Human Services (HHS), saw a media opportunity. A shipment of
two million tablets was due to arrive at John F. Kennedy International
Airport in New York City.
``I would like to get photos of the product coming off of the FedEx
plane so we can be prepared to support the story with visuals if this
turns out the way we hope,'' wrote Waters.
Lenihan of the FDA told the group of health officials that ``if it is
the product we think it is and it is not toxic we will release it to
ASPR''--the Assistant Secretary for Preparedness and Response, a
division within HHS.
Reached by email, Lenihan referred Reuters back to the FDA press
office. Waters did not respond to an email seeking comment.
One of the participants in the March 21 email discussion appeared to
raise the issue of which agency should get credit for the deal. Joseph
Hamel, ASPR's manager of strategic innovation and emerging technology,
asked in an email to the group: ``How do you want to handle? FDA win?
ASPR win? Happy either way, please let us know.''
Hamel did not return an email seeking comment.
Asked about the email exchanges, an HHS spokesman echoed the FDA's
statement, saying the agency would not comment on ``alleged, leaked
emails.''
``GROSS FAILURE''
The pills and ingredients welcomed by the administration had origins
that should have raised red flags and prompted greater scrutiny, said
the three sources who spoke to Reuters.
In 2015, Bayer's plant in Pakistan, Bayer Pakistan Private Ltd, was
cited by that country's regulators for making Resochin that was lower
in potency than labeled, according to inspection documents reviewed by
Reuters.
A whistleblower complaint led to the discovery of more than 21 million
Resochin tablets that were too weak, more than 12% under the specified
weight of 400 milligrams, according to the Pakistani regulatory
records.
Officials blamed the problem on a ``gross failure'' of manufacturing
operations, citing improperly calibrated machines, poorly trained
workers and insufficient staffing. Weak medications can fail to treat
the illness for which they're prescribed and harm patients.
The investigation was ultimately resolved with Bayer's agreement to
destroy the 21 million doses.
Regarding the 2015 incident, the company told Reuters: ``All batches
produced with lower content due to an error in production were never
released, the corresponding batches destroyed.''
According to FDA records reviewed by Reuters, the active ingredients
for the drug are made at a plant in Indore, India, run by Ipca
Laboratories Ltd, an Indian drug manufacturer and ingredient supplier
that exports its products globally.
In 2016, the FDA issued a warning letter to Ipca regarding three of its
plants in India that make chloroquine ingredients and finished pills
for companies other than Bayer. The plants did not include the one
making the active ingredient for Bayer's Resochin. Nonetheless, the
U.S. government sources said, Ipca's troubled history calls into
question its general practices.
The FDA found the company was deleting, manipulating, and fabricating
laboratory data, according to the agency's records. The company vowed
at the time to ``resolve these issues at the earliest.''
In 2017, the agency restricted drugs and ingredients from those three
plants from entering the U.S. market, a regulatory sanction called an
import alert. Then in August 2019, the FDA accused one of the Ipca
plants of a ``cascade of failure'' for not properly maintaining its
quality data, agency records show.
Ipca did not respond to questions from Reuters about its track record
with the FDA.
On March 20, a day after Trump praised the antimalarial drug from the
podium, the FDA lifted its import alert for Ipca's chloroquine
ingredients and completed tablets from the three restricted plants,
according to a March 21 statement filed by Ipca with the Indian stock
exchange.
The company pledged in the statement to adhere to stringent
manufacturing standards, ``and thus help mankind in the best possible
way in these testing times.''
______
From Vanity Fair, April 24, 2020
``Really Want to Flood NY and NJ'': Internal Documents Reveal Team
Trump's Chloroquine Master Plan
By Katherine Eban
Forget testing, ventilators, and PPE. Donald Trump's big plan
to beat COVID-19 involved distributing millions of doses of an
unproven drug. Behind the scenes, senior administration
officials pushed hard to bend the rules and back up his boasts.
On the afternoon of Saturday, April 4, President Trump stood at the
White House podium and escalated his marketing blitz on behalf of
hydroxychloroquine, hyping the old malaria drug's alleged promise in
treating COVID-19, as well as his administration's success in acquiring
huge amounts of it.
``We have millions and millions of doses of it--29 million to be
exact,'' he said, as the official tally of COVID-19 cases in the U.S.
topped 260,000 and governors across the country pleaded for federal
support to acquire tests, ventilators, and protective gear for health
care workers. ``We're just hearing really positive stories, and we're
continuing to collect the data.'' That evening, according to emails
obtained by Vanity Fair, Trump's political appointees would ramp up the
pressure on career health officials to make good on the President's
extravagant promises, despite clear warnings from federal clinicians
about the risks and unproven benefits of chloroquine-based treatments
for COVID-19.
Vanity Fair has assembled this account based on documents and
interviews provided by multiple federal officials with knowledge of
internal Trump administration proceedings.
The President had been touting hydroxychloroquine for weeks, sparking
worldwide shortages of the drug and prompting negotiations with Indian
prime minister Narendra Modi to lift export restrictions on its active
ingredients. But on March 24, the federal government's top interagency
working group of clinicians and scientists privately threw cold water
on his claims, according to a federal official with knowledge of the
working group's deliberations. In an internal consensus statement, a
medical countermeasures group within Health and Human Services
recommended that chloroquine-based COVID-19 treatments should be
studied only in controlled, hospital-based clinical trials, as their
safety and efficacy was ``not supported by data from reliable clinical
trials or from non-human primates'' and carried ``potential risks.''
The medicines-which are used to treat malaria as well as autoimmune
conditions such as lupus-can have serious side effects, including heart
arrhythmias.
And yet, just hours after that April 4 press conference, White House
officials pushed ahead with a massive behind-the-scenes pressure
campaign on the government's top health officials to deliver huge
amounts of chloroquine drugs to just about anyone who wanted them,
according to documents reviewed by Vanity Fair. That night, Brett
Giroir, the assistant secretary for health in the Department of Health
and Human Services, sent an email with the subject line
``Hydroxychloroquine'' to a group including FEMA administrator Pete
Gaynor, HHS assistant secretary for preparedness and response Robert
Kadlec, and Navy Rear Admiral John Polowczyk, who leads a supply-chain
task force at FEMA.
The email read:
_______________________________________________________________________
WH call. Really want to flood NY and NJ with treatment courses.
Hospitals have it. Sick out patients don't. And can't get. So go
through distribution channels as we discussed. If we have 29 million
perhaps send a few million ASAP? WH wants follow up in AM. We can get a
lot more of this. Right Bob? Millions per week?
_______________________________________________________________________
The emails indicate that the administration's top health officials were
closely involved in a frenzied effort to make unproven chloroquine
treatments widely available, even though the FDA's new emergency rule
limited distribution of the drug as a COVID-19 treatment to
hospitalized patients. One hour after the first email, Gaynor replied
to Kadlec, Giroir, and Polowczyk, seeming to suggest that FDA
commissioner Stephen Hahn was on board with expanding COVID-19
patients' access to the drug: ``Hahn asked to distribute to hospitals
and the drug stores.''
In a second email that appears to have been sent the same night, Gaynor
indicated that he was working closely with Rear Admiral Polowczyk: ``Me
and Adm P are on it. More to follow in the am.''
A FEMA spokesperson did not answer questions about the involvement of
Pete Gaynor or other officials in the chloroquine plan but said, ``FEMA
does not maintain stocks of medicine.'' In response to a request for
comment, an FDA spokesman responded: ``Given increased demand, Dr. Hahn
considered whether the donated drugs could be distributed in the
commercial market to ensure a stable supply for malaria, lupus, and
rheumatoid arthritis patients.''
An HHS spokesperson said that, while clinical trials of the drugs
proceed, some of the government's hydroxychloroquine ``was provided to
wholesale distributors to further supply hospitals as well as retail
pharmacies that were experiencing product shortages for people who use
the drug for the maintenance of chronic conditions such as rheumatoid
arthritis and lupus.'' The spokesperson added that the hospitals and
pharmacies that receive donated medications are not permitted to
``charge for the drug itself.''
The White House did not respond to a request for comment.
The intra-White House battle over the use of chloroquine drugs for
treating COVID-19 broke into the open in dramatic fashion on April 21,
when the administration's top coronavirus vaccine developer, Rick
Bright, was pushed out of his position as the head of the Biomedical
Advanced Research and Development Authority (BARDA), a small agency
within HHS that partners with private scientific ventures to create
vaccines, drugs, and diagnostics. The next day Bright issued a
statement, first reported by The New York Times, stating that he was
fired for resisting efforts ``to fund potentially dangerous drugs
promoted by those with political connections.''
``Specifically, and contrary to misguided directives,'' he said, ``I
limited the broad use of chloroquine and hydroxychloroquine, promoted
by the administration as a panacea, but which clearly lack scientific
merit.'' On April 23, attorneys for Bright said they would file a
formal whistleblower complaint on his behalf.
Even before Trump began making public statements from the podium, his
political appointees had begun rallying around the idea of amassing
chloroquine drugs to treat COVID-19, despite the paucity of evidence
for their benefits. On March 18, according to records obtained by
Vanity Fair, the German drug manufacturer Bayer first petitioned the
FDA to let it donate millions of doses of a chloroquine drug called
Resochin. Normally such a move would be prohibited since the FDA had
never inspected the plant in Karachi, Pakistan, where Resochin is made.
But the FDA set aside its usual safeguards and approved the donation,
after sampling and testing the drugs to make sure they met U.S.
standards. On March 19, Bayer issued a press release to announce that
it was ``working with appropriate agencies on an Emergency Use
Authorization for the drug's use in the U.S.''
The next day Trump first spoke of hydroxychloroquine from the White
House podium, citing its ``very, very encouraging early results. And
we're going to be able to make that drug available almost
immediately.'' Because the drug had ``been around for a long time,'' he
added, ``if things don't go as planned, it's not going to kill
anybody.'' Trump said he had spoken the night before with New York
governor Andrew Cuomo about the drug's promise, and ``he wants to be
first on line.''
Inside the administration, as the White House cobbled together a plan
to make chloroquine drugs widely available to the American public,
Trump's political appointees began exerting tremendous and unwelcome
pressure upon career health officials. As part of the plan, Oracle, the
technology company co-founded by billionaire Trump fundraiser Larry
Ellison, designed and built an app to collect data from physicians and
patients tracking the response to various experimental treatments for
COVID-19. (A source familiar with Oracle's app called it ``an
information collector; it does not recommend therapies or treatment
plans.'')
Under the plan, which set off alarm bells within the health agencies,
chloroquine drugs would be available to patients through pharmacies,
not just to hospitalized patients. ``There wasn't a plan for physician
oversight or monitoring,'' one federal official told Vanity Fair.
``That's what concerned clinicians the most. Career FDA, NIH, CDC, and
BARDA [personnel] were all very concerned about lack of physician
oversight or adverse event monitoring with the expanded-access
program.''
On the evening of March 23, the FDA's chief counsel, Stacy Amin,
emailed lawyers and other officials within HHS, the National Institutes
of Health, and the FDA, urging action. The proposal that she relayed,
as she spelled it out, was to have BARDA sponsor what is called an
investigational new drug study. An IND permits a new drug in
preclinical development to be shipped across state lines to be studied.
In this case the IND would have covered an old drug with a potential
new use. Amin, who served as a special assistant to President Trump
before assuming her current role at the FDA in September 2018, wrote,
``The President is announcing this tonight and I believe the WH would
like it set up by tomorrow with data to flow into the Oracle
platform.'' She then asked, ``What needs to be done and what
requirements do we think can be waived or use enforcement discretion?''
According to the FDA's spokesman, ``The FDA, including Ms. Amin, has
discussed and explored various ways to collect this data but ultimately
did not support doing it through an IND, has not waived any regulatory
requirements, and never sought any unapproved use of the drugs that
wouldn't be under doctor supervision in connection with this or other
related efforts.''
The order to implement such a complex and unorthodox plan on a
timetable driven by the President's press announcements stunned
numerous BARDA employees. Within hours, one official wrote to a
colleague, ``We have been hit by a bus. Now we hit back.'' He said he
would try to amend the proposal and find a ``workable'' solution.
Days of debate ensued as employees within the agency pushed back.
By late March, health officials across multiple agencies had settled on
an alternate plan, which they viewed as safer for patients. On March
28, the FDA issued an emergency use authorization (EUA) to allow
chloroquine drugs from the Strategic National Stockpile to be
administered to hospitalized COVID-19 patients who could not access
clinical trials. The stockpile is a cache of equipment and supplies
managed by HHS that can be accessed in the event of medical
emergencies.
In the statement related to his firing, Rick Bright seemed to refer to
that authorization when he wrote, ``I rightly resisted efforts to
provide an unproven drug on demand to the American public. I insisted
that these drugs be provided only to hospitalized patients with
confirmed COVID-19 while under the supervision of a physician.''
But top officials were not satisfied with the more restrictive approach
and kept pushing for more widespread distribution of the drug. In an
email that appears to have been addressed to Gaynor at some point after
the emergency use authorization was issued, Brett Giroir argued
strongly against limiting the drugs to hospitals. ``NOPE. Needs to go
to pharmacies as well,'' he wrote. ``The EUA matters not. The drug is
approved [and] therefore can be prescribed as per doctor's orders. That
is a FINAL ANSWER.''
Giroir's rationale for ignoring FDA limitations appeared to hinge on a
technicality: Because chloroquine is FDA-approved for conditions
including malaria and lupus, doctors could technically prescribe it for
any ``off-label'' treatments they saw fit. He added, presumably in
reference to shortages prompted by Trump's P.R. campaign, ``And
pharmacies need it for ON LABEL use as well.''
According to Dr. Adarsh Bhimraj, head of the neurologic infectious
diseases section of the Cleveland Clinic, the impulse to rush untested
medicines to patients is understandable but unwise. ``These people are
sick. We want to do something,'' he said, drawing on his own experience
treating patients with COVID-19. Nevertheless, he added, ``It's
important as clinicians that we step back, reflect, and pause. Let's
look at the evidence before we prescribe any medications.''
Dr. Bhimraj chaired the panel for the Infectious Diseases Society of
America that recently issued treatment guidelines stating COVID-19
patients should only get treated with chloroquine drugs in hospital-
based clinical trials. Based on the human data so far, he said, ``We
don't know if the benefits outweigh the harm,'' and only ``double-
blinded, placebo-controlled studies'' can answer that question.
As HHS prepared to announce donations of chloroquine to the Strategic
National Stockpile, and chalk up a ``win'' for the White House, safety
concerns dogged the plan.
The FDA's chief of staff, Keagan Lenihan, emailed a group of federal
officials including Amin to warn that after the chloroquine pills
donated by Bayer arrived at John F. Kennedy International Airport in
New York, they would need to be quarantined and tested. ``If it is the
product we think it is and it is not toxic we will release it'' to the
office that oversees the national stockpile, Lenihan wrote.
``Apparently, where Bayer is getting this product from is a
manufacturing facility they use for Africa.'' In fact, the facility in
question is used to supply the Pakistan market, and has been inspected
by Pakistani regulators, not the FDA. Lenihan continued, ``Potentially
serious issues with product so let's be careful when we take that
win.'' Bayer has previously pointed out that the FDA tested Resochin
``and found it to be of appropriate quality for release to the
(stockpile) for emergency use.''
As health officials navigated a minefield of long-standing regulations
that were impeding the White House campaign, the message from the
presidential podium was exultant: Trump had zeroed in on a potential
cure and had slashed red tape to speed it to patients in need. On April
4, the President declared that the tech giant Oracle had donated a
``very sophisticated'' web portal to gather real-time data on how
patients were responding to the new treatments.
Since then, a steady drumbeat of small-scale studies and medical
recommendations has cast increasing doubt on the treatment that Trump
once hailed as a ``game-changer.'' On April 21, a study of 368 COVID-19
patients at veterans hospitals showed that about 28% of those treated
with hydroxychloroquine died, compared with 11% of those who didn't
receive the medication.
On the same day the National Institutes of Health issued detailed
treatment guidelines, stating, ``There are insufficient clinical data
to recommend either for or against using chloroquine or
hydroxychloroquine for the treatment of COVID-19.'' The agency advised
clinicians using the drugs to closely monitor patients for adverse
effects, particularly cardiac risks.
Whether owing to the accumulation of evidence against
hydroxycholoroquine's efficacy, the resistance of career health
officials, or something else entirely, the Trump administration appears
to have dropped its crusade on behalf of the purported miracle cure-at
least for now. It's been over a week since the president last used a
daily coronavirus briefing to promote the drug. This week, the U.S.
death count from COVID-19 is expected to pass 50,000.
______
From Vanity Fair, May 5, 2020
``Political Connections and Cronyism'': In Blistering Whistleblower
Complaint, Rick Bright Blasts Team Trump's Pandemic Response
By Katherine Eban
Two weeks after being pushed out of his post, the former head
of a $1.5-billion federal health agency formally accuses top
officials of pressuring him to approve unproven chloroquine
drugs and award pricey contracts to friends of the
administration.
He was pressured to invest in drugs and vaccines that lacked scientific
merit, because the people selling them had friends in the Trump
administration, up to and including the President's son-in-law, Jared
Kushner. He was forced to transfer funds to acquire drugs for the
Strategic National Stockpile, America's most important reserve of
lifesaving medications, based not on health needs but on ``political
connections and cronyism.'' He was instructed to use his department's
budget to purchase flu medications of questionable efficacy. And when
the COVID-19 crisis erupted, he was pressured to approve a plan that
would ``flood'' cities with unproven and untested doses of chloroquine
drugs, from uninspected manufacturing plants in Asia. When his efforts
to work through the system failed, he decided he had a ``moral
obligation to the American public'' to ring the alarm about the plan,
``which he believed constituted a substantial and specific danger to
public health and safety.'' In retaliation, he was ``smeared,'' with
officials unfairly accusing him of dropping the ball on vaccine
development and PPE preparation.
These are just some of the allegations contained in a blistering, 63-
page complaint that Dr. Rick Bright, former head of the Biomedical
Advanced Research and Development Authority (BARDA), filed today with
the U.S. Office of Special Counsel. According to his lawyers, Bright
will testify before Congress next week.
Vanity Fair has submitted requests for comment to the White House and
the Food and Drug Administration, and will update this article with any
responses. In a statement, Department of Health and Human Services
spokesperson Caitlin Oakley said: ``Dr. Bright was transferred to NIH
to work on diagnostics testing--critical to combatting COVID-19--where
he has been entrusted to spend upwards of $1 billion to advance that
effort. We are deeply disappointed that he has not shown up to work on
behalf of the American people and lead on this critical endeavor.''
Bright has become the first high-level federal whistleblower to
publicly allege that the Trump administration has responded to the
COVID-19 crisis by unduly pressuring health officials, and putting
politics and profit ahead of science. Bright, the government's top
coronavirus vaccine developer, had spent a decade at BARDA, a small but
powerful agency within the Department of Health and Human Services
(HHS), whose mandate is to partner with private companies to help
accelerate the development of vaccines, drugs, and diagnostics.
According to Bright's complaint, BARDA manages almost $50 billion worth
of contracts and acquisitions, on an annual budget of just over $1.5
billion. He was named director in 2016.
On April 22, after HHS reassigned him to a smaller role at the National
Institutes of Health, Bright alleged in a fiery statement that he had
been sidelined because he ``resisted efforts to fund potentially
dangerous drugs promoted by those with political connections.'' One of
the drugs Bright identified in his statement was the malaria medication
hydroxychloroquine, which President Trump had promoted extensively as a
``game changer.'' Bright said he had ``rightly resisted efforts to
provide an unproven drug on demand to the American public.''
His original statement prompted an immediate call for investigations.
Rep. Frank Pallone Jr. (D-N.J.), chairman of the House Energy and
Commerce Committee, asked the HHS inspector general to probe Bright's
departure, and Rep. Anna G. Eshoo (D-CA.) announced that her
subcommittee on health would hold congressional hearings.
Today's complaint goes much further, enumerating a series of instances
in which politics encroached on science. According to the complaint,
Bright's superiors at the Department of Health and Human Services began
pressuring him to ``ignore expert recommendations and instead to award
lucrative contracts based on political connections and cronyism,''
starting around the spring of 2017. Bright says he ``repeatedly
clashed'' with his boss, Dr. Robert Kadlec, the assistant secretary for
preparedness and response, over the ``outsized role'' played by
Kadlec's friend John Clerici, a pharmaceutical consultant. That year
Clerici tried to get Bright to renew a contract with one of his
clients, Aeolus Pharmaceuticals, that was set to expire. ``In
attempting to justify the extension of this failed contract,'' Bright
says in his complaint, ``Mr. Clerici emphasized that Aeolus's Chief
Executive Officer was a `wildcard' and a friend of Jared Kushner,
President Trump's son-in-law and a Senior Advisor to the President.''
In a statement to The New York Times, Clerici said, ``I unequivocally
deny all of the allegations lodged by Dr. Bright and his lawyers.''
Tensions escalated over the course of the next year, the complaint
alleges, as Bright objected repeatedly to Kadlec's efforts to award
multimillion-dollar contracts to Clerici clients. Last fall Bright
``rejected pressure by Dr. Kadlec to invest millions of dollars in
EIDD-2801, a drug developed at Emory University by a longtime friend of
Dr. Kadlec. EIDD-2081 was presented as a `miracle cure' for influenza,
Ebola, and nearly every other virus, even though the developer had not
yet conducted clinical trials and no data had been compiled to
demonstrate either the efficacy or safety of the drug in humans.'' That
incident, the complaint says, further strained Bright's relationship
with Kadlec, setting the scene for their eventual rupture over COVID-
19. ``The fact that Dr. Kadlec and his staff repeatedly made decisions
to benefit those like Mr. Clerici and his clients, but which were not
in the best interest of the health or safety of Americans, continued to
be of tremendous concern to Dr. Bright,'' the complaint states.
The COVID-19 crisis only magnified the brewing conflict between
scientific safeguards and political expediency. In a January 23
meeting, Bright demanded urgent access to funding, personnel, and
clinical specimens necessary to develop lifesaving medicines for use in
a possible pandemic. He was met with reassurances from HHS brass that
the virus's spread was under control, according to the complaint. Also
in January, Mike Bowen, the co-owner of a leading mask manufacturer
named Prestige Ameritech, offered to scale up production of N95 masks.
``U.S. mask supply is at imminent risk,'' Bowen told Bright, according
to the complaint. Bowen reached out again and again in the coming days,
but Bright was unable to get Kadlec and HHS to take the threat
seriously, the complaint states, leading Bowen to write to Bright,
saying, ``Rick, I think we're in deep shit.''
Bright's allegations, and his refusal to accept his demotion quietly,
come as the Trump administration continues to muzzle scientists and
remove government watchdogs. On Friday, House Democrats said that the
White House had blocked the government's top infectious disease expert,
Dr. Anthony Fauci, from testifying at an upcoming appropriations panel
hearing. That same day Trump nominated a new Health and Human Services
inspector general, effectively replacing the acting official who had
issued a report in early April confirming that hospitals around the
country were experiencing widespread shortages of critical medical
supplies and protective equipment. The administration had denied that
such shortages existed.
The crisis at BARDA came to a boiling point after top agency health
officials found themselves under immense pressure to fulfill a vision
that Trump had outlined from the White House podium: to build a
stockpile of repurposed malaria drugs, hydroxychloroquine and
chloroquine, that he claimed had ``very, very encouraging early
results.''
There was scant evidence of the drug's utility--and plenty of questions
about its safety as a treatment for COVID-19. Chloroquine drugs, which
are used to treat malaria as well as autoimmune conditions such as
lupus, can have serious side effects, including heart arrhythmias. One
infectious disease doctor described hydroxychloroquine as a ``zombie
drug,'' advanced as a possible treatment for acute respiratory distress
in various outbreaks, including the H5N1 and H7N9 strains of avian flu,
with disappointing results. ``It's back every seven years.''
It is unclear what, exactly, drew Trump administration officials to
double down on hydroxychloroquine as a potential game-changing cure. On
March 13, a Google Doc on the use of chloroquine drugs, which had been
cobbled together by a cryptocurrency investor and a New York City
lawyer, drew the attention of billionaire inventor Elon Musk, who
tweeted about it on March 16.
By March 17, according to documents obtained by Vanity Fair, officials
within HHS were already working to corral donations of the drug, though
they seemed to know it was unlikely to amount to a miracle cure. ``Not
a blockbuster drug for this fight, but a good drug'' is how Joe Hamel,
the manager of strategic innovation and emerging technology at the
Assistant Secretary of Preparedness and Response (ASPR), a division
within HHS, described chloroquine treatments in an email to colleagues.
The next day a health scientist at BARDA noted to colleagues that the
guidance from two HHS working groups was to ``wait for clinical data on
the numerous clinical trials that are ongoing before making
recommendations on the use of chloroquine for COVID-19. Currently,
there is no data available to support that chloroquine provides
clinical benefit in the treatment or prevention of COVID-19.''
But Trump did not wait. On March 19, he first touted the drug at a
White House press conference, setting off a crisis that ricocheted from
the Food and Drug Administration (FDA) to HHS to BARDA, as staff looked
to circumvent safeguards and load up the Strategic National Stockpile
with millions of doses, procured from far-flung manufacturing plants
around the globe. (The Strategic National Stockpile is a cache of
equipment and supplies managed by HHS that can be accessed in the event
of medical emergencies.)
This left Dr. Bright, and other top administration health officials,
scrambling for answers to urgent questions about the quality, safety,
and efficacy of the drugs. The debate played out inside contentious
White House coronavirus task force meetings and a flurry of emails, as
documents obtained by Vanity Fair reveal.
According to Dr. H. Clifford Lane, deputy director for clinical
research and special projects at the NIH's National Institute of
Allergy and Infectious Diseases (NIAID), the administration proposed
that the NIH launch a massive study involving as many as tens of
thousands of patients. It was an idea that the NIAID flatly rejected.
``We were very keen to do some studies, to figure out what effect the
drug does have,'' Lane says, ``but in the traditional way we do it''--
meaning via smaller-scale studies on hospitalized patients who could be
closely monitored and evaluated.
Nonetheless, on or around March 23, administration officials devised a
plan for Bright's agency, BARDA, to sponsor a new experimental drug
study, under which the chloroquine drugs could be widely disseminated.
The scheme set off a furious round of debate within HHS, as BARDA
officials pushed back, concerned that broad use of the drug could pose
a clinical danger to the American public.
By late March, health officials across multiple agencies had settled on
an alternate plan, which they viewed as safer for patients. On March
28, the FDA issued an emergency use authorization (EUA) to allow
chloroquine drugs from the Strategic National Stockpile to be
administered to hospitalized COVID-19 patients who could not access
clinical trials. As Bright said in a statement on his firing, ``I
insisted that these drugs be provided only to hospitalized patients
with confirmed COVID-19 while under the supervision of a physician.''
But top officials appear to have ignored the restriction that Bright
fought to insert into the FDA's emergency rule. As Trump continued to
expound on the benefits of hydroxychloroquine from the podium, they
worked behind the scenes to move thousands of doses from the stockpile
into the nation's retail pharmacies, where patients could access the
drug with a simple doctor's prescription. In part, this was intended to
assist non-COVID-19 patients struggling with shortages prompted by the
president's promotion of the drug, but there was also discussion of
``off-label'' prescriptions for treatment of the novel coronavirus.
On April 5, Navy Rear Admiral John Polowczyk, who leads a supply-chain
task force at FEMA, spelled out the distribution plan in an email to
top administration colleagues: ``Distro to Hospitals and retail
pharmacies and geography: NYC area--100k to hospitals, 150k to retail
Detroit--50k to hospitals, 100k to retail Chicago--50k to hospitals,
NO--20k hospitals--50k retail Total hospitals--220k hospitals, 400k
retail. Total 620k first shipments.''
This resulted in a query from an official within ASPR's Strategic
National Stockpile division: ``All, just wanted to assure everyone is
aware that the EUA,'' the FDA's emergency rule, ``for
hydroxychloroquine and chloroquine appears to limit use to the
treatment of hospitalized patients.'' A FEMA spokesperson referred
questions about the distribution plan described by Polowczyk to HHS and
the FDA.
But with Trump cheerleading wide use of the drug, his top appointees
appeared uninterested in the more restrictive fine print. Only after a
study of veterans with COVID-19 found that patients treated with
chloroquine died at twice the rate of those who didn't get the drug did
Trump scale back his cheerleading. By then Rick Bright had fought all
he could within the system to limit the drug's use. Within a week of
the study's publication, Bright had been pushed out of BARDA and
decided to blow the whistle.
______
From Vanity Fair, May 14, 2020
``He Was Fired for Being Right'': Rick Bright Warns Congress ``Time Is
Running Out'' to Contain Coronavirus
By Katherine Eban
As Trump rage-tweeted and representatives bickered amid bottles
of hand sanitizer, the ousted head of BARDA described trying to
mount an effective federal response to COVID-19--and paying a
heavy price.
The United States could be facing ``the darkest winter in modern
history,'' according to testimony this morning by Dr. Rick A. Bright,
the federal government's top vaccine developer turned whistleblower.
Speaking in steady, measured tones at a widely anticipated hearing
before the House Energy and Commerce Committee's Subcommittee on
Health, Bright warned that, without a ``standard, centralized,
coordinated plan to take our nation through this response'' to the
COVID-19 crisis, the federal government risked a resurgence of the
virus that could ``be devastating.''
``The window is closing to address this pandemic,'' Bright testified.
``Time is running out because the virus is still spreading
everywhere.''
The hearing marked the first time that a top government scientist has
testified candidly, and in unstinting detail, about the shortcomings of
a federal response that, as Bright described it, has been dominated by
politics, cronyism, and falsehoods, rather than science.
Members of Congress, wearing latex gloves and masks and seated amid
containers of Clorox wipes and hand sanitizers, sparred over the claims
made by Dr. Bright, who remained calm throughout the more-than-three-
hour hearing. Wearing a gray suit and crisp red tie, he testified that
the administration needed to ``be truthful with the American people''
about the ``real risk and dire consequence of this virus.''
Asked by Rep. Anna Eshoo (D-CA), the committee chairwoman, to say
whether the Trump administration's response to the pandemic had been a
success or a failure, Bright paused, then said, ``I believe we could
have done better. . . . There are critical steps we did not take in
time.'' However, there was no mistaking his view of the
administration's failures. As he testified later in the hearing, ``We
don't have a single point of leadership right now . . . and we don't
have a master plan for this response.''
His stark testimony came in a week when Dr. Anthony Fauci, alongside
other top health officials, testified before a Senate panel and warned
that reopening the economy too soon could lead to a resurgence ``that
you may not be able to control.''
On Tuesday the U.S. Office of Special Counsel stated in a letter to
Bright's lawyers that it had found a ``substantial likelihood of
wrongdoing'' by the Department of Health and Human Services in removing
Bright as head of the Biomedical Advanced Research and Development
Authority, a small but powerful agency within HHS, whose mandate is to
partner with private companies to help accelerate the development of
vaccines, drugs, and diagnostics. BARDA manages almost $50 billion
worth of contracts and acquisitions, on an annual budget of just over
$1.5 billion. Bright was named director in 2016.
The OSC has given the HHS secretary, Alex Azar, 60 days to conduct an
investigation into Bright's removal and report his findings. On April
22, after HHS reassigned him to a smaller role at the National
Institutes of Health, Bright alleged in a fiery statement that he had
been sidelined because he ``resisted efforts to fund potentially
dangerous drugs promoted by those with political connections.'' Chief
among those drugs was the malaria medication hydroxychloroquine, which
President Trump had promoted extensively as a ``game changer.''
On May 5, Rick Bright filed a 63-page whistleblower complaint with the
OSC. That unleashed a furious public relations battle within Health and
Human Services to contain the fallout from his allegations, and to
paint Bright as a mediocre leader of BARDA who served as an obstacle to
innovation, rather than as a steward of it.
In a three-page statement issued this morning, HHS said it ``strongly
disagrees'' with Dr. Bright's allegations, and accused him of working
with ``partisan attorneys who are politicizing the response to COVID-
19. His whistleblower complaint is filled with one-sided arguments and
misinformation.'' The statement also accused him of continuing to draw
a government salary and failing to take up the new position offered to
him. ``Rick Bright has chosen to stay home,'' the statement said.
In a statement, Dr. Bright's lawyers countered HHS' claims, saying that
Dr. Bright ``never refused'' to report to his new post at the National
Institutes of Health and planned to do so next week, unless HHS
secretary Alex Azar ``grants a stay of his reassignment,'' as requested
by the Office of Special Counsel. They also added, ``Rather than
investigating Dr. Bright's serious allegations of wrongdoing . . . HHS
leadership has decided to lodge baseless allegations against him in an
effort to distract attention'' from essential issues that should be
addressed to save lives.
This morning, in anticipation of today's hearing, President Trump
tweeted, ``I don't know the so-called Whistleblower Rick Bright, never
met him or even heard of him, but to me he is a disgruntled employee,
not liked or respected by people I spoke to and who, with his attitude,
should no longer be working for our government!''
In her opening statement, Rep. Eshoo said that Bright had filed ``one
of the most specific and troubling whistleblower complaints I have ever
seen,'' and stated, ``He was fired for being right.''
Rep. Michael Burgess (R-TX) accused Rep. Eshoo of trampling on minority
rights and of ``procedural fouls'' in setting up the hearing.
Over the course of three hours, Bright testified that his urgent
warnings to top Health and Human Services officials from January
through March about a critical shortage of needed supplies--from
syringes and swabs to personal protective equipment for health care
workers--led to his being cut out of key, high-level meetings. ``I was
told that my urgings were causing a commotion, and I was removed from
those meetings,'' he said.
But he said it was his opposition to a Trump administration plan to
promote broad access to an unproven and potentially dangerous drug,
chloroquine, for use in treating COVID-19, that led to his removal from
his post at BARDA.
The battle over hydroxychloroquine within the administration began in
mid-March, as President Trump hailed the malaria drug as a ``game
changer'' for COVID-19, a claim that sparked worldwide shortages of the
drug and a frantic effort inside the administration to build a
stockpile of the medicine and find a way to disseminate it widely.
Regulations and long-relied-upon safeguards stood in the way, as career
health officials at HHS and the FDA faced tremendous pressure to help
implement the Trump administration's plan. Top officials clashed over a
push for the FDA to approve a donation from Bayer of 3 million pills of
a chloroquine drug, Resochin, which had been made in manufacturing
plants in India and Pakistan that had never been inspected by the FDA.
At BARDA, Bright was asked to sponsor an investigational new drug
study, as a legal and organizational mechanism to disseminate the
drugs. Bright pushed back, saying that he opposed a plan that would
allow Americans wide access to the drugs without close supervision from
their doctors.
As he testified at today's hearing, it was a lack of limited clinical
data as well as concerns about the drug's known cardiac risks that made
him push for ``carefully controlled clinical studies under the close
watchful eye of a physician.''
Bright went on to say that he was removed, in part, in retaliation for
pushing back against making chloroquine drugs more widely available to
Americans, even those who might not actually be infected, outside of
more closely supervised hospital settings.
Bright testified that he had been briefly reassured when the FDA passed
an emergency rule that required chloroquine drugs in the stockpile to
be used only for hospitalized patients. But he said his ``concerns were
escalated'' once he learned that HHS leadership continued to push to
make the drugs available outside of that rule.
Expressing those concerns, he testified, was ``the straw that broke the
camel's back.''
Asked by Rep. John Sarbanes (D-MD) about what needed to be done to
improve the government's response, Bright said, ``We need to unleash
the voices of the scientists in our public health systems in the United
States so they can be heard.''
______
From Vanity Fair, May 27, 2020
``I'll Send You the Contact'': Documents Expose FDA Commissioner's
Personal Interventions on Behalf of Trump's Favorite Chloroquine Doctor
By Katherine Eban
Looking past concerns about the drug's safety, not to mention
his own agency's recommendations, Stephen Hahn took time during
the COVID-19 crisis to lend a helping hand to Dr. Vladimir
Zelenko, a hero among fringe Trumpworld figures.
It was Sunday, April 5, and Dr. Stephen Hahn, the commissioner of the
U.S. Food and Drug Administration, faced a world of problems. Less than
two months after the first American death from COVID-19, the U.S.
health care system was under siege, with more than 300,000 confirmed
cases of the new disease-the most of any nation in the world-and almost
10,000 deaths. Hahn was under fire over faulty test kits the FDA had
approved, and angry members of Congress were demanding that his agency
prevent the hoarding of an old malaria drug called hydroxychloroquine,
which President Trump was hyping without evidence as a miracle cure.
Nevertheless, Dr. Hahn found time that afternoon to carry out an
unusual mission. He contacted an obscure family practitioner in Monroe,
New York, with whom he had never before been in touch, to ask if the
doctor had ``time for a quick call.'' Once on the phone with Dr.
Vladimir Zelenko, Hahn posed a question: How could he--the commissioner
of a federal health agency with a $5.7-billion annual budget and the
responsibility to safeguard the nation's drugs, medical devices, and
food supply--be of help?
Zelenko was a 46-year-old ``simple country doctor,'' as he described
himself to The New York Times, who claimed to have witnessed positive
results after prescribing a cocktail of drugs including
hydroxychloroquine to patients in the Orthodox Jewish community of
Kiryas Joel, New York. His message aligned perfectly with the
pronouncements Trump had been making from the White House podium: that
hydroxychloroquine, when used early and liberally, was a game-changing
treatment for COVID-19. That, in turn, had earned Zelenko a growing
platform on right-wing media.
Two days after that first phone call, in a series of text messages
obtained by Vanity Fair, Zelenko returned to Hahn for help setting up a
clinical trial of some 750 outpatients at St. Francis Hospital in
Roslyn, New York. ``The Catholic Health System (St. Francis Hospital)/
Dr. Zelenko COVID-19 trial is ready to go,'' Zelenko wrote to Hahn,
copying one of the hospital's doctors involved in the trial. ``We need
ASAP 1. Hydroxychloroquine 200mg. 10,000 pills 2. Azithromycin 500mg
5,000 pills 3. Zinc sulfate 220 mg 5,000 pills. This treatment will be
deployed in outpatient primary care.''
Hahn responded, ``Not sure what the ask of FDA is.'' To which Zelenko
replied, ``We need the medication to run the study.'' Hahn then asked,
``Do you have IRB approval?'' This referred to an institutional review
board that hospitals use to oversee clinical trials and research. The
doctor answered, ``Hopefully this week.''
``Congratulations,'' Hahn offered. ``Really well done.'' He then
advised the doctor to reach out to the Federal Emergency Management
Agency (FEMA) to obtain hydroxychloroquine from the Strategic National
Stockpile, a federal cache of emergency equipment and supplies managed
by the Department of Health and Human Services (HHS). When the doctor
expressed uncertainty over how to do that, Hahn offered, ``I'll send
you the contact.''
Federal agency chiefs normally focus on high-level problems and
solutions, delegating any ground-level efforts through the chain of
command. Assisting with a lone clinical trial hardly seemed worthy of
the commissioner's time. More troubling, perhaps, was the question of
why Hahn-whose agency two weeks earlier had established restrictions on
the use of certain chloroquine drugs in the national stockpile to
hospitalized patients, as a way to avert potential risk to patients-
appeared to be bending over backward to assist a doctor who, in line
with President Trump, was advocating unfettered use of the drug.
Hahn, 60, a radiation oncologist who previously served as chief medical
executive of the University of Texas MD Anderson Cancer Center, has
repeatedly insisted that he has felt no political pressure while
carrying out his agency's pandemic response. ``I can assure you 100%
that the President has never pressured me to make a decision regarding
any regulatory aspect of the FDA's work,'' he recently told The
Washington Post.
But Hahn's previously unreported intervention on behalf of Zelenko--who
was both promoting a COVID-19 treatment that the government's top
medical experts had warned against and seeking drugs that the FDA's own
rules restricted--calls his claims of independence into doubt. ``I am
pretty appreciative to Stephen Hahn,'' Zelenko told Vanity Fair in an
interview. ``I think he helped in this process.''
The FDA declined Vanity Fair's request to interview Dr. Hahn. FDA
spokesman Michael Felberbaum instead provided a statement: ``Throughout
the pandemic, the FDA has heard from people across all levels of
government, academia, industry, and the public interested in providing
or seeking assistance or information from the agency. In that vein, Dr.
Hahn and others at the FDA have connected with a variety of entities on
ways to combat COVID-19 and put them in touch with the appropriate
people for follow-up, including agency staff who assess the science and
the data regarding potential prevention and treatment options.''
But experienced observers of the FDA find Hahn's conduct troubling.
``The primary import of his action is to add the agency's scientific
weight to these unproven claims put forth by Trump and Zelenko,'' said
Dr. Peter Lurie, president of the Center for Science in the Public
Interest and a former associate FDA commissioner. ``It feels like so
much about Trump and this epidemic. You say one thing and you encourage
something else. `We're providing it under restricted conditions, but--
wink-wink--you have little to fear in providing it in situations beyond
that.' ''
In the weeks following their first phone call, as Hahn continued to
assist Zelenko, the commissioner found himself a party to Zelenko's
growing political entanglements. By April 26, Hahn had been copied on
an email alongside Trump chief of staff Mark Meadows and former New
York City mayor turned Trump lawyer Rudy Giuliani. The email was sent
to Zelenko by Jerome Corsi, a right-wing conspiracy theorist who had
been investigated as part of the Mueller probe. In it, Corsi--who is
involved in a for-profit telemedicine platform where doctors prescribe
hydroxychloroquine--expressed his anxieties about the ``heavy legal
scrutiny'' facing the drug.
A growing body of clinical studies indicates that hydroxychloroquine is
ineffective in treating COVID-19 and may actually increase mortality.
The World Health Organization, the National Institutes of Health, the
FDA, and the pharmaceutical company Sanofi, which sells
hydroxychloroquine under the brand name Plaquenil, have all issued
guidelines cautioning against the kind of early, prophylactic use of
the drug that Trump has hyped and Zelenko advocates. On Friday a
retrospective study of 96,000 COVID-19 patients on six continents,
published in the medical journal The Lancet, found that hospitalized
patients treated with hydroxychloroquine and an antibiotic--part of the
drug combination Zelenko has plugged--were 45% likelier to die.
Zelenko claims that clinical trials of hydroxychloroquine with poor
outcomes are part of a political conspiracy from a ``corrupted''
medical establishment, and are ``clearly designed to fail and to
substantiate a false narrative.'' Last week Trump claimed, honestly or
not, that he himself had been taking hydroxychloroquine.
President Trump began touting hydroxychloroquine from the White House
podium on March 19, claiming there were ``very, very encouraging early
results.'' Dr. Hahn, who was also present, offered a more measured
assessment, stating that ``a large, pragmatic clinical trial'' could
help answer the question of the drug's effectiveness.
His caution reflected the doubts of top federal clinicians and
scientists. In early March, the director of the influenza and emerging
infectious diseases division within HHS's Biomedical Advanced Research
and Development Authority (BARDA) wrote to a colleague that the drug
had ``not panned out to clinical benefit,'' according to an internal
email obtained by Vanity Fair. Others flagged the drug's well-
established risk of cardiac arrhythmias.
Nonetheless, the White House was moving ahead with a plan to promote
the drug and launch a vast clinical trial. On March 19, Trump alluded
to that plan when he declared that the government would be ``quickly
studying this drug . . . as it's given out to large groups of people,
perhaps in New York and other places.''
Two days after that press conference, Dr. Zelenko uploaded a video to
YouTube in which he addressed the president directly. Zelenko claimed
that he had used hydroxychloroquine early on hundreds of patients, not
a single one of whom had been hospitalized. He even advocated treating
patients with his regimen of hydroxychloroquine, zinc, and azithromycin
before confirming a diagnosis, as he believed clinical intuition was
more important than a positive test. In the video, he told Trump, ``I
am suggesting that you please advise the country that they should be
taking this medication in an outpatient setting.'' He added, ``I
personally love you.''
The day after Zelenko uploaded the video, Trump's chief of staff, Mark
Meadows, contacted him to ask for his patient data. Meadows did not
respond to an email seeking comment.
Two days later, on March 24, the federal government's top interagency
medical countermeasures group recommended that chloroquine-based COVID-
19 treatments should be studied only in controlled, hospital-based
clinical trials, as their safety and efficacy were ``not supported by
data from reliable clinical trials'' and carried ``potential risks.''
On March 28, the FDA issued its EUA allowing chloroquine drugs from the
Strategic National Stockpile to be administered only to hospitalized
COVID-19 patients who could not access clinical trials.
Remarkably, the recommendation did nothing to curb the Trump
administration's ambition to ``flood New York and New Jersey'' with
treatment courses obtainable even at drugstores, as spelled out in a
series of internal emails first obtained by Vanity Fair. Inside the
federal government, career officials had been pushing back for weeks
against a White House plan they considered dangerous, but by the
evening of Saturday, April 4, it was clear that Hahn had fallen in line
with the administration. ``Hahn asked to distribute to hospitals and
the drug stores,'' FEMA administrator Peter Gaynor wrote to colleagues
in an internal email.
It was the following day when Hahn first reached out to Zelenko.
Hahn's services on behalf of Zelenko included a personal introduction
to the director of the National Library of Medicine, a division of the
National Institutes of Health that oversees clinicaltrials.gov, the
website where any legitimate clinical trial must be listed in order to
publish study results in a peer-reviewed journal. In a statement, a
spokesperson for the National Library of Medicine said that Zelenko had
contacted the director, Patricia Flatley Brennan, and ``shared lessons
learned from treating patients that he thought would be valuable to
others. Dr. Brennan suggested that he write up a case report for
publication.''
As Zelenko worked with St. Francis Hospital to hammer out the details
of a clinical trial that would test his preferred cocktail of
hydroxychloroquine, zinc, and one of two antibiotics--azithromycin or
doxycycline--on COVID-19 outpatients, Hahn intervened. He shared the
contact information for a FEMA official with hospital investigators, so
St. Francis could obtain hydroxychloroquine directly from the Strategic
National Stockpile.
``Stephen Hahn helped us get medication,'' Zelenko said. ``We were
having trouble-he advised us who to talk to in FEMA.''
One current HHS official said of Hahn's intervention to help a single
hospital get stockpiled drugs, ``That is way outside what one would
consider normal for a commissioner to do. . . . I have never heard of
anyone at FDA doing anything like that.''
Dr. Avni Thakore, a cardiologist at St. Francis Hospital and the
study's principal investigator, told Vanity Fair that the study of
hydroxychloroquine in COVID-19 patients seemed like a natural fit for
the hospital, which has a national reputation in cardiac care. ``It is
a safety protocol,'' she said of the study, which plans to remotely
monitor the heart rhythms of trial enrollees by providing them with
mobile electrocardiogram devices. She also emphasized that the trial
was inspired not only by Zelenko's clinical observations, but also by
other sources: ``early results from some small studies, and
observational reports, doctors sharing their observations, all of that
combined.''
As Zelenko's celebrity grew, he became a fixture on podcasts hosted by
Jerome Corsi and, through him, Rudy Giuliani. Before long, Corsi
himself would contact Hahn.
Corsi, who obtained a Ph.D. in political science from Harvard in 1972,
is the best-selling author of books questioning John Kerry's war record
and Barack Obama's citizenship. He briefly served as the Washington,
D.C., bureau chief of Infowars, the conspiracy website run by Sandy
Hook truther Alex Jones, though he later sued Jones for defamation. He
became a target of the Mueller investigation as a result of his
contacts with Roger Stone and his alleged foreknowledge of WikiLeaks
document dumps. The Mueller team eventually declined to press charges,
and Corsi sued Stone for defamation.
In late April, Corsi was planning a promotional campaign for a
telemedicine platform on his website, corsination.com, that enabled
doctors to conduct video consultations with patients and directly
prescribe them hydroxychloroquine and other drugs. According to Corsi's
marketing materials, Dr. Zelenko would serve as the program's medical
director.
But on April 20, Corsi accidentally emailed those marketing plans not
to Zelenko but to Aaron Zelinsky, a U.S. prosecutor who'd worked on the
Mueller investigation--a mishap first reported by The Washington Post.
Zelinsky, now spearheading a COVID-19 fraud-fighting task force out of
the Maryland U.S. Attorney's Office, scrutinized the materials and
zeroed in on Corsi's claim that ``Zelenko has an FDA approved
randomized test of HCQ under-way.'' No such trial was listed on
clinicaltrials.gov, raising the prospect of fraud.
Zelenko said he had mistakenly made the claim to a group of physicians
in the telemedicine program, having confused approval from the
hospital's institutional review board with FDA approval. ``I kind of
misspoke,'' he told Vanity Fair. He also said he had agreed to serve as
an unpaid medical adviser, not a paid director, for Corsi's
telemedicine program.
When Zelinsky inquired about the erroneous claim, Corsi and Zelenko
panicked. Zelenko appealed for help to a doctor at St. Francis Hospital
who was one of the study's principal investigators. The doctor wrote a
``To Whom It May Concern'' letter on April 22, stating: ``Dr. Zelenko
not only embraced the idea of a controlled trial, but has been
instrumental in helping us develop the trial to the point where, in
less than two weeks, we are ready to initiate it.''
On Sunday, April 26, Corsi expressed his concerns in an email to
Zelenko that Vanity Fair obtained. Corsi cc'd the message to a large
and unlikely group: Dr. Hahn; Mark Meadows (via his personal email);
Giuliani; a volunteer paramedic director in Orange County; a rabbi; the
lawyers for Corsi and Zelenko; and two of the doctors involved in the
fledgling St. Francis clinical trial. (Reached by Vanity Fair, Corsi
declined to comment on his decision to copy Hahn and the others on the
email.)
Corsi noted in the email that the ``HCQ issue is under heavy legal
scrutiny.'' Taking Zelenko to task for making inflated scientific
claims about his protocol, Corsi wrote, ``I am concerned that you have
to speak very precisely.'' He went on to stress how scrupulous he had
been about following the letter of the law in setting up the TeleMD
program: ``under advice by legal counsel, emphasizing that we are
marketing a teleconference with an MD who can legally write
prescriptions for HCQ.''
The email had the quality of skywriting, as if it were intended to
telegraph to the email recipients, and to any federal prosecutor,
Corsi's commitment to scientific legitimacy. It is not clear what
impact the email had. But one recipient of the email described it as a
``CYA'' effort.
The doctors at St. Francis Hospital, who were copied on the email,
submitted their clinical trial design to clinicaltrials.gov that same
day, though it is unclear whether they did so before or after receiving
Corsi's email. Within six days the trial was posted on the website,
complete with what appeared to be an imprimatur of legitimacy, a
National Clinical Trial number.
In an interview, Corsi was keen to assert his view that the posting of
the clinical trial ``makes legitimate what Dr. Zelenko was saying . . .
on a government website, a government-recognized clinical trial.''
______
From The New England Journal of Medicine, June 11, 2020
Drug Evaluation During the COVID-19 Pandemic
By Benjamin N. Rome, M.D., and Jerry Avorn, M.D.
The search for a treatment for COVID-19 is testing our country's
ability to quickly develop, test, and deploy medications, presenting
both opportunities and challenges to our drug-assessment apparatus.
Several aspects of the U.S. response raise serious concerns,
highlighting how the processes for evaluating and approving drugs can
go awry during a public health crisis.
The global pandemic has put pressure on clinicians and the Food and
Drug Administration (FDA) to act swiftly to make medications available
to patients. When very limited observational and anecdotal evidence
raised the possibility that the antimalarial drugs chloroquine and
hydroxychloroquine may have activity against SARS-CoV-2, President
Donald Trump quickly began celebrating the promise of their widespread
use, stating on national television that he had a ``hunch'' that such
therapy was effective and that the drugs could be a ``game changer'' in
addressing the pandemic. More recently, he openly encouraged patients
to take the drugs and suggested he might do so himself, despite having
tested negative for the virus.
After Trump's initial assertions, the FDA--still facing criticism that
its delays in approving testing kits for the virus hindered prevention
efforts--issued an Emergency Use Authorization (EUA) on March 28 that
allowed for use of the drugs to treat patients with COVID-19. Although
the EUA's scope was limited to permitting distribution of chloroquine
and hydroxychloroquine from a federal stockpile, its issuance was
widely yet incorrectly reported by Trump and others as meaning that the
FDA had approved the drugs for this indication. The Centers for Disease
Control and Prevention (CDC) went so far as to publish doses of
chloroquine and hydroxychloroquine for use in patients with COVID-19,
though it later removed them from its website. Meanwhile, serious
concerns have been raised about the adequacy of the available studies
of these drugs.\1\
---------------------------------------------------------------------------
\1\ Kim AHJ, Sparks JA, Liew JW, et al. ``A rush to judgment? Rapid
reporting and dissemination of results and its consequences regarding
the use of hydroxychloroquine for COVID-19.'' Ann Intern Med 2020 March
30 (Epub ahead of print).
These developments represent fundamental threats to the U.S. drug-
evaluation process. Advocating that the FDA should quickly approve
drugs without randomized trial data runs counter to the idea of
evidence-based medicine and risks further undermining the public's
understanding of and faith in the drug-review process, which requires
``substantial evidence'' of safety and efficacy based on adequate and
well-controlled trials before a drug can be marketed. Though this
unprecedented emergency provides a compelling reason for the FDA to act
as efficiently as possible, the agency and the medical community can
still maintain the highest scientific standards while acting
---------------------------------------------------------------------------
expeditiously.
The new EUA represents only the second time the FDA has ever used
emergency authority to permit use of a medication for an unapproved
indication. During the 2009-2010 ``swine flu'' outbreak, the agency
allowed use of peramivir--an investigational intravenous neuraminidase
inhibitor--in severely ill hospitalized patients with H1N1 influenza.
Under that EUA, peramivir was administered to some 1,200 to 1,500
patients, with no rigorous tracking of which patients received it or
collection of outcome data.\2\ Ultimately, a randomized, controlled
trial failed to show any benefit of peramivir as compared with placebo
in severely ill hospitalized patients with influenza; the drug was
approved in 2014 with an indication only for uncomplicated influenza
and not for use in severely ill hospitalized patients.
---------------------------------------------------------------------------
\2\ Pavia AT. ``Editorial commentary: what did we learn from the
emergency use authorization of peramivir in 2009?'' Clin Infect Dis
2012;55:16-18.
Hydroxychloroquine is already marketed for other conditions, so
physicians were allowed to prescribe it off-label to patients with
COVID-19 even before the EUA or CDC dose recommendations were issued.
In addition, for investigational drugs that are not yet marketed,
providers can request ``expanded access'' for severely ill patients who
lack alternative treatment options and are not eligible for clinical
trials--permission the FDA nearly always grants. This option has
already been used for remdesivir, an investigational antiviral drug
whose manufacturer has provided it to more than a thousand patients
---------------------------------------------------------------------------
with COVID-19 outside clinical trials.
Even before the pandemic, many conservative and libertarian politicians
and advocacy groups supported expanding patients' ``right to try''
unapproved experimental drugs. This position has intensified a commonly
held but spurious belief that slow processes and overly onerous
requirements by the FDA prevent patients from accessing many clinically
useful drugs. In fact, the FDA presides over one of the fastest drug
approval processes in the world, with a majority of drugs gaining
approval in the United States before they are approved in Europe or
Canada.\3\ The FDA approves the overwhelming majority of drug
applications it receives, and over the past several decades it has been
approving more drugs on the basis of limited evidence, such as fewer
clinical trials per drug, trials with suboptimal design, and trials
using surrogate measures--which may or may not predict actual clinical
benefit--as end points.\4\
---------------------------------------------------------------------------
\3\ Downing NS, Aminawung JA, Shah ND, Braunstein JB, Krumholz HM,
Ross JS. ``Regulatory review of novel therapeutics--comparison of three
regulatory agencies.'' N Engl J Med 2012;366:2284-2293.
\4\ Darrow JJ, Avorn J, Kesselheim AS. ``FDA approval and
regulation of pharmaceuticals, 1983-2018.'' JAMA 2020;323:164-176.
Widening access to experimental therapies that have not been fully
evaluated is likely to have several unintended consequences. First,
benefits to patients are unknown and may be negligible (as in the case
of peramivir), in which case expanded access undermines physicians'
attempts to practice evidence-based medicine. Second, medications such
as hydroxychloroquine have well-documented risks; subjecting patients
to these risks would be unjustifiable in the absence of meaningful
clinical benefit. Third, distributing unproven drugs under expanded
access or EUAs may detract from the resources needed to carry out
clinical trials, including the patient base and necessary funds. Since
key outcome data are often not collected outside a trial, this
redirection of resources will hamper our ability to quickly determine
---------------------------------------------------------------------------
whether these drugs are truly safe and effective.
Finally, with drugs that are already marketed for other conditions,
widespread off-label use can limit access for patients who need them
for their established use. After Trump promoted hydroxychloroquine,
prescribing of the drug increased rapidly, leading to substantial
shortages affecting patients taking it for rheumatoid arthritis or
lupus--indications for which it has been proven effective.
During a pandemic that is causing morbidity and mortality to grow
exponentially, there is an understandable temptation to make unproven
therapies widely available and not wait for rigorous clinical trial
data. However, well-conducted randomized, controlled trials in these
acutely ill patients can actually be carried out quite rapidly.
Thousands of new patients with COVID-19 present for care each day, and
many can be (and are) quickly enrolled in pragmatic clinical trials.
The most relevant clinical outcomes for evaluating these drugs--
including death, hospitalization, number of days spent in intensive
care, and need for a ventilator--are readily assessed and available
within days or weeks.
At least 25 drugs are under investigation for use in COVID-19, with 10
in active clinical trials. The first published major randomized,
controlled trial of an antiviral drug combination (lopinavir-ritonavir)
began enrolling patients in China just a week after the virus had been
identified.\5\ Contrary to expectations, its results were negative,
providing important clinical guidance.
---------------------------------------------------------------------------
\5\ Cao B, Wang Y, Wen D, et al. ``A trial of lopinavir-ritonavir
in adults hospitalized with severe COVID-19.'' N Engl J Med
2020;382:1787-1799.
If data emerge showing that any regimen is truly effective in treating
COVID-19, the FDA should be able to review those data and provide an
approval decision within days or weeks. The agency has already
established a Coronavirus Treatment Acceleration Program to assist
manufacturers in navigating administrative requirements and to expedite
---------------------------------------------------------------------------
the review process.
Adequate clinical trials will soon confirm or refute the usefulness of
several candidate drugs in treating COVID-19. But the weeks leading up
to provision of that evidence reveal a great deal about threats to our
approach to evaluating medications. Issues such as inadequate trial
design, overreaching public declarations, and widespread use of
unproven treatments will continue to present themselves during this
pandemic and beyond.
Rigorous premarketing evaluation of drugs' safety and effectiveness in
randomized, controlled trials remains our primary tool for protecting
the public from drugs that are ineffective, unsafe, or both. It is a
false dichotomy to suggest that we must choose between rapid deployment
of treatments and adequate scientific scrutiny. For the COVID-19
pandemic and other pressing medical challenges, the health of
individual patients and the public at large will be best served by
remaining true to our time-tested approach to clinical trial evidence
and drug evaluation, rather than cutting corners and resorting to
appealing yet risky quick fixes. The pandemic will inevitably leave
considerable morbidity, mortality, and loss in its wake. Damage to the
country's medication-assessment process--and the public's respect for
it--should not be part of its legacy.
______
Communications
----------
Association for Accessible Medicines
601 New Jersey Ave., NW, Suite 850
Washington, DC 20001
202-249-7100
[email protected]
https://accessiblemeds.org/
The Association for Accessible Medicines (AAM) is pleased to submit the
following statement for the record for the Senate Finance Committee's
hearing on ``COVID-19 and Beyond: Oversight of the FDA's Foreign
Manufacturing Inspection Process.'' As the nation's leading trade
association for the developers, manufacturers and distributors of FDA-
approved generic and biosimilar prescription medicines, AAM and our
members are committed to the secure and consistent supply of critical
medicines to improve the health of America's patients and as a critical
tool in the effort to lower prescription drug costs.
Introduction
As the Finance Committee examines the pharmaceutical supply chain, we
wish to stress three points:
The generic drug industry currently manufactures approximately
70 billion doses in the U.S.;
AAM and its members strongly support the Generic Drug User Fee
Amendments (GDUFA) program enacted in 2012 and reauthorized in 2017,
which has provided the resources for FDA to dramatically increase its
capacity to inspect facilities, both domestic and foreign, that support
an application; and
Building on today's U.S.-based production and FDA's oversight,
AAM and its members have released the ``Blueprint to Enhance the
Security of the U.S. Pharmaceutical Supply Chain'' to provide Congress
and the Administration with recommendations on how to further
strengthen the pharmaceutical supply chain and enhance the U.S.
manufacturing of essential medicines.
The COVID-19 pandemic reminds us of the incredible value offered by the
generic and biosimilar industry, the benefits of a resilient and
redundant global supply chain, and industry's daily commitment to
manufacturing safe, effective and high-quality medicines.
AAM's members have experienced substantially increased demand for
certain medicines that has far exceeded historical trends,\1\ navigated
export restrictions on active pharmaceutical ingredients (API) and
finished dose (FD) generic medicines,\2\ re-
routed the delivery of medicine as air travel was significantly
curtailed around the globe,\3\ and absorbed much of the increased costs
charged for the transportation of medical products to ensure that
America's patients are able to access critically needed medicines
during the coronavirus pandemic.\4\ In response, AAM's member companies
have stepped up to meet these challenges.\5\
---------------------------------------------------------------------------
\1\ Ellen Gabler and Michael Keller, ``Prescriptions Surged as
Trump Praised Drugs in Coronavirus Fight,'' New York Times, April 25,
2020, updated May 19, 2020.
\2\ Rajesh Roy, ``India Again Allows Export of Antimalarial Drug
Touted for Coronavirus,'' Wall Street Journal, April 7, 2020.
\3\ Ian Duncan, ``Drug Industry Warns That Cuts to Passenger
Airline Service Have Put Medical Supplies at Risk,'' Washington Post,
May 2, 2020.
\4\ AAM Survey of Biosimilar and Generic Drug Manufacturers,
``Pharmaceutical Shipping Costs Spike in Response to Global COVID-19
Pandemic,'' April 30, 2020.
\5\ AAM, ``Generics and Biosimilars Industry Supply Chain and
Response to COVID-19,'' April 10, 2020.
Implementation of the CARES Act Will Enhance FDA's Regulation of the
---------------------------------------------------------------------------
Global Supply Chain
We understand why the Finance Committee would raise questions about
recent reports that may paint a distorted picture of a global supply
chain that is overly reliant on China and other countries for API. Our
statement clarifies and provides more accurate analysis of where API
and finished dosage form (FDF) facilities are located, according to
testimony provided by FDA to Congress last year. Moreover, Congress
took important action as part of the Coronavirus Aid, Relief, and
Economic Security (CARES) Act (H.R. 748) enacted in March. The CARES
Act includes several important steps intended to help strengthen the
pharmaceutical supply chain. Specifically, the CARES Act:
Increases the transparency of the pharmaceutical supply chain by
providing FDA with additional information on potential disruptions in
the supply chain, on manufacturers' contingency plans to ensure
continued supply and on the volume of medicines manufactured (Section
3112);
Stresses the importance of air transportation in maintaining
well-functioning pharmaceutical supply chains (Section 4005);
Evaluates U.S. dependence on overseas manufacturing with a
forthcoming report from the National Academies (Section 3101); and
Strengthens the national stockpile to ensure access to drugs,
vaccines and other biological productions (Section 3102).
We believe these provisions will help answer some of the questions
raised once implemented and will serve to further inform policymakers
about the economic realities of the generic and biosimilar markets. In
this statement, we provide additional information on the role of
generics and biosimilars in improving patient health, how more
affordable treatments enhance patient access, details FDA's oversight
role and inspections process, and outline our industry's robust
commitment to quality.
Generics and Biosimilars Are Integral to Patient Health
Generic medicines play an integral role in health care and enhance
patient access to life-saving treatments. The expiration or
invalidation of patents and the resulting introduction of multiple
generic and biosimilar manufacturers competing against each other on
price result in significant savings for patients and the health care
system. Over the last 10 years, manufacturers of generic medicines have
delivered savings of nearly $2 trillion--including $293 billion in
2018--to patients and the health care system.\6\
---------------------------------------------------------------------------
\6\ AAM, ``The Case for Competition: 2019 Generic Drug and
Biosimilars Access and Savings in the U.S. Report,'' September 2019.
Biosimilar medicines represent another critical step forward in
reducing high drug prices. Biosimilars are safe, effective and more
affordable versions of costly brand biologics. By the year 2025, over
70 percent of drug approvals are expected to be biological products.\7\
Experts estimate that FDA-approved biosimilars could save more than $54
billion over the next 10 years.\8\ In doing so, biosimilars will mean
greater access to lifesaving cures for an estimated 1.2 million
patients.\9\
---------------------------------------------------------------------------
\7\ U.S. Pharmacist, ``Biosimilars: Current Approvals and Pipeline
Agents,'' October 2016.
\8\ RAND, ``Biosimilars Cost Savings in the United States,''
October 2017.
\9\ The Biosimilars Council, ``Biosimilars in the United States:
Providing More Patients Greater Access to Lifesaving Medicines,''
August 2017.
The introduction of generic and biosimilar competition significantly
reduces the price of medicine, and patients benefit from greater, more
affordable access to FDA-approved drugs. Experience shows prescription
drug prices decline by more than half the first-year generics enter the
market.\10\ Early experience with the nascent biosimilars market in the
U.S. shows that these more affordable alternatives are also providing
value and savings to patients, on average priced 40 percent lower than
their branded biologic counterparts.\11\
---------------------------------------------------------------------------
\10\ IMS Institute for Healthcare Informatics, ``Price Declines
After Branded Medicines Lose Exclusivity in the U.S.,'' January 2016.
\11\ AAM analysis of IQVIA WAC Data, December 2018.
However, one must also consider the underlying economic realities of
the generic and biosimilar markets. Prices for generic drugs are
plummeting--falling for 40 of the last 45 months--and creating a market
in which many drugs are simply and increasingly not economical to
produce.\12\ The biosimilars market is still developing with 17 of the
26 FDA-approved biosimilars launched with only a handful regularly
prescribed.\13\ Biosimilar manufacturers are increasingly looking to
provide Europe's patients with access first, rather than the U.S., due
to the barriers to competition and a policy environment that
inadequately supports their uptake and use domestically.\14\
---------------------------------------------------------------------------
\12\ Morgan Stanley, April 2020.
\13\ Biosimilars Council, ``FDA Biosimilars Approvals,'' April
2020.
\14\ Biosimilars Council, ``Failure to Launch: Barriers to
Biosimilar Market Adoption,'' September 2019.
Setting the Record Straight on the Global Production of Medicines and
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the FDA's Gold Standard of Safety
In testimony before the House Energy and Commerce's Subcommittee on
Oversight and Investigations on December 10, 2019, Dr. Janet Woodcock,
Director, Center for Drug Evaluation and Research at FDA, provided a
detailed breakdown of where API and FDF of prescription drugs--
inclusive of brand-name and generic medicines--are located.\15\ The
U.S. is home to 47 percent of FDF facilities and 28 percent of API
facilities as of August 2019, according to the FDA.\16\
---------------------------------------------------------------------------
\15\ Janet Woodcock, M.D., Director of CDER, FDA, testimony,
Subcommittee on Oversight and Investigations of the Committee on Energy
and Commerce, hearing on ``Securing the U.S. Drug Supply Chain:
Oversight of FDA's Foreign Inspection Program,'' December 10, 2019.
\16\ Ibid.
As depicted in Figures 1 and 2 from FDA's testimony, and included
below, the number of FDF and API facilities regulated by FDA is as
follows:
FDF Facilities, By Geographic Region
U.S.--47 percent
Europe--18 percent
India--11 percent
China--7 percent
Rest of World--13 percent
API Facilities, By Geographic Region
U.S.--28 percent
Europe--26 percent
India--18 percent
China--13 percent
Rest of World--13 percent
[GRAPHIC] [TIFF OMITTED] T6220.016
Globalization of the supply chain--a market reality for brand-name drug
companies and generic and biosimilar manufacturers--is often mentioned
as a matter of concern, but the record should in fact bolster
confidence in the system. The U.S. has one of the safest drug supply
chains in the world.
FDA's Oversight of the Pharmaceutical Supply Chain
FDA ensures all pharmaceuticals meet the same high-quality standards
regardless of where brand-name drugs, biologics, generics and
biosimilars are manufactured. All pharmaceuticals, whether generic or
brand, must be manufactured in accordance with rigorous regulatory
standards that require high levels of diligence and accompanying
documentation.\17\ FDA and other governmental requirements cover each
of the following areas:
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\17\ 21 Code of Federal Regulations Parts 210, 211, 600-680;
Inspection of Biological Drug Products, FDA Compliance Program Guidance
Manual, Chapter--45 Biological Drug Products, Section 7345.848.
Acquisition of raw materials and drug packaging components,
including auditing the manufacturers and suppliers of critical
ingredients;\18\
---------------------------------------------------------------------------
\18\ 21 CFR Sec. 211.182.
---------------------------------------------------------------------------
Testing of active ingredients using qualified equipment and
validated methods;\19\
---------------------------------------------------------------------------
\19\ 21 CFR Sec. 211.84.
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Constructing and maintaining manufacturing equipment and
facilities that have been constructed and maintained to provide
sanitary conditions and to protect against contamination;\20\
---------------------------------------------------------------------------
\20\ 21 CFR Sec. 211.42, Sec. 211.56 (facilities), Sec. 211.65,
Sec. 211.67 (equipment).
---------------------------------------------------------------------------
Appropriate and documented training of manufacturing
personnel;\21\
---------------------------------------------------------------------------
\21\ 21 CFR Sec. 211.25.
---------------------------------------------------------------------------
Validation of manufacturing processes to ensure that they
consistently produce safe, effective and uniform medicine;\22\
---------------------------------------------------------------------------
\22\ 21 CFR Sec. 211.100.
---------------------------------------------------------------------------
Thorough contemporaneous documentation of each manufacturing
step, with oversight by an employee other than the operator for
critical manufacturing steps;\23\
---------------------------------------------------------------------------
\23\ Ibid., 21 CFR Sec. 211.101(c), Sec. 211.180(a), Sec. 211.186,
Sec. 211.188(b).
---------------------------------------------------------------------------
Taking samples of prescription drugs during the manufacturing
process at predetermined intervals, and testing the samples for potency
and, where appropriate, sterility;\24\
---------------------------------------------------------------------------
\24\ 21 CFR Sec. 211.110.
---------------------------------------------------------------------------
Maintaining rigid controls over labels placed on drug
containers, to ensure the correct labels are placed on every
package;\25\
---------------------------------------------------------------------------
\25\ 21 CFR Sec. 211.122, Sec. 211.125, Sec. 211.130, Sec. 211.134.
---------------------------------------------------------------------------
Thorough testing of prescription drugs before packaging to
ensure that they are free of microbial contamination or other defects,
and that they meet tight specifications for uniformity, potency and
lack of impurities;\26\
---------------------------------------------------------------------------
\26\ 21 CFR Sec. 211.113, Sec. 211.165, Sec. 211.194.
---------------------------------------------------------------------------
Retention of samples of all manufactured batches of prescription
drugs;\27\
---------------------------------------------------------------------------
\27\ 21 CFR Sec. 211.170(b).
---------------------------------------------------------------------------
Routine stability testing to ensure that prescription drugs,
including biologics, will remain safe and effective for the duration of
their shelf lives;\28\
---------------------------------------------------------------------------
\28\ 21 CFR Sec. 211.165.
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Release of each batch of prescription drugs for distribution
only upon review of all batch records and testing data by a quality
unity that is independent of manufacturing personnel;\29\
---------------------------------------------------------------------------
\29\ 21 CFR Sec. 211.22, Sec. 211.142, Sec. 211.167, Sec. 211.192.
---------------------------------------------------------------------------
Continuous oversight by management and regular audits by an
independent quality unit of the manufacturer or outside
consultants;\30\
---------------------------------------------------------------------------
\30\ 21 CFR Sec. 211.180(e), (f).
---------------------------------------------------------------------------
Rigorous documentation of every step in the storage and
distribution of manufactured prescription drugs;\31\ and
---------------------------------------------------------------------------
\31\ 21 CFR Sec. 211.150(b), Sec. 211.196; Drug Supply Chain
Security Act, Title II of the Drug Quality and Security Act of 2013.
---------------------------------------------------------------------------
Prompt reporting to FDA and thorough investigation of any
complaints about distributed medicines, or any reports that the
prescription drugs may have failed to remain safe and effective.\32\
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\32\ 21 CFR Sec. 211.198.
When FDA finds any deviation from the strict standards of production,
FDA can take swift action. Potential actions include: mass recall of
products; issuing public Warning Letters; imposing import alerts and
barring the admission into the U.S. of violative API or FDF; seizing
violative medicines; seeking court orders suspending distribution of
drug products until FDA approves resumption of operations; and pursuing
criminal prosecution of individuals and companies when necessary.\33\
FDA does not hesitate to exercise these powers, taking action not only
when prescription drugs are determined to be defective, but when FDA
believes that the system of manufacturing is inadequate to guarantee
that all prescription drugs are safe and effective.
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\33\ FDA Public Databases on Drug Recalls, Warning Letters, and
Import Alerts; Ned Sharpless, M.D., ``Expanding Criminal Enforcement
Operations Globally to Protect Public Health,'' FDA, October 2019.
GDUFA, originally enacted in 2012 and then reauthorized in 2017,
included a $4 billion commitment from the generic drug industry.\34\
One primary reason the generic drug industry supported the user fee
program for generic drugs was the imbalance between the frequency of
inspections for domestic manufacturers and foreign manufacturers,
especially those located in China and India. Statistics at the time
showed that large generic manufacturers located in the U.S. could
expect to be inspected by FDA once every two to three years. In
contrast, major suppliers of prescription drugs based in China and
India were inspected, on average, less than once every 10 years.
---------------------------------------------------------------------------
\34\ FDA, Five-Year Financial Plan for the Generic Drug User Fee
Amendments, 2018.
GDUFA has significantly increased and continues to augment the funding
of FDA's generic drug review and inspection programs. GDUFA
substantially increased FDA's review capacity and the frequency of
inspections. FDA hired nearly 1,200 employees to strengthen oversight
under GDUFA implementation and 338 additional employees were added as a
result of GDUFA II.\35\
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\35\ Kathleen Uhl, Director of Office for Generic Drugs,
Presentation: Director's Update, February 2016.
Indeed, GDUFA fees and the foreign drug manufacturer inspections by FDA
that the fees enable have dramatically changed where FDA has focused
its inspection and enforcement efforts. Until 2012, the majority of FDA
Warning Letters relating to manufacturing violations issued to
mainstream drug manufacturers were based on inspections at facilities
located in the U.S. In 2011, for instance, 45 percent of FDA Warning
Letters for drug manufacturing violations were based on inspections of
facilities outside of the U.S. More recent data, for 2016, shows 98
percent of FDA Warning Letters were issued to facilities located
outside of the U.S.\36\ The increase in enforcement actions against
drug manufacturing facilities located outside of the U.S. is directly
attributable to an increase in the number of FDA inspections. However,
it is important to remember that most manufacturers that are inspected
are found to be fully compliant with the regulations.\37\
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\36\ Independent review of FDA's public database of Warning
Letters.
\37\ FDA, ``Facts About the Current Good Manufacturing Practices
(CGMPs),'' June 2018.
FDA utilizes a risk-based inspection strategy, established under Title
VII of the Food and Drug Administration Safety and Innovation Act
(FDASIA), to maintain a robust inspections footprint around the world.
FDA has established offices in China and India and uses GDUFA funding
to support those offices. FDA's global inspection efforts are
prioritized and focused on facilities in a way to prevent, uncover and
combat data integrity issues and manufacturing problems. Using a risk-
based site selection surveillance inspection model, FDA prioritizes
domestic and foreign inspections based on multiple factors carefully
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selected to appropriately target the agency's resources.
In fiscal year 2017, FDA conducted 935 inspections of generic drug
manufacturing facilities in the U.S. and around the world.\38\ This
includes 547 international inspections and 388 domestic inspections.
Moreover, the level of inspections increased between fiscal year 2013
and fiscal year 2017 (five years) from a total of 721 inspections. As
former FDA Commissioner Scott Gottlieb, M.D., noted at the time, ``We
expect these trends to continue due to resources from GDUFA II.''\39\
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\38\ FDA, FY2017 Performance Report to Congress for GDUFA, May
2018.
\39\ Scott Gottlieb, tweet on FY 2013-17 Inspectional Data, January
2019.
AAM and its members remain committed to ensuring FDA continues to have
the resources to perform thorough inspections of facilities that
manufacture all medicines approved in the U.S. We are pleased that the
number of FDA's foreign inspections continue to rise, in no small part
based on funding provided by AAM's member companies through GDUFA and
the Biosimilars User Fee Act (BsUFA).
AAM's Blueprint to Strengthen the U.S. Pharmaceutical Supply Chain
As part of the industry's ongoing commitment to patient access, AAM
released a six-element framework that lays out concrete actions to
ensure that U.S. patients and the U.S. health care system have access
to a secure and consistent supply of critical medicines.\40\ AAM's
``Blueprint for Enhancing the Security of the U.S. Pharmaceutical
Supply Chain'' builds upon the existing generic drug supply chain in
the U.S., which produces approximately 70 billion doses annually and
provides more than 36,000 jobs in nearly 150 manufacturing facilities
across the country. AAM and its members seek to provide solutions that
will enable expanded investment in the manufacturing of medicines
domestically.\41\ Creating the conditions that support and encourage
this investment are critical to ensuring the most critical medicines--
those most essential to our country's health and security--are
manufactured in the U.S. In order to establish this environment, AAM's
Blueprint recommends the following:
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\40\ AAM, ``A Blueprint for Enhancing the Security of the U.S.
Pharmaceutical Supply Chain,'' April 30, 2020.
\41\ Based on a 2016 survey of AAM's member companies.
Identify the list of medicines most critical for U.S.-based
manufacturing;
Provide new grant and tax incentives to secure the U.S. supply
chain;
Supply the Strategic National Stockpile, the U.S. Department of
Veterans Affairs, and other agencies with essential medicines on a
long-term basis;
Reduce regulatory inefficiencies to streamline the federal
approval for U.S.-based facilities to manufacture medicines; and,
Promote a global, cooperative approach to diversifying the
supply chain.
The Blueprint includes actionable short-term steps to expedite more
U.S.-based production of essential medicines, while putting in place a
series of incentives to enhance the security of the U.S. pharmaceutical
supply chain. Given modern manufacturing facilities can take 5-7 years
and cost up to $1 billion to build, a long-term, consistent commitment
from the federal government is critical to building an expanded generic
manufacturing base in the U.S.
Importantly, the Blueprint offers a targeted approach to addressing
potential vulnerabilities in the U.S. pharmaceutical supply chain,
while building on the existing capacity in the U.S. and what is widely
recognized as one of the safest drug supply chains in the world.
Through its rigorous approval process, manufacturing regulations and
continuous inspections of manufacturing facilities, FDA ensures that
``medicines at all levels of the supply chain, from active
pharmaceutical ingredients (API) to the finished product sold to
consumers at the pharmacy counter are safe, effective and high
quality.''\42\ This is why every administration of both parties and,
including the current Secretary of Health and Human Services Alex Azar,
are publicly on record assuring America's patients that FDA would not
approve generics if they were not safe and effective treatments.\43\
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\42\ Statement from FDA Commissioner Scott Gottlieb, M.D., and
Director of FDA's CDER Janet Woodcock, M.D., ``FDA's continuing efforts
to maintain its strong oversight of generic drug quality issues
domestically and abroad,'' February 2019.
\43\ Alaric DeArment, ``FDA commissioner praises generic industry's
efforts on quality, shortages, follow-on biologics in GPhA speech,''
Drug Store News, February 2013.
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Our Industry's Commitment to Quality and Patient Safety
Patient safety is the number one priority for AAM and its member
companies. AAM's members adhere to a code of business ethics and the
``Safety of Medicines'' is its first principle.\44\ Every AAM member
company pledges to ``conform to high standards of quality, safety and
efficacy as determined by regulatory authorities in each economy in
which they operate.''\45\ This commitment to quality, safety and
efficacy applies regardless of where medicines are manufactured.
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\44\ AAM, Code of Business Ethics, March 2018.
\45\ Ibid.
Patients should know and be confident in the quality of the generic
medicines prescribed and consumed. Generics and biosimilars are just as
safe and effective as their brand-name drug counterparts. Independent
research consistently demonstrates the clinical equivalence of generic
medicines compared to the brand-name drug.\46\
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\46\ FDA, Generic Drugs: Questions and Answers, June 2018.
Patients can trust the safety and effectiveness of generic medicines.
And it is important that patients take their medicines as prescribed by
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their physicians. As Secretary Azar has previously stated:
Every single drug I take is a generic. They are exact copies.
They wouldn't get approved by the FDA if they weren't.\47\
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\47\ Secretary Azar, interview on Fox and Friends, October 2019.
While it is not always possible to combat all of the misinformation
that exists, we encourage lawmakers to avoid, to the extent possible,
repeating and sometimes promoting inaccurate information on quality
that can potentially result in placing patients in harm's way by way of
promoting non-compliance of their prescribed medication regimen. As FDA
has emphasized, not taking one's medicine as prescribed by a doctor or
as instructed by a pharmacist, due to unsubstantiated claims on
quality, could have the undesired effect of exacerbating a patient's
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illness or disease, and lead to worse health outcomes.
Moreover, and as described previously, FDA provides regulatory
oversight of the manufacturing of generic and biosimilar medicines.
Manufacturing facilities located overseas, as well as in the U.S., are
routinely inspected by FDA to ensure the medicines are of the highest
quality for patients. A standardized, transparent and dynamic system is
in place and is working for doctors, pharmacists and patients.
Quality Is Standard
Exacting standards ensure the reliability of the medicines we take.
These standards make it possible for us to trust that a pill dispensed
from a pharmacy in Oregon in the spring will match, in every way that
matters, a pill picked up at a drug store counter the following winter
in Miami.
Dr. Jeremy Greene, professor of medicine and the history of medicine at
Johns Hopkins University and author of ``Generic: The Unbranding of
Modern Medicine,'' explained in a recent interview with United States
Pharmacopeia (USP):
There's a mutual interest among manufacturers, whether they are
brands or generics, for establishing and disseminating a public
standard that helps us determine if a drug is what it says it
is.\48\
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\48\ Jeremy Greene, ``Similarity and difference in the world of
drugs,'' USP, accessed October 2019.
The various stakeholders--health care professionals, industry, and
government--that keep our drug supply safe agree upon the standards,
and USP publishes the standards and the methods that manufacturers and
regulators can employ to demonstrate that medicines are what they
should be. These standards apply to a drug's molecular structure, and
to the amount of active and inactive ingredients it contains to ensure
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a drug's efficacy and safety.
USP strives for comprehensive standards, which is no small task.
According to its latest annual report, more than 3,700 reference
standards and more than 6,700 documentary standards have been
issued.\49\ USP's collaborative work with FDA to set drug quality
standards for nearly 80 years has made drugs marketed in the U.S. the
gold standard worldwide for safety and quality.
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\49\ USP Annual Report, ``USP by the numbers: Fiscal year 2019,''
accessed October 2019.
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Transparency Enhances Quality
All of the links along the supply chain have an obligation to be open
and transparent about issues related to safety and quality. This is how
the system secures the accountability necessary to earn and retain the
trust of the medical profession and, ultimately, the patients.
FDA has a robust around-the-clock program for inspecting pharmaceutical
manufacturing facilities worldwide. The Office of Regulatory Affairs
(ORA) conducts assessments, inspections, research and surveillance of
pharmaceutical manufacturing facilities. AAM's member company
manufacturing facilities, all over the world, must be ready for FDA
inspection whenever they are operating, 365 days a year. Our member
companies have established interlocking processes and procedures to
ensure the quality and integrity of the medicines manufactured in these
facilities.
Generic manufacturers not only readily comply with inspections audits;
they also fund this oversight through GDUFA, which supports FDA
staffing and best practices in protecting public health and
accelerating innovation. These fees total nearly $500 million
annually.\50\ Foreign as well as domestic companies identify and
register all facilities involved in the manufacturing of generics and
their active ingredients. BsUFA operates on similar principles.
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\50\ FDA, ``GDUFA II Fee Structure Summary,'' accessed October
2019.
Reports from the public, health care professionals and the industry of
potentially defective drug products help FDA identify sites for
inspection or investigation. Most companies that are inspected are
found to be fully compliant with the regulations.\51\ In addition,
Post-marketing Surveillance Programs are in place to identify adverse
reactions that did not appear during the drug approval process.
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\51\ FDA, ``Facts About the Current Good Manufacturing Practices
(CGMPs),'' June 2018.
Critics may point to product recalls to draw attention to issues in the
supply chain, but we believe the rarity of these events demonstrates
the system's effectiveness. Indeed, recalls are occasionally required
not when a flaw or defect is identified in a medicine, but rather when
FDA believes that there is inadequate assurance of adequate quality
systems at a plant because manufacturing does not strictly comply with
the rigorous regulatory requirements. We would also note that while 90
percent of prescriptions filled in the U.S. are generic medicines,
generic drugs account for only 56 percent of any prescription drug
recalls.\52\ Brand products on the other hand account for only 10
percent of prescriptions filled, but 44 percent of the total
recalls.\53\
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\52\ FDA database, ``Recalls, Market Withdrawals, and Safety
Alerts,'' 2011-18.
\53\ Ibid.
When an issue is discovered, the proper mechanisms are activated, and
industry works with FDA to appropriately address it. In the unlikely
event that flawed medication does reach a patient, we should take
comfort that all medicines can be traced to the manufacturer. The
manufacturer of the product immediately notifies stakeholders in the
supply chain, and then pharmacists or physicians reach out to notify
patients and to determine alternative prescription options. Obviously,
these recalls are widely publicized; transparency contributes to
quality.
The Global Supply Chain Is Dynamic
FDA and the industry are constantly adapting to manufacturing
innovations. Current Good Manufacturing Practice (cGMP) regulations
address methods, facilities and controls used in manufacturing,
processing and packaging. The globalization of the supply chain, which
is a fact of life for brand, generic and biosimilar drugs, is often
mentioned as a matter of concern, but in fact, the record bolsters
confidence in the system. While it is true that so-called fake drugs
circulate in developing nations through mail-order and online
pharmacies, U.S. regulations, guidance and legislation are in place to
minimize the possibility that they could reach America's patients.\54\
Further, the only additional method of preventing counterfeit or
unapproved medications from reaching the U.S. market would be to
rigorously examine and test all incoming parcels and packages that
could contain medications--a measure that AAM would support. Only a
tiny fraction of incoming parcels and packages are currently examined.
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\54\ Fight the Fakes, ``US FDA Gives Tips on Spotting Fake
Medicines,'' June 2014.
These factors ensure patients can take their medications with
confidence. Dr. Michael Kopcha, Director of the Office of
Pharmaceutical Quality (OPQ) in FDA's Center for Drug Evaluation and
---------------------------------------------------------------------------
Research (CDER), may have put it best when he said:
The quality of our drug supply is better than ever before.
There is no difference in the quality of drugs based only on
where they are made.\55\
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\55\ Michael Kopcha, ``CDER Conversation: Assuring Drug Quality
Around the Globe,'' FDA, May 2019.
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Conclusion
Patients can and should trust in the safety and effectiveness of
generic and biosimilar medicines. FDA ensures all pharmaceuticals meet
the same high-quality standards regardless of where medicines are
manufactured. Globalization of the supply chain--a market reality for
brand-name drug companies and generic and biosimilar manufacturers--is
often mentioned as a matter of concern, but the record should in fact
bolster confidence in the system. The U.S. has one of the safest drug
supply chains in the world. And this is the result of the daily
commitment to quality from AAM's member companies and FDA oversight.
With that said, there are steps that the federal government can take to
enhance the U.S.-based production of critical medicines and we look
forward to working with the Finance Committee and its members to
advance the recommendations outlined in the ``Blueprint for Enhancing
the Security of the U.S. Pharmaceutical Supply Chain.''
______
A Blueprint for Enhancing the Security of the
U.S. Pharmaceutical Supply Chain
INTRODUCTION
A closely connected, diverse, high-quality and resilient pharmaceutical
supply chain based in the United States and in U.S. allied countries
(such as Canada, Europe, India, Israel, Japan, Jordan and Mexico) is
the best means to ensure that U.S. patients and the U.S. health care
system have access to a secure and consistent supply of critical
pharmaceuticals. The United States already plays an important role in
this supply chain, with generic companies providing more than 36,000
jobs at nearly 150 facilities, and manufacturing more than 70 billion
doses of prescription medicines annually.\1\
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\1\ Based on a 2016 survey of Association for Accessible Medicines'
member companies.
With strategic support from the U.S. government, the economic footprint
of the generic drug industry in the U.S. can expand even more, leading
to increased national security, a stronger, more redundant supply chain
for key pharmaceuticals or their components and an expanded employment
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base.
[GRAPHIC NOT AVAILABLE IN TIFF FORMAT]
A. IDENTIFYING THE LIST OF MEDICINES MOST CRITICAL FOR U.S.
MANUFACTURING
List of Essential Medicines. Within 180 days of enactment, the
Secretary of HHS shall establish a list of essential medicines for the
United States. Essential medicines are defined as the active
pharmaceutical ingredient (API) and finished dosage form (FD). The list
of essential medicines shall include medicines deemed most critical to
the U.S. health care system, vital during a secretary-designated public
health emergency, and/or those that, if shortages occurred, could
impact U.S. national security. In developing the list, the secretary
shall consult with the U.S. Food and Drug Administration (FDA), Centers
for Disease Control and Prevention (CDC), National Institutes of Health
(NIH) and other public health agencies, as well as the Secretary of
Defense and Secretary of State. The list shall be subject to a 60-day
public comment period.
Assessment of Supply Chain. Within one year of enactment, the
Secretary of HHS shall prepare an assessment of the global supply
chain's ability to source and manufacture the medicines on the list of
essential medicines.\2\ The assessment shall identify the location and
number of facilities involved in the production of FD and API. The
secretary shall consider several factors in preparing the assessment,
including but not limited to the number of manufacturers of each FD and
API; the number of manufacturers with approved Abbreviated New Drug
Applications (ANDA); the market shares for manufacturers of each FD and
API; the volume of FD and API manufactured at each facility; the extent
of supply redundancy for each FD and API; and the geographic location
of FD and API facilities. Information provided to HHS as part of the
assessment shall be confidential and not subject to public disclosure
due to its proprietary nature and potential to impact the market. The
Secretary of HHS shall prepare and submit a report providing
recommendations to Congress on how to strengthen the supply chain to
ensure sustainable U.S. patient access to all essential medicines.
---------------------------------------------------------------------------
\2\ The Coronavirus Aid, Relief, and Economic Security (CARES) Act
(H.R. 748) included several important steps intended to help strengthen
the pharmaceutical supply chain. The CARES Act increases the
transparency of the pharmaceutical supply chain by providing FDA with
additional information on potential disruptions in the supply chain, on
manufacturers' contingency plans to ensure continued supply and on the
volume of medicines manufactured (Section 3112); stresses the
importance of air transportation in maintaining well-functioning
pharmaceutical supply chains (Section 4005); evaluates U.S. dependence
on overseas manufacturing with a forthcoming report from the National
Academies (Section 3101); and strengthens the national stockpile to
ensure access to drugs, vaccines and other biological products (Section
3102). The policies outlined in this paper build on and enhance these
provisions.
Designation of ``High Priority'' Essential Medicines. From the
list of essential medicines, and informed by the assessment of the
supply chain, the Secretary of HHS shall publish a list of ``high
priority'' essential medicines for the purpose of ensuring U.S.
production and supply of those medicines. The secretary shall update
the list annually and may designate additional medicines--including
those not previously deemed essential--as ``high priority'' during a
secretary-designated public health emergency. The list, and any
---------------------------------------------------------------------------
updates, shall be subject to a 30-day public comment period.
B. INCENTIVES TO SECURE THE U.S. PHARMACEUTICAL SUPPLY CHAIN
Within six months of the completion of the list of ``high priority''
medicines, HHS, acting through the Office of the Assistant Secretary
for Preparedness and Response (ASPR), will seek new and specific
proposals from pharmaceutical manufacturers to determine how individual
companies can help secure the U.S. harmaceutical manufacturing base for
priority medicines. Proposals would include the list of specific FDs
and APIs the company proposes manufacturing in the United States, and
the specific type of incentives necessary to make the facilities
economically viable. HHS would be authorized to make:
Long-Term Price and Volume Guaranteed Contracts. Guaranteed
volume and price agreements are essential to ensuring the viability of
U.S.-based generic manufacturing for ``high priority'' medicines and to
inoculate those investments against low-priced imports of the same
medicine. When engaging with the industry, however, HHS must encourage
multiple suppliers in the market and ensure, whenever possible, that no
one company supplies the entire market (this protects against supply
disruptions). The price and volume agreements would provide purchase
guarantees that could be spread across the Strategic National Stockpile
(SNS) and all federal agencies that procure medicines through the
Federal Supply Schedule. For the SNS, HHS may take possession of such
purchases or may pay manufacturers an inventory management fee to
produce and maintain the specified quantity on behalf of the SNS.
Specific volume and price levels would be negotiated on a company-by-
company basis.
Grants. HHS shall provide grants to support construction,
alteration or renovation of facilities for the U.S.-based manufacture
of medicines included on the high priority medicines list. Grants shall
also be provided to pharmaceutical manufacturers to relocate production
facilities from outside of the United States back to the United States
to cover expenses in moving production and include funds to offset the
cost of building new factories and research centers. Such grants shall
be available only to manufacturers with an approved ANDA or authorized
generic or to external/contract manufacturers of approved ANDAs or
authorized generics. To support a diverse and reliable supply, such
grants shall be available to multiple manufacturers of the same
medicine. Grants will be administered by HHS/Biomedical Advanced
Research and Development Authority (BARDA).
C. OTHER NECESSARY ELEMENTS TO SUPPORT AN EXPANDED U.S. PHARMACEUTICAL
ECONOMIC FOOTPRINT
Certain additional measures will be necessary to support the economic
viability of a U.S.-based pharmaceutical investment. The following
elements will not be negotiated at an individual company level, like
those listed above, but will instead be adopted for the entirety of the
U.S. generics or biosimilars pharmaceutical manufacturing base:
Tax Incentives. New tax incentives must be passed that promote
U.S. pharmaceutical companies relocating foreign manufacturing back to
the United States, build new greenfield sites, refurbish already
existing manufacturing facilities and/or repurpose existing production
lines to focus on pharmaceuticals that appear on HHS's list of ``high
priority'' medicines.
} Manufacturers of medicines designated as ``high priority''
medicines shall be eligible for a tax deduction during whichever of the
two periods is longer: throughout the period the medicine is deemed
``high priority'' or during the initial period that company has agreed
with HHS to supply from its expanded investment. Specific tax
incentives that will facilitate the onshoring of U.S. pharmaceutical
manufacturing include:
} A dollar-for-dollar credit against federal taxes to
pharmaceutical manufacturers for 50% of wages, investments and
purchases made for manufacturing medications on the priority medicines
list in the United States.
} A tax reduction modeled after the Section 199 Domestic
Production Activities Deduction, which provided a tax deduction of as
much as 9% of the company's income attributable to U.S. manufacturing
operations.
} Increase the R&D credit rate to 20% for the alternative
simplified credit.
} Provide full expensing for the construction of new factories
built to move production from overseas to the United States.
Regulatory Efficiencies. To expedite the approval of a facility
and all the products to be produced in it the FDA will streamline its
regulatory review and approval processes, removing duplicated actions
and reducing the time for approvals across the board. The agency will
expand cooperation with the manufacturer, working collaboratively to
evaluate and approve the facility and the tech transfer processes
concurrently, as opposed to waiting until after the facility is built
and the equipment is installed/validated.
To accomplish these goals, the FDA will create an internal, intra-
agency working group focused on helping to expedite reviews and
approvals to onshore pharmaceutical manufacturing. This working group
will consist of resources from the Office of Regulatory Affairs; the
Office of Pharmaceutical Quality; the Office of Compliance; reviewers
from both chemistry and microbiology disciplines; and the Office of
Generic Drugs. This working group will focus on reviewing for approval
the transfer of production back into either U.S.-approved facilities or
newly constructed facilities at new or existing sites, including those
utilizing advanced manufacturing technology. This working group will
grant meetings with the company to discuss the overall transfer plans.
For example:
} Inspector(s) and Office of Pharmaceutical Quality staff will
make site visit(s) during the construction or validation phase.
} The mechanism will be similar to a pre-ANDA meeting--that is, a
developmental phase inspection and then a pre-submission inspection.
} Microbiology reviewer(s) will conduct site visits.
} Decouple submission and inspection. Inspections will be
completed within 30 days of request for inspection, regardless of
submission.
D. INCREASING U.S. PHARMACEUTICAL SUPPLY CHAIN SECURITY THROUGH GLOBAL
COORDINATION
The International Pharmaceutical Supply Chain Agreement. To
promote the benefits of a globally diverse supply chain, the United
States Trade Representative (USTR), working with HHS, should negotiate
a plurilateral agreement with U.S. allies to promote a cooperative
approach to securing the U.S. supply chain, ensuring diversity of
supply and responding to global health care challenges and natural
disasters, without resorting to export controls or other trade
barriers. In addition, coordinating the expansion of pharmaceutical
manufacturing with U.S. allies will allow for economies of scale and a
coordinated approach to global pandemics. Possible signatories would
include U.S. allies such as Canada, Europe, India, Israel, Japan,
Jordan and Mexico.
Definitions
``Generic drug'' means ``any drug that is marketed under an
abbreviated new drug application (ANDA) as well an `authorized generic
drug.' ''
``Manufacture'' has the meaning set forth in the Buy American
Act, 41 U.S.C. Sec. Sec. 8301 8305: ``completion of an article in the
form required for use by the government in the United States. For drugs
this means readied for use as a medicine for human consumption.''
______
Statement Submitted by Peter Kolchinsky, Ph.D.
Safe and inexpensive generic drugs must be made in America
Reliable, high-quality generic drugs are the great value proposition of
continued biomedical innovation. They are the ultimate price control on
branded drugs and a unique phenomenon in all of healthcare, where
nothing else goes generic--not hospitals, not services, not surgery.
Drugs are a manufactured good. The high prices of branded drugs that
are necessary to incentivize investment in risky research projects are
like a finite set of mortgage payments. Once a mortgage is paid off,
America takes ownership of an inexpensive public good. Through their
taxes and insurance premiums, our parents paid for branded drugs and
passed them on to us as inexpensive generics, as they might a home.
Over 90% of all prescriptions in America are for generic drugs \1\ and
each new drug we invent to improve our standards of care is built on a
foundation bought and paid for by past generations.
---------------------------------------------------------------------------
\1\ https://www.iqvia.com/-/media/iqvia/pdfs/institute-reports/
medicine-use-and-spending-in-the-us---a-review-of-2018-outlook-to-
2023.pdf?_=1591031020789.
Consider how easy it is to save money on medicines thanks to generics.
If your cholesterol is high, your doctor might prescribe Lipitor, using
the brand name of Pfizer's long-generic drug out of habit instead of
the generic name ``atorvastatin.'' No worries. Your local pharmacy is
permitted by law to fill your prescription using pills made by any FDA-
approved manufacturer of atorvastatin. Your pharmacy does the shopping
around for you, playing dozens of manufacturers off one another to get
the lowest price. You do not have to worry about which company makes
your atorvastatin because it is now a commodity; everyone has to make
it to standards of bioequivalence defined by the FDA. You probably care
more about the manufacturer of your toilet paper than you care about
who makes your atorvastatin, presumably because you trust the FDA.
False Economy
But here is the dilemma: It is hard to manufacture drugs reliably,
consistently, and to the highest standard. A company has to care about
getting the conditions just right and run quality tests at every stage
to make sure that the intermediates and final product are exactly as
they should be. And while the company that sells a new, branded drug
for a high price has a strong profit motive to keep quality high,
especially because it has to prove to physicians that this new medicine
can be trusted, the same cannot necessarily be said for generic drug
companies.
Generic drugs do not always work as well as they should, and
globalization has greatly exacerbated this problem. Generic drugs have
not earned and do not deserve our blind trust. As transplant surgeons,
cardiologists, infectious disease specialists, and psychiatrists have
increasingly recognized, a generic version of an essential medicine
manufactured by one company can be more or less potent than the
original version or a generic manufactured by a different company. A
generic might not have the stated amount of an active ingredient. It
may contain deadly impurities. In some cases a generic might release a
day's worth of drug into the bloodstream all at once; in other cases it
might release a drug too slowly. That could mean an infection otherwise
easily controlled might instead turn deadly. Blood pressure or high
cholesterol could remain unchecked. Or in the case of an organ
transplant, a patient taking a generic version of an immunosuppressant
might lose their precious new organ to rejection. Not all generics are
substandard; some are manufactured correctly and behave the same as
branded equivalents. But a growing number of Americans are hesitant to
take that risk, and rightly so. Some physicians will only prescribe the
branded version of a drug, which often spurs a protracted fight with
insurance plans that, like the FDA, consider generics interchangeable
with branded drugs and only want to pay for low-cost generics.
One key reason why generics are unreliable is because they are
increasingly manufactured overseas, where labor costs and regulatory
bars are low. This shift has put factories that manufacture generic
drugs practically beyond FDA oversight, which has long been crucial to
holding companies accountable for quality standards. In a competitive
market that takes quality for granted and prioritizes lower costs, it
only takes one bad apple out of a dozen manufacturers to drive all the
honest players out of business. As detailed in Katherine Eban's eye-
opening book, Bottle of Lies, the FDA cannot frequently or adequately
inspect the Indian and Chinese manufacturing plants that produce so
much of our generic drug supply. Instead of making high-quality
medicines, many of these companies circumvent quality regulations
through an escalating game of cat-and-mouse with the FDA. Quality
testing might be done on samples of Pfizer's own Lipitor, with the
resulting data passed off as evidence that these factories'
atorvastatin generics work just as well. When companies are run by
people without integrity and regulators cannot hold them accountable,
the dark side of human nature can flourish. In this case, cutting costs
comes at the expense of Americans' health, health worldwide, and the
value proposition of biomedical innovation.
I am not suggesting that generic drugs made in America are inherently
safer because Americans are more ethical. But what I find somewhat
reassuring is that drugs made in America are made on the FDA's home
turf where the leading drug regulator in the world can do a more
effective job of monitoring quality. In the US, where it can conduct
surprise inspections, the FDA issues plenty of warning letters: more
than 50 in the last 12 months related to Drug Quality Assurance.\2\ But
the violations overseas are extreme and all the worse considering that
the FDA typically gives several weeks' notice to companies that its
inspectors are coming; time used to clean up their operations, or, in
some cases, cook their books and coach employees to lie.
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\2\ https://www.fda.gov/drugs/enforcement-activities-fda/warning-
letters-and-notice-violation-letters-pharmaceutical-companies.
An American consumer can hold a local pizza shop accountable for having
a dirty bathroom or rancid cheese by writing a bad review and eating
elsewhere. But Americans have no such power to demand American-made
---------------------------------------------------------------------------
drugs manufactured under FDA supervision. Just try it.
Look in your medicine cabinet to see which companies make the generic
drugs you find there. Odds are good that they are based in India. Now
google that company's name together with the term ``483'' and odds are
good you will see that all of these companies committed drug quality
violations in the last 12 months. You might ask your doctor or
pharmacist to fill your next prescription only with generics made in
America. But neither will know how to do that. Your pharmacist is
driven by competitive forces to purchase drugs at the lowest possible
cost, which increasingly means from overseas manufacturers. If she even
has any control over where her pharmacy purchases its atorvastatin, she
would be hard-pressed to order from a more expensive US-based
manufacturer if her competitors are ordering cheaper
Indian-made drugs. Other than writing a prescription for the branded
version together with the phrase ``Dispense as Written'' (to ensure
that the pharmacist does not instead dispense a generic), there is
nothing your doctor can do. But before you think that prescribing only
branded drugs is the solution, consider the fact that this will make
most drugs unaffordable. Insurance plans balk at paying brand prices
for drugs that have gone generic unless a physician personally fights
for an exception, which few have the time to do. The system is
fundamentally based on the idea that, for a given drug, all generic
versions available in the US are equally safe and effective as one
another and the brand. The consumer has no choice!
COVID and Contracting: An Opportunity
Policymakers are considering repatriating America's drug supply chain
to avoid future shortages in the context of temporary disruptions
caused by COVID-19. But they should think bigger. We should repatriate
the American drug supply to restore and preserve the integrity of all
generic drugs in America.
That might seem like overkill. Better quality testing of final
products, as the pharmacy Valisure has started doing, might suffice in
some cases. The trouble is that the kinds of analytical assays done in
a lab can only detect some of the defects in a poorly made generic. A
drug can be made so that it meets all the lab test specifications, for
example, containing the right amount of the active drug and dissolving
at the right rate in a beaker, and yet it could still be made in such a
way that it acts differently in the human body. That is why the FDA
requires that generics companies prove their final products behave very
similarly to branded originals in human bioequivalence studies. Once
they do, then the process that makes that product must be locked down
and the company must document that it remains religiously adherent to
that process. The presumption is that, as long as they do, then the
final product can be trusted to continue to act as documented in
humans. But if generics manufacturers never even made their generic to
appropriate specs, lied about their human bioequivalence data, or did
not continue to adhere to a process that might have been the right
process initially, then it is not a given that subsequent lab tests
will detect the failure of their final products to function in patients
as intended. Those drugs might still cause dose dumping or not release
enough drug at the right point in the gut, resulting in potentially
important differences in therapeutic outcome. The bottom line is that
generic manufacturing must be done to careful specifications, and
Americans need both the quality of the final products and the processes
by which they continue to be made to be carefully monitored by a
regulator, which in the current framework is the FDA. That can only be
done truly reliably in the US (though close, trusting cooperation with
certain countries that have similar concerns about low-quality generics
is conceivable).
Repatriating the entire competitive generic drug market as it exists
today would be counterproductive. We can rebuild the market smarter and
more cost-effectively by using long-term procurement contracts: the
model we already trust to ensure that America has pandemic flu vaccines
and drugs for smallpox. This idea is already gaining traction. Just
recently, the federal government awarded a four-year $354 million
contract to Phlow,\3\ a Virginia-based generic drug manufacturer, to
produce certain essential generic medicines. That is the right idea.
Now we need to scale that approach many times over with several other
companies.
---------------------------------------------------------------------------
\3\ https://www.prnewswire.com/news-releases/phlow-corporation-
awarded-354-million-hhsas
prbarda-contract-to-manufacture-essential-medicines-in-shortage-
301061648.html?tc=eml_clear
time.
This type of long-term contracting can achieve better quality and might
also result in even lower prices than we have today. No doubt
competition achieves the lowest profit margins possible under free
market principles. But the fixed costs stack up. Even with low profit
margins, the total costs of maintaining all those competitors can be
high. Instead of trying to get twenty different generics manufacturers
to all produce atorvastatin and compete on price, America can negotiate
long-term contracts with a smaller number of companies, allowing them
to enjoy greater economies of scale and greater profits while America
---------------------------------------------------------------------------
pays less overall. Let's call this ``Contractual Genericization.''
Say 20 companies end up making generic atorvastatin in the US,
competing on price such that no one company makes very much in profit.
But each of those companies has to cover its fixed costs without
enjoying economies of scale, and the FDA has that many facilities to
inspect to ensure high quality. Instead of 20 companies each having to
cover $5M of fixed cost to make a drug ($100M total), we might have two
companies serve the US market that each only need to cover $20M of
fixed costs ($40M total) due to economies of scale (though each company
would still manufacture the drug at two or more locations to mitigate
against shortages)--two management teams instead of twenty; fewer,
larger factories, instead of many smaller ones. Because of the $60M
difference, America could pay those two companies more generously under
contract, allowing them to make more profit on an absolute basis, and
America would still save money compared to the free-market competitive
system. Their greater profitability would give them a strong incentive
not to screw up, since failure could mean transfer of the contract
(essentially management of high-quality manufacturing facilities) to
another company.
Still, there is no doubt that the underlying costs of making drugs in
America are higher than doing so elsewhere. Even under long-term
procurement contracts, American-made generic drugs might not be less
expensive than the ones we get now. But when the drugs we get now are
not actually reliable, then whatever low price we pay for them is too
high. Better to pay what we must for generic drugs that actually work
as intended than pay less for inferior and dangerous products.
The real benefit to Americans of onshoring generic drug manufacturing
through contracting would be that we could rely on much tighter quality
controls. Not only would generic drugs be American-made, creating
American jobs by companies paying taxes in America, but they would be
high-quality American made. And with proper funding and incentives,
innovation and automation of manufacturing--so-called advanced
manufacturing techniques--can help reduce the costs of producing
America's drug supply on American soil.
Repatriating generic drug manufacturing does not require that every
atom of every drug be made in America. American manufacturers could
still purchase commodity chemicals from overseas, provided that they
were able to pivot to other sources in case of disruptions and could
guarantee quality control of those chemicals before they go into final
products. The final steps of packaging exactly the right chemicals in
the right combinations at the right pressures in the right formulations
with the right coatings has to happen on US soil, where FDA oversight
is rigorous.
We can't do this all at once. We need to start by repatriating our drug
supply from countries like India and China that have poor track records
of adhering to Current Good Manufacturing Practices (cGMP) per FDA
requirements. We can leave countries like Ireland (where many drug
companies manufacture products for lucrative tax breaks) for last and
decide at that time whether it is prudent to cut ourselves off entirely
from foreign production.
It is also important that high-quality generics are available globally.
As it is, many countries do not trust generic drugs, and rightfully so
if one considers that overseas manufacturers have a history of sending
the best of t heir tainted goods to the US and selling the worst to
Africa, South America, and their own countries. If the US led the way
in making high-quality generic drugs, we could end up exporting them to
other countries. At the very least, out of pure self-interest if not
compassion, America should ensure that everyone in the world gets the
proper doses of all antibiotics, since underdosing leads to
antimicrobial resistance that could land on our shores.
Generic Drug Contract With America
The framework I am proposing, the Generic Drug Contract with America,
would accomplish at least three important goals:
(1) Restore the quality of the American generic drug supply by
repatriating most or all generic drug manufacturing to the US where the
FDA can keep a close eye on the process.
(2) Protect the American drug supply from disruptions like we have
seen due to COVID-19.
(3) Create tens or even hundreds of thousands of high-quality
American jobs where they are most needed by tying government contracts
for American-made generics to requirements (with federal subsidies)
that these companies build their factories in regions and communities
that have been hollowed out by globalization.
This model can also help solve another growing problem that Congress
has not even begun to contemplate. Some drugs cannot go generic under
our existing legal, ethical, and regulatory frameworks. Increasingly,
the technologies we are using to treat diseases are complex and some
are near-impossible to copy. If we cannot trust generic manufactures to
make atorvastatin reliably, they may never be able to make some of the
antibody-drug conjugates and gene therapies that have recently come to
market and are on the rise.
The cost of branded drugs that will go generic are worthy, finite
mortgage payments that America makes towards a medicine that it will
eventually own as a public good (i.e., generic). But the costs of
ungenericizable drugs are rent from day one. Companies that sell
ungenericizable drugs need never worry about a patent cliff. They need
never hustle to invent a new drug to replace lost revenues when older
ones face competition. They can just keep making the same thing
indefinitely. And while even branded drugs often compete with other
branded drugs (for example, there are several statins, several SGLT2
diabetes drugs, and several insulin analogs), having two or three
competitors in a class makes for an oligopoly, which still can tacitly
collude to extract rents. But there are many cases where only one drug
in a class is particularly well suited to some patients and therefore
represents a true monopoly. Reliable generics are the true disruptors
of oligopolies and monopolies, but that path is not available to
certain types of drugs.
The order established by the Hatch-Waxman Act in 1984, which introduced
the idea of modern generics that are interchangeable amongst themselves
and with the original branded version, did not contemplate biologics or
how such drugs could ever go generic. Recombinant insulins launched in
the early 1980s, and other biologics only really started coming to
market in the 1990s. Yet not until the ACA passed in 2009 with a
component called the Biologics Price Competition and Innovation Act
(BPCIA) did we get a pathway for biosimilars. Biosimilars are as close
to generics for biologics as we can get and yet far from close enough.
The trouble is that the BPCIA was always on weaker ground than Hatch-
Waxman in terms of driving cost savings because it is harder to
establish interchangeability for a biologic than for a small molecule
drug (though that is arguably not as easy as we once thought either).
Without interchangeability at the pharmacy level, an insurer cannot
just have a pharmacist switch all patients over from a branded biologic
to its biosimilar and save a plan money. That is because insurers (and
even their employer clients) are addicted to the rebates they have
negotiated on branded biologics, which they risk losing by covering
cheaper biosimilars of a given drug without the assurance of
successfully saving money by having patients actually switch to those
biosimilars.\4\
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\4\ If a payer spends $200M/year on a branded drug but gets a 40%
rebate ($80M) in exchange for exclusive formulary status, that payer
spends a net $120M on the branded drug. If a biosimilar comes along at
a 65% discount, then converting all patients to it would result the
drug costing the payer $70M a year, $50M less than they are spending
now. That is attractive. But if only 10% of patients switch to the
biosimilar, then the payer spends $7M on the biosimilar and $180M on
the branded drug (since the rebate would be gone), resulting in greater
cost. That is how a rebate without interchangeability protects a
brand's monopoly from biosimilars.
If trying to create a US-based competitive market for generic
atorvastatin seems hard and expensive, then doing it for insulins and
antibodies will be impossible. For example, Abbvie's Humira, an
autoimmune disease antibody, is the most lucrative drug in history.
It's been on the market for 18 years, much longer than the 10-15 years
typical of more easily genericized small molecule drugs. It does not
make sense to wait until five or ten other US companies figure out how
to make Humira before America considers its $15B/year mortgage on that
---------------------------------------------------------------------------
drug paid off.
The most reliable manufacturer of any biologic is the company that has
been making it for years as a branded drug. The same contracting
mechanism that we use to contract with a few companies to make the US
generic drug supply can also be used to contract with biopharmaceutical
companies to continue to make their biologics at a contracted price
once their patents expire--one that is low, but remains profitable.
Yes, that is a price control. But it is a fix for the market's failure
to achieve the same end through competition.
The Generic Drug Contract with America would achieve a key fourth goal:
(4) Ensure that even conventionally ungenericizable drugs become
inexpensive after their patents expire, bringing modern drugs in line
with the intent of the groundbreaking Hatch-Waxman Act of 1984 that
established generic drugs as we know them.
Just as Hatch-Waxman allowed for exclusivity extensions to incentivize
certain kinds of development of branded drugs, such as demonstrating
how they should be used in children (i.e., 6-month pediatric
extension), similarly this Contractual Genericization would allow for
exclusivity extensions to incentivize companies to continue to upgrade
their branded drugs.
The Great American Drug Deal
The biotechnology industry I know thrives on solving healthcare
problems. Its efforts to stop COVID are on full display, ingenuity
flowing like water through the cracks of a rock, searching out its
weaknesses. This same ingenuity is also targeted at thousands of more
familiar healthcare problems. Hepatitis C infection can now be readily
cured with a short course of pills. The lives of many cystic fibrosis
patients have been transformed over the past five years with oral
medications. At the pace we are developing new treatments, there is a
good chance that a mother giving birth to a girl today will never have
to worry about her daughter dying prematurely of breast cancer.
This scientific hustle exists on a foundation of public funding for
basic science and some public support for drug development. But it is
largely fueled by private capital: the cumulative savings of the world,
from billionaires to schoolteachers' pension funds, searching for an
attractive return. And it is America's willingness to pay high prices
for new drugs during their patented period of market exclusivity that
is the draw for all this private capital. The fact that other countries
pay less than we do for branded drugs is a function of their
willingness to deny breakthrough medicines to their citizens and
America's resolve to back innovation even if it has to do so on its
own. But America relies on drugs going generic to ensure that our
country gets value for its investment. And the fact that branded drug
revenues are finite keeps scientists and investors constantly working
to develop the next breakthrough. Thanks to the mortgage model brought
about by the Hatch-Waxman Act, the biotechnology industry evolved into
a community of builders that charge finite mortgages. If generic drug
quality remains unreliable and newer drugs remain difficult or
impossible to genericize, the biotechnology industry risks regressing
into rent extracting landlords.
For a free market to work, it cannot allow monopolies to extract high
rents indefinitely. America created the FTC to regulate companies that
grew into natural monopolies, in some cases breaking them up. America
also passed laws that regulated natural monopolies, such as PURPA in
1978, to make sure Americans are not price gouged by electric
companies.
As the medical historian Jeremy Greene points out in Generic, his
excellent overview of how America's generic drug model was negotiated
into existence, while other countries tried to control the price of
branded drugs, America kept its drug costs in check by requiring
branded drugs to go generic. That has been our model and it has worked
to control costs and to incentivize innovation. Without genericization,
America would be spending hundreds of billions of dollars more per year
on branded drugs. Because of generics, America spends about $271B on
branded drugs and only $73B on generics.\5\ As long as we ensure that
all drugs go generic, through competition or contract, then if we are
still spending $271B on branded drugs in 2035, it is because all
currently expensive drugs have become inexpensive generics and the
biotechnology industry has invented an entirely new set of branded
drugs. All of these brands will necessarily have to be better than the
generic drug foundation on which they stand. We are builders and what
we are building will ensure that our children and grandchildren live
healthier lives than we do.
---------------------------------------------------------------------------
\5\ https://www.iqvia.com/-/media/iqvia/pdfs/institute-reports/
medicine-use-and-spending-in-the-us---a-review-of-2018-outlook-to-
2023.pdf?_=1591031020789.
We need a Generic Drug Contract with America to ensure the quality of
our generic drugs, to ensure that all drugs go generic and offer
America value for its investment, to protect the incentives that drive
further biomedical innovation from being throttled by the alternate and
far worse measure of price controls on branded drugs, to ensure
America's drug supply against global disruption, and to revitalize
---------------------------------------------------------------------------
America's heartland with good jobs.
Of course, it is impossible to talk about drugs without also addressing
affordability. As we call for quality generics, we must also call on
our society to make appropriately prescribed branded drugs affordable
to patients via proper insurance, which means not allowing out-of-
pocket costs to exceed what patients can afford. Consider why an
insurance plan demands that a physician get prior authorization before
prescribing a drug and then, upon deciding the drug is appropriate for
the patient and granting the authorization, still requires a high out-
of-pocket cost. Is that insurer nudging that patient to disregard her
physician's recommendation? That is not insurance and therein lies
America's problem with affordability: it lacks a proper healthcare
insurance system. The entire drug industry operates on profit margins
in the low teens, which means that a price cut across the board of just
20% would wipe out profits and company valuations (and with them the
value of executive stock-based compensation), and yet does absolutely
nothing to make a $10,000 drug affordable to a patient that struggles
with a $6,000 deductible (which means that even if a drug costs $8,000,
the patient would still have to cover the entire deductible).
So the Generic Drug Contract with America is really part of the greater
Biotech Social Contract, which requires insurance reform to lower out-
of-pocket costs for all Americans and extend insurance to everyone.
Amid the COVID crisis, the federal government has already seen the
wisdom in covering COVID-related costs for the uninsured, a logical
public health measure. Hopefully those temporary patches on the gap-
ridden system of American healthcare coverage will be made permanent
and expanded to other diseases, because cancer, diabetes, and many
other disorders are no less a personal crisis for each patient who
suffers from them and their families. Indeed, there are reform bills in
Congress that propose caps on out-of-pocket costs and pair those limits
with reforms targeting drug manufacturers. This Generic Drug Contract
with America embraces the genericization of drugs, ensuring that they
are efficiently manufactured at high quality in the US, as the reform
necessary for the biopharmaceutical industry to hold up its end of the
bargain.
There will be those who oppose the Generic Drug Contract with America.
They may have good reasons. However, we should dispatch the ones that
are clearly untrue. This is not an assault on free trade; this is a
necessary response to unreliable trade. This would not be an
unprecedented incursion of government price regulations into
pharmaceuticals; the government already contracts with individual
companies to make the entire US supply of particular drugs where there
could not be a reliable and cost-effective ``free market,'' such as
pandemic vaccines and other biodefense countermeasures. California is
already exploring the possibility of making all of its own generics.
The federal government has contracted with Phlow to make many generic
drugs that normally would be sourced from overseas.
I am proposing that we think bigger and, over the course of this next
decade, make bold strides to repatriate most if not all of our generic
drug supply under contracts. We must ensure that we always can look
forward to paying off the mortgage of a drug to take possession of an
inexpensive, reliable, public good while innovators move on to the next
set of upgrades of our medical armamentarium. And someday those too
will go generic.
______
Natural Products Association
440 1st St., NW, Suite 520
Washington, DC 20001
(202) 223-0101
Fax (202) 223-0250
Statement of Daniel Fabricant, Ph.D., CEO and President
Introduction
The Natural Products Association (NPA) was founded in 1936 to ensure
that Americans have access to safe and affordable natural products, and
also to promote and protect the interests of retailers and suppliers of
natural nutritional foods and natural products. We are the oldest and
largest trade association in our industry. While the industry has
existed for many years, it has only recently--since the late 1980s--
transformed into a major engine of economic growth, customer
satisfaction, and job creation throughout the United States.
When the Dietary Supplement Health and Education Act of 1994 (DSHEA)
was passed there were an estimated 4,000 dietary supplement products on
the market. Twenty-five years later, there are between 50,000 and
80,000 products on the market. This is in large part because more and
more consumers are turning to these products to maintain their health
and wellness. But the recent outbreak of COVID-19 also reaffirms the
importance of consistency from the Food and Drug Administration when
regulating imported finished products.
The Federal Food, Drug, and Cosmetic Act (the FD&C Act) requires that
manufacturers and distributors who wish to market dietary supplements
that contain ``new dietary ingredients'' notify the FDA about these
ingredients. The notification must include information that is the
basis on which the manufacturer or distributor has concluded that a
dietary supplement containing a new dietary ingredient will reasonably
be expected to be safe under the conditions of use recommended or
suggested.
Issue
China is the single largest global supplier of cost-effective raw
materials for the nutritional supplement industry, responsible for 60%
of the ingredients supplied for finished product manufacturing in the
nutritional supplement. Furthermore, in the last several years,
thousands of dietary supplements have flooded the American market while
the number of New Dietary Ingredients (NDI) submitted to the FDA to
establish the safety of new dietary ingredients in supplements has
dropped.
The FDA recently received a budget increase of $3 million to modernize
its regulatory process for dietary supplements. Despite recent budget
increases, FDA has failed to take significant action to protect
consumers from adulterated products and from the proliferation of CBD
products, which still remain illegal in the U.S. NPA has repeatedly
requested action from the FDA on CBD, including establishing a safe
level of daily consumption.
By neglecting its enforcement obligations on NDIs and CBD products, the
FDA has allowed unsafe and untested dietary supplement products into
the country, and potentially unsafe products on store shelves.
Adulterated ingredients that have not completed the NDI notification
process are entering our country at an alarming rate. This puts
American consumers at risk and compliant U.S. supplement makers at a
terrible disadvantage.
According to industry estimates, about 90% of dietary supplement
products on the market are not required to file an NDI because they
have been generally recognized as safe. Meaning, they contain dietary
ingredients which have been present in the food supply and are
generally recognized as safe. However, that means approximately 4,600
products on the market have not received FDA scrutiny. Furthermore, the
Agency has only received 1,100 NDINs, highlighting concerns that these
products contain counterfeit ingredients.
When a dietary ingredient is introduced into the food supply for the
first time, manufacturers are required to notify the FDA of their
intent to market an NDI-
containing supplement at least 75 days before the supplement is
marketed in the United States. The NDI notification must thoroughly
identify the ingredient, how it is used in the supplement, and present
evidence the manufacturer relied upon to determine the ingredient is
reasonably safe. This provides the FDA with significant oversight on
the dietary supplement manufacturers' safety assessment of the NDI-
containing dietary supplement.
The Food Safety and Modernization Act (FSMA) directed the Agency to
issue guidance pertaining to new dietary ingredients. Specifically,
Congress directed the Agency to clarify ``when a dietary supplement
ingredient is a new dietary ingredient, the manufacturer or distributor
of a dietary ingredient or dietary supplement should provide the
Secretary with information as described in section 413(a)(2) of the
Federal Food, Drug, and Cosmetic Act, the evidence needed to document
the safety of new dietary ingredients and appropriate methods for
establishing the identity of a new dietary ingredient.''
When an American firm's NDI is acknowledged, its valuable intellectual
property is supposed to be protected. However, the Director of FDA's
Office of Dietary Supplement Programs admitted that this is not always
the case, stating that ``it is not all uncommon for stakeholders to say
that FDA needs to do a better job of enforcing NDIN. There is a degree
of sympathy to that view, but we don't know what we don't know.''
Unfortunately, the practice of adulterated products NDIs is all too
common, and it harms legitimate manufacturers. Imported dietary
supplements are considered adulterated when they purport to contain
ingredients that have not gone through the NDIN process or are
misrepresenting the ingredients that the dietary supplements actually
contain. In 2008, Mitsubishi Gas and Chemical Inc. (MGC) received a
successful 2008 NDIN submitted to CFSAN. In 2010, a piggybacked
ingredient began to appear on the market before engaging in the FDA's
NDIN compliance process for safety concerns. Testing of the product
revealed differences between MGC's product and the non-compliant
products, including product impurities. When the piggybacked product
finally filed NDIs, the FDA questioned the safety of these products,
including that the notifier failed to address organ damage after
consumption in an experimental animal model. Yet, this product remains
on the market. Members of the Natural Products Association, including,
Natural Alternatives International, Lonza, and others all face similar
scenarios.
Proposed Solution
NPA proposes a two-pronged public-private partnership approach to
ensure the safety of the global dietary supplement supply chain:
Import Alerts: The Agency has not published an import alert for dietary
supplements in several years. The agency last used this authority in
2014 in response to safety concerns related to the importation of
Kratom. Creating an import alert for new dietary ingredients that have
failed to comply with the NDIN regulations would provide the Agency
with the ability to police the market in a way that is resource
efficient and consistent with the goals of protecting the public's
health, and provide the intellectual property protection the industry
desperately needs. This process would restore integrity to the NDIN
process, protect intellectual property, and provide the necessary
safety net our consumers rely on. Since the FDA is prioritizing
resources and only performing ``for-cause inspections'' during the
COVID-19 crisis, issuing an import alert for products that are
adulterated would require no addition al resources and would be an
effective measure that would provide important information to the
Agency to facilitate their enforcement of current dietary supplement
regulations. Placing responsibility back on the importer to ensure that
products being imported to the United States are in compliance with the
FDA's laws and regulations is more than an appropriate step providing a
necessary safety net for American consumers.
Stronger Self-Regulatory Collaboration: The second recommendation is to
expand the number of companies who agree to meet industry specific
quality assurance standards in NPA's Supplement Safety and Compliance
Initiative (SSCI) SCI is an industry-driven initiative led by the
nation's leading retailers to provide a harmonized benchmark to
recognize various safety standards throughout the entire dietary
supplement supply chain. SSCI is a bold step forward in providing
quality assurance from harvest to retailer shelf. Dietary supplements
must meet or exceed the SSCI benchmark to be accepted in major
retailers, all with the goal of providing quality products and
increasing consumer confidence.
______
Ohio State University, Fisher College of Business
John V. Gray, Professor
Department of Management Sciences
612 Fisher Hall
2100 Neil Avenue
Columbus, OH 43210
614-247-8021 Phone; 614-292-1272 Fax
[email protected] (preferred)
U.S. Senate
Committee on Finance
Dirksen Senate Office Bldg.
Washington, DC 20510-6200
Committee:
It is time to stop implicitly incentivizing the foreign production of
drugs. Producing in low-cost countries is cheaper due to lower
regulatory costs, not just due to lower input costs. There are ways to
lower the incentive to offshore pharmaceutical production:
Currently, foreign inspections are typically pre-announced;
domestic ones are not. Foreign inspections should routinely be
unannounced. They must be as stringent as domestic ones.
Non-domestic producers should be forced to fund the additional
costs of running a stringent inspection regime if they want to sell
their drugs in the USA. This fee can be location specific. It can
partially depend on whether the FDA can rely on a local agency to help
regulate production in the chosen production location; it could be
waived where regulations and inspection regimes are deemed already
comparable (e.g., possibly the MHRA \1\ in the U.K.). Blocked visas and
similar bureaucratic obstructions should be met with the right to
refuse import of drugs until inspections are completed.
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\1\ https://www.gov.uk/government/organisations/medicines-and-
healthcare-products-regulato
ry-agency.
It is time to make it easier for consumers, doctors, and pharmacists to
know not only where their drugs are produced. but to be able to
evaluate their quality risk more easily. Unlike many products, it is
difficult for consumers, doctors, and pharmacists to detect quality
deviations in the drugs they take, prescribe, or administer. In the
generics space, which is the vast majority of the market, purchasing
and consumption decisions are generally made entirely based on cost.\2\
If quality performance were more transparent, producers of generic
drugs can compete on quality, not just cost.
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\2\ https://pubmed.ncbi.nlm.nih.gov/23337525/.
Currently, the industry considers the production site of a given
drug to be a trade secret. This needs to change. Consumers, doctors,
and pharmacists should know exactly where their drugs were made.
Specifically, regulations should force transparent ``Made In'' labeling
for drugs, as follows (this can be a website link, QR code, or similar
if room on packaging and/or updating packaging is too onerous):
Packaged by: (list plant and address)
Finished drug product made by: (list plant and
address)
Active Pharmaceutical Ingredient (API) made in:
(list plant and address)
Excipients made in: (list countries)
This, combined with already-available inspection and warning
letter information, could make it possible for a consumer, doctor, or
pharmacist to get an indication of the quality risk of a drug with
reasonable effort. Today, it is extremely difficult to do so, as drugs
cannot be linked to their manufacturing plants.
Beyond providing production location--an important first step--
more can be done to make the quality risk of drugs visible. The FDA has
been working on risk models \3\ for some time, creating risk scores for
plants. Similar risk scores can be created at the drug level. Scores
recently have been created for valsartan \4\; it's quite possible other
drug-level models exist. Once these risk scores are determined to be
reasonably predictive of drug problems in the field (the definition of
``reasonably'' can be made public; i.e., what is the predictive
accuracy for what dependent variable?), these risk scores should also
be made available.
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\3\ https://www.fda.gov/media/116004/download.
\4\ https://www.medrxiv.org/content/10.1101/2020.05.22.20110775v1.
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Even better, third-party testing of scientifically valid random
samples should be performed and made public, at least to healthcare
professionals. Valisure \5\ has created a market for itself as ``the
pharmacy that checks.'' But, why should pharmacies have to test drugs
to ensure their safety? CVS and Walgreens do not do this, meaning that
the majority of consumers get drugs that rely on testing by the firms
selling the drugs. I make two points about the testing of drugs for
quality:
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\5\ https://www.valisure.com/.
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Unlike many consumer products, consumers/patients
generally cannot know if there is a problem with their drug by looking
at it. Further, even after taking the drug, it is hard to pinpoint that
any side effects are the result of drug quality. This lack of quality
visibility makes testing more critical in the drug industry than in
many other industries. It also increases the risk that manufacturers,
facing cost and delivery pressures, allow drugs to be shipped that did
not meet all process and/or product specifications.
Relatedly, testing the quality of drugs is not as
easy as testing many consumer products. Take, for example, electronics.
Electronics production lines often have functionality testing built in,
as the last step of the process, meaning that 100% of the product are
tested for all--or at least most--potential defects. 100% of drugs
cannot be tested, as the tests are destructive. Further, 100% of
possible defects cannot be tested. For example, unforeseen
contaminants, for which tests are not conducted, could enter the drug
supply. Or, processing steps could not be followed in a way that
affects stability (i.e., the efficacy and safety of the drug over
time); such process deviations may not be evident from tests conducted
shortly after production. Further, testing is typically at the batch
level. As more production moves to continuous manufacturing, isolating
the drugs affected by a test becomes more difficult.
Transparency in drug manufacturing location and quality will
make it more profitable to operate with high quality, and less
profitable to operate with low quality. The market, with knowledge of
quality, will be willing to pay more for high-quality drugs and less,
or possibly nothing, for low-quality drugs. This will naturally lead to
higher levels of quality being built into the manufacturers' processes,
through market mechanisms.
It is also time to treat drug availability as a national security
issue. Regulators should not be caught between a rock and a hard place
in deciding whether to shut down the production of potentially low-
quality drugs at a plant and risk a shortage, or whether to allow
potentially compromised product into the market to ensure drug
availability. Government planning should include:
Identifying drugs whose shortage could pose a national security
threat.
Consider Active Pharmaceutical Ingredients (APIs)
and even excipients in this analysis (i.e., the upstream components
needed to produce these drugs).
For these drugs, ensure domestic capability exists to produce
them; or to ramp up production in the time before shortage (again,
including APIs and excipients). Or, increase the availability of these
drugs after a supply loss using the stockpile \6\ (the stockpile needs
to be cycled through regularly to avoid expiration). The investment in
capacity to produce/ramp-up vs. investment in the stockpile is a
tradeoff that will depend, among other things, on: the shelflife/
stability of the drug (and the cost to store), the cost of production
capacity, and the time to ramp up new capacity. It needs to be a drug-
by-drug analysis.
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\6\ https://www.phe.gov/about/sns/Pages/default.aspx.
These regulatory fixes should lead to improvement in both the quality
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and availability of drugs.
Sincerely,
John V. Gray
______
TruTag Technologies, Inc.
2200 Powell Street, Suite 1035
Emeryville, California 94608
The FDA witnesses in the Senate's COVID-19 and Beyond: Oversight of the
FDA's Foreign Drug Manufacturing Inspection Process hearing provided
expert testimony on the nuances of regulating medication during the
COVID-19 pandemic. The global nature of America's pharmaceutical supply
chain inherently complicates FDA efforts to safeguard the American
consumer. As a member of the FDA's Emerging Technology Program, TruTag
stands ready to assist the FDA and the American public in ensuring that
both regulators and consumers have the ability to verify that their
medication is manufactured in certified facilities, regardless of
packaging.
The stresses on the medical supply chain presented by the COVID-19
pandemic require novel solutions to ensure that criminal entities
cannot take advantage of American consumers. Two key points mentioned
by the FDA witnesses in the June 2nd Senate hearing are the importance
of developing new enforcement and regulatory tools and an emphasis on
increasing transparency and accountability in the pharmaceutical supply
chain. TruTag Technologies' proprietary silica microtagging is
perfectly suited for supporting both of these critical tasks. By
encoding existing silica coatings with precise spectral signatures,
TruTag Technologies has been able to create a tracking solution which
seamlessly meshes with pharmaceutical manufacturing without increasing
the cost to consumers. Not only can regulators leverage TruTag
Technologies' innovation to verify pharmaceutical origin, facilitating
regulatory agility in the event of new public health crises,
counterfeiting, or diversion; TruTag Technologies' mobile app enables
the American consumer to directly confirm the identity and composition
of their medication, regardless of packaging or labeling. Additionally,
because TruTags are integrated into the pill coatings themselves,
TruTags are impossible to counterfeit, unlike existing serialization
and QR code techniques.
We at TruTag Technologies applaud the FDA's efforts to catalyze new
technological development to ensure that the United States has access
to an extensive supply of verified, safe pharmaceuticals; we urge our
legislators to support the FDA in this vital role.
______
U.S. Pharmacopeia
It is incontrovertible that the COVID-19 pandemic has exposed
vulnerabilities in the medicine supply chain. As outlined in our
comments below, USP believes that now is the time to put in place
policies and investments to build a more resilient supply chain to help
ensure patient trust in the consistent supply of safe, quality
medicines and medical products.
We greatly appreciate the Committee's effort to ensure that the
medicines Americans rely on meet the quality expectations reflected in
federal law. The United States drug supply is among the safest in the
world. However, given the complexity of the global supply chain for
medicine and the vulnerabilities exposed during this pandemic, we
believe that it is imperative to take specific steps to strengthen it.
Within this context, we are pleased to submit the following statement
for the record on the hearing ``COVID-19 and Beyond: Oversight of the
FDA's Foreign Manufacturing Inspection Process.''
Increase transparency in the global supply chain for medicines
Over the last decade, drug manufacturing in the United States has
become increasingly dependent on foreign sources for both finished drug
products and active pharmaceutical ingredients (API). It is estimated
that 70% of API manufacturers for products intended for the U.S. market
are located outside of the United States, mostly in China and India. In
this respect, the supply chain is not ``global'' but is
``concentrated,'' which creates considerable risk when acute
disruptions occur and raises concerns about America's ability to ensure
the availability of essential medicines. This was evident earlier this
year when cities in China shut down and the production of some
medicines was halted. India also restricted the export of certain
medicines. Disruptions such as geopolitical crises, natural disasters,
and pandemics like COVID-19 can cause major interruptions in the supply
of quality medicines and have a global impact.
USP believes that more transparency is needed in order to more
accurately pinpoint where medicines and their ingredients are produced.
For example, while API manufacturers are currently required to register
with FDA, they do not have to report the quantity of API they produce.
By requiring API manufacturers to report quantities, FDA would have a
clearer picture of how much API is produced and by which manufacturers.
Furthermore, while there has been a greater focus on API, there are
other, inactive ingredients, also known as excipients, that comprise a
finished drug product. Additional transparency over the source and
quantity of these ingredients is needed.\1\ Drug labeling requirements
are also essential in tracking the supply chain of medicines.
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\1\ USP's policy paper on building a more resilient supply chain
includes additional recommendations for addressing vulnerabilities in
the global supply chain (see Attachment 1).
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Invest in advanced manufacturing technologies for domestic production
of the most critical medicines and API
Among the key elements necessary to build a more resilient supply chain
is the development and adoption of advanced drug manufacturing
technologies such as continuous manufacturing. Continuous manufacturing
is an approach that automates and integrates medicine production from
start to finish. This reduces the capital investment, physical
footprint, and environmental impact compared to traditional batch
manufacturing. Continuous manufacturing, if broadly adopted, will
greatly increase efficiency to produce critical drugs and API, while
also ensuring adherence to appropriate quality standards throughout the
process. This technology has been deployed for the manufacture of
several innovator drug products, but it has yet to be adopted on a
wider scale for the most essential (and generally generic) medicines
that are often needed in a crisis situation.
USP has been working to address barriers to adoption of continuous
manufacturing by providing testing and analytical research needed to
ensure quality in this process. Further, USP is taking steps to develop
training for the workforce needed to broadly operationalize this
technology. Specifically, we are engaging with academic research
centers, manufacturers, and regulators to identify and articulate
appropriate standards and practices that will make advanced
manufacturing, including continuous manufacturing, more accessible and
feasible for industry uptake.
We are pleased that there is bipartisan support in Congress for
legislation (H.R. 4866, S. 3432) that would help promote development of
continuous manufacturing through designation of National Centers of
Excellence in Continuous Pharmaceutical Manufacturing. As proposed,
only qualifying institutions of higher learning would be eligible for
designation as a Center of Excellence. We believe that other non-profit
organizations, such as USP, could play an important role in this space
and urge that the definition of eligible institutions be expanded to
include qualifying non-profit organizations. USP supports this
legislation and believes that we can play a robust role in helping to
accelerate adoption of continuous manufacturing.
Additionally, as Congress considers further action to combat COVID-19
and strengthen the pharmaceutical supply chain, USP urges that
additional resources be made available to federal agencies to support
advanced manufacturing, and that incentives, including market-based
initiatives, are provided to better enable manufacturers to invest in
these new technologies.
Invest in a comprehensive Strategic National Stockpile (SNS)
The pandemic has exposed areas for improvement in the breadth of the
nation's stockpile of medicines and medical equipment as well as
important ancillary products. As the United States re-evaluates the SNS
and bolsters its ability to prepare for, and respond to a pandemic, USP
believes that ensuring the quality of medicines in the SNS, preparing
for the need to test the quality of medicines purchased to respond to a
pandemic, and enhancing medicine manufacturing capacity should be
priorities.
In response to a request for information from the Department of Health
and Human Services, we proposed that USP reference standards be part of
a managed initiative that makes these standards \2\ readily available
to help ensure the quality of drugs and other medical products included
in the SNS (see Attachment 2). Enabling readily available access to USP
reference standards would:
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\2\ USP public quality standards include two components that work
together: documentary standards and reference standards. Documentary
standards include monographs, which are
substance-specific or product-specific and articulate the quality
expectations for a medicine, including its identity, strength, and
purity. Documentary standards, both in monographs and in general
chapters, also describe the tests to validate that a medicine and its
ingredients meet these criteria and provide tests to predict and
demonstrate how the medicine will be released as it enters the human
body. These standards are included in the United States Pharmacopeia-
National Formulary (USP-NF) online platform. A USP physical standard,
also known as a reference standard, is a highly characterized specimen
of a drug substance or ingredient that facilitates testing to the
specifications outlined in the USP-NF. Reference standards are used in
conjunction with documentary standards to verify that a medicine and
its ingredients adhere to quality requirements. They are rigorously
tested and evaluated by multiple independent commercial, regulatory,
and academic laboratories to confirm accuracy and reproducibility.
1. Allow government agencies to evaluate the quality of medicines
purchased to respond to public health emergencies, regardless of the
manufacturer or manufacturing process;
2. Help the government evaluate and ensure the continued quality
of medicines in the SNS; and
3. Help industry and government-funded programs expand
manufacturing capacity of medicines associated with public health
emergencies, such as the COVID-19 pandemic.
Utilize public standards to identify impurities in drug products
The significant safety concerns associated with unsafe levels of
certain impurities in drug products were recently underscored when
nitrosamine impurities were found in some widely used medicines,
leading to major product recalls.
Insights gained from the toxicological science and sources of
impurities, such as nitrosamines, can be applied to develop risk-based
approaches to address impurities of potential concern. USP is working
to support manufacturers and regulators with tools and solutions for
testing, assessing risk, and understanding potential sources of these
impurities. For example, we are developing a documentary standard, in
the form of a general chapter,\3\ that provides broadly applicable
risk-based approaches and validated tests for manufacturers, with
accompanying physical reference standards that can be used to verify
that a medicine and its ingredients pass tests to ensure adherence to
quality requirements. These will be available later this summer. We are
confident that these tools (which are validated at USP laboratories),
will be useful resources to improve product quality. In the longer
term, USP is working on risk-based predictive tools for handling
impurities so that problems can be detected earlier, in the hopes of
preventing large-scale drug recalls.
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\3\ USP general chapters are documentary standards that provide
broadly applicable information to industry on accepted processes,
tests, and methods to support product development and manufacturing for
innovative, generic, and biosimilar medicines.
When testing for impurities in general, it is essential to use a method
demonstrated to be suitable for its intended purpose. Use of
inappropriate tests and methods can increase the risk of generating
misleading results, potentially leading to poorer quality of medicines
and/or requiring industry and regulators to perform potentially
unnecessary follow-up. This can impact the supply chain and has the
potential to undermine patient and practitioner confidence in essential
---------------------------------------------------------------------------
medicines.
Advances in chemistry make it possible to synthesize drug components
using different methods, which can lead to the development of
impurities that were not present in previous manufacturing processes.
Impurities included in a USP monograph represent those expected to be
present in a product when manufactured under the conditions approved by
FDA in a specific drug application. Post-approval changes in synthesis
and manufacturing processes can introduce new impurities that monograph
tests are not designed to detect. Manufacturers are required to share
such process changes and information about new impurities with FDA.
Greater transparency and increased information sharing through the
creation of a shared systematic mechanism between industry, FDA, and
USP regarding impurities in drugs (including their presence, acceptable
limits, and control) can help ensure that standards are updated to
include the most current and relevant quality and safety information
for all manufacturers. Furthermore, faster detection of impurities can
occur if manufacturers and regulators can publicly share information on
new impurities, as appropriate.
Conclusion
We thank the Committee for holding this hearing and drawing attention
to these important patient safety and medicine quality concerns as we
continue to address the impact of COVID-19. USP looks forward to
providing information and expertise and is committed to continue
working with Congress, FDA, and stakeholders to advance our shared goal
of helping to ensure the supply of quality medicines for patients.
About USP
USP is an independent, scientific, non-profit organization dedicated to
improving health through the development of public quality standards
for medicines, foods, and dietary supplements. Having created quality
standards for medicines in and outside of the United States for 200
years, USP has a unique lens into the global medicine supply chain.
Today, we provide thousands of manufacturers around the world with
critical standards for ensuring the safety and quality of their
medicines, including API.
Our mission is to improve global health through public standards and
related programs that help ensure the quality, safety, and benefit of
medicines and foods. USP standards are developed by Expert Committees
and Panels comprised of more than 800 independent, scientific experts
who collaborate in a transparent process. USP is governed by more than
460 organizations from the scientific, healthcare practitioner,
consumer, and industry communities, including dozens of government
agencies, who together comprise the USP Convention.\4\ Our staff are
based in the United States and around the world in locations where
America's medicines and their ingredients are manufactured, including
India and China. USP staff work with regulators, industry, health care
practitioners, and other stakeholders to help ensure that our standards
are utilized effectively to safeguard patients.
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\4\ USP's other governing bodies include its Board of Trustees,
Council of Experts, and Expert Committees.
In addition to being legally recognized in the United States, USP
standards are recognized in the laws of 40 other countries and are
utilized in more than 150 countries. While there are many components to
the regulatory framework to safeguard medicine quality, publicly
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available quality standards and adherence to them remain foundational.
______
Attachment 1
USP Global Public Policy Position
Key Elements to Building a More Resilient Supply Chain
Issue
Today, patients in the United States and around the world depend on
medicines--and the ingredients used to make those medicines--sourced
from and manufactured around the globe. This global supply chain for
medicines, while providing some inherent risk mitigation, has numerous
vulnerabilities that can be challenged by acute disruptions. When such
a disruption occurs, concerns arise regarding the quality and safety--
as well as shortages--of medicines, particularly those used for
critical treatments. Unfortunately, the COVID-19 pandemic brought these
impacts into sharp focus.
11 Key Elements for a More Resilient Supply Chain
USP supports a comprehensive public policy framework to build a more
resilient supply chain, including advancing the use of pharmacopeial
standards across the supply chain, to help ensure the supply of quality
medicines. We propose the following key elements be integrated into
policy frameworks to build more resilience into the medicines supply
chain.
Foster more, not less, supply chain diversity
1. Increase geographic diversity for ingredients and manufacturing--
Policymakers should incentivize geographic diversity among the sources
of medicine ingredients and drug manufacturing to reduce the risk of
shortages from acute disruptions that occur in one geographical
location (e.g., earthquake, hurricane, political disruption) or that
move from one part of the world to others (e.g., pandemic).
2. Establish baseline of local production capacity--Governments and
manufacturers should facilitate the development of local production
capabilities to secure a supply of essential quality-assured medicines
and vaccines for their population when acute disruptions arise.
Invest in more manufacturing capacity for critical medicines
3. Facilitate an adequate supply of therapeutics and vaccines--
Governments should help ensure an appropriate supply of the medicines
and vaccines needed to address the most urgent public health concerns
by leveraging capital investments to facilitate additional
manufacturing capacity, implementing policy reforms to encourage
greater competition, and ensuring access to quality and affordable
medicines.
4. Invest in advanced technologies--Governments should incentivize
advanced technologies (e.g., continuous pharmaceutical manufacturing)
through direct investments and other measures to enable more efficient
and nimble production of essential medicines and vaccines and to buffer
against disruptions in supply during a global crisis.
Enable more transparency and data sharing
5. Increase transparency across the supply chain--To enable
appropriate actions--in and across countries--to address and avoid
potential supply chain concerns, governments should expand public
reporting requirements to healthcare providers and industry for
indicators on existing or potential drug shortages. Drug manufacturers
and ingredient suppliers should be required to monitor and report to
governments on their capacity and the quality of ingredients they
source.
6. Enhance global cooperation--Pharmacopeias and regulators around the
world should increase information-sharing and consider recognition and
reliance agreements. This will help to efficiently mobilize resources
during public health emergencies such as pandemics, coordinate access
to essential medicines and vaccines, and disincentivize a market for
substandard and falsified medicines.
Conduct crisis contingency planning and action
7. Require contingency planning--Policymakers should encourage and
incentivize medicine manufacturers to develop backup plans, including
for production lines and quality control. Manufacturers of critical
medicines also should have other redundancies in place in the event of
an acute disruption, to ensure continued access to quality medicines.
8. Build and maintain critical medical product stockpiles--Governments
should build and maintain stockpiles of critical medicines and medical
products to be prepared to meet the needs of patients and healthcare
providers if product shortages result from a crisis. The composition of
products in national stockpiles should be continually reviewed and
modified to address the most likely shortages of the most critical
products. Medical supplies to protect the safety of frontline
healthcare workers should be a priority.
9. Plan for distribution resilience--Governments should issue
enforceable guidance to ensure the free flow of ingredients and
materials (including quality standards and physical reference
standards) to enable medicine manufacturing to continue during a
crisis. In addition, governments should develop contingency plans to
ensure that distribution logistics are in place to transport critical
medical products to providers.
Strengthen regulatory systems and quality assurance
10. Strengthen regulatory oversight--Governments should invest in
stronger regulatory systems that can efficiently review applications
for therapeutics and vaccines, and enforce existing regulations that
protect patient safety, including adherence to quality standards.
Reliance mechanisms or regional regulatory systems can operate as
networks to share information on quality, efficacy, and safety, thereby
reinforcing regulatory oversight.
11. Bolster quality assurance systems and adherence to public quality
standards--Regulators should strengthen quality assurance systems
through investments in workforce training and national drug quality
control laboratories and should stress adherence to science-based
public quality standards, which are essential to maintaining the trust
of healthcare professionals and patients in medicine quality. Moreover,
countries around the world should ensure compliance to international
standards, including good manufacturing practices and science-based
public quality standards, so that medicines and ingredients from more
locations can be trusted in the global supply chain.
Discussion
Over the last decade or so, global medicines supply chains have moved
from being vertically integrated, where a drug manufacturer owns or
controls most aspects of production (including suppliers), to
horizontal, where many functions in the supply chain (such as the
production of both active pharmaceutical ingredients (APIs) and
inactive ingredients) are increasingly outsourced to many companies
around the world. In many cases, these companies are concentrated in
certain geographical areas.
The COVID-19 pandemic has exposed vulnerabilities in the current way
the medicines supply chain works, including geographically concentrated
sourcing and manufacturing, uneven regulatory environments, and
regulatory enforcement or inspection capacity constraints. Many
countries may soon, if they have not already, face disruptions such as
medicine shortages, concerns over substandard or falsified medicines,
and price volatility. Having policies in place to build a more
resilient supply chain can help ensure the continued availability of
safe, quality medicines for patients around the globe-even in times of
a pandemic crisis. While the current COVID-19 crisis points to the
supply chain impact of a pandemic, other acute supply chain disruptors
include weather events such as hurricanes and earthquakes, as well as
product recalls.
The globalization of supply chains has led to geographic concentration
of manufacturers of both ingredients and finished medicines in certain
locations where labor and raw material costs may be lower,
environmental regulations more permissive, and infrastructure
subsidized by the public sector. While this concentration has likely
led to lower costs for many medicines and their ingredients, it poses a
risk to the reliability of supply in crisis situations and raises
quality and safety concerns.
During a pandemic, sourcing from only a few countries can have
unintended consequences. For example, countries that make medicines and
APIs may withhold essential public health resources--including
therapeutics intended for COVID-19--as well as other therapies needed
to address national health priorities. For instance, India briefly
withheld exports on selected medicines, including some antibiotics and
painkillers, and has restricted the export of antimalarials now being
considered as potential (though still unproven) treatment options for
COVID-19.\1\, \2\ Countries may also compete with each other
to procure medications. Diversifying sources of both pharmaceutical
ingredients and finished medicines can help reduce the risk of
concentration in only one place, and appropriate incentives to
facilitate this diversification should be considered.
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\1\ Government of India Ministry of Commerce and Industry.
Department of Commerce. Directorate General of Foreign Trade. Amendment
in Export Policy of APIs and formulations made from these APIs. New
Delhi. March 3, 2020. https://dgft.gov.in/sites/default/files/Noti%2050
_pdf.
\2\ Government of India Ministry of Commerce and Industry.
Department of Commerce. Directorate General of Foreign Trade. New
Delhi. Amendment in Export Policy of Hydroxychloroquine. https://
dgft.gov.in/sites/default/files/notification%2054_0.pdf.
Increased line-of-sight across all parts of the supply chain can also
help make the supply chain stronger. Regulators, along with pharmacies,
hospitals, and providers, need to know more about where medicines and
ingredients are manufactured and how they have passed through the
supply chain. This information can inform risk mitigation decisions and
help governments and providers plan for the supply of quality medicines
needed to treat patients. This is essential to building and maintaining
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the public's trust.
Today, regulators have limited and inconsistent information on the
sources of the ingredients in medicines or the volume of medicines
produced from manufacturing facilities around the world. Information-
sharing between regulators and industry is also needed to see clearly
across the supply chain. New reporting requirements for finished drug
products and ingredient makers can increase transparency and should be
balanced with appropriate protections for trade secrets and
confidential commercial information. Further, if manufacturers can use
new technologies (e.g., AI) to strengthen their ability to monitor
their suppliers, and thereby understand the global presence of both
their suppliers and their subcontractors, they may be able to mitigate
problems more immediately as they arise.
A requirement for drug and API manufacturers to develop contingency
plans in the event of a disruption in production would help to ensure a
continued supply of quality medicines. Such measures should include
establishing alternative sources of API and other ingredients, shifting
production lines, and implementing quality control. These contingencies
should also apply to ensuring the availability of medical products such
as personal protective equipment, bags for intravenous fluids,
syringes, and other supplies needed to provide care that would be
impacted by supply chain disruptors.
Strong regulatory oversight is needed to withstand disruptions in the
supply chain. Strengthened oversight by regulatory authorities includes
deployment of tools such as supplier verification and audits to ensure
the quality of ingredients, along with track-and-trace mechanisms to
determine drug and ingredient current and past locations. Risk-based
analysis can help countries understand the most critical--or
vulnerable--points in the supply chain. In the absence of tracking and
tracing of products, especially as the supply chain diversifies,
quality testing can serve as a last line of defense. During times of
crisis, aggressive enforcement action by regulatory bodies against
substandard and falsified products, unverified or false claims of
treatments or cures, and price gouging, is needed to prevent further
harm.
Advanced manufacturing technologies, such as continuous manufacturing,
provide more streamlined, consistent, and efficient production of
medicines than traditional approaches. Efforts to operationalize this
technology, including incentives to allow for its rapid deployment,
should be pursued. Given the current global pandemic, countries should
incentivize and accelerate longer-term efforts to help expand the
continuous manufacturing infrastructure in both the United States and
in other countries for generic and branded medicine production.
Enhanced global cooperation can help countries secure critical
medicines, especially in light of challenges caused by border closures
as a result of COVID-19. Regulatory authorities that share information
have expedited the approval of essential vaccines and medicines,
prevented the distribution of substandard and falsified medicines, and
quickly mobilized resources during drug shortages and public health
emergencies. A recognition or reliance arrangement, whereby one agency
recognizes or relies on another's work as equivalent to its own, allows
medicine regulators to make use of shared information while being able
to make their own decisions. Examples of information that regulators
can share with each other include clinical assessments, manufacturing
site inspections, and post-market safety data.
Maintaining the quality of medicines during a global crisis is
paramount to ensuring they work in the way they are intended. In
responding to disruptions, countries may purchase medicines from
untested suppliers, which in turn could create a market for substandard
or falsified medicines.\3\ Low- and middle-income countries are
especially vulnerable, as their already under-resourced regulatory
systems would come under additional stress. Consumers may also buy
medicines from the Internet, where oversight is weaker and bad actors
proliferate. In addition, the urgency to develop new therapeutics and
vaccines cannot be separated from the need to assure quality. Ensuring
pharmacopeial standards are met across the supply chain can help
regulators and industry ensure continued access to quality medicines.
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\3\ Pisai, Elizabeth. ``The COVID pandemic increases the chance
that your other medicines won't work.'' Medium. March 29, 2020. https:/
/medium.com/@elizabethpisani/the-cov1d-pandemic-increases-the-chance-
that-your-other-medicines-wont-work-66b7e272bb20.
Encouraging greater competition, especially for products with either a
single source or few manufacturers, would help lead to increased access
to critical medicines. Once a vaccine for COVID-19 is discovered and
approved for use, local capacity to manufacture may become a priority
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to ensure widespread, equitable, and rapid distribution.
It also is important that governments plan for resilience in
distribution. Regulators should issue standing guidance that clarifies
the ingredients, materials, and standards that must remain available in
global commerce for the manufacture of critical medicines. Moreover,
contingencies for the transport of medicines and medical supplies is
essential to account for the potential malfunction of traditional
transportation modalities in a crisis situation. In addition to
contingency planning for medicines, it is equally essential for
personal protective equipment to protect the safety of frontline
healthcare workers. Distributors, including wholesalers, must follow
good distribution practices to assure medicine and ingredient quality
through procurement, purchasing, transport, distribution, repackaging,
relabeling, storage, and documentation. Logistics and transport
considerations are critical to ensuring essential medicines can make it
to patients.
Finally, to be prepared to meet the needs of patients and healthcare
providers if product shortages result from a crisis, governments should
build and maintain stockpiles of critical medicines and medical
products with unexpired inventory. The composition of products in
national stockpiles should be continually reviewed and modified to
address potential shortages of the most critical medical products.
Call to Action
USP encourages investment and policy reform toward building a more
resilient global supply chain. The current vulnerabilities in the
supply chain are the result of a number of factors, so solutions to
address these vulnerabilities must account for these variations. The
key elements outlined above require action by all those in the supply
chain, including manufacturers, distributors, policymakers and
regulators, and public health experts.
About USP
Founded in 1820, USP is an independent, nonprofit, science based
organization that safeguards the public's health globally by developing
quality standards for medicines, dietary supplements, food ingredients,
and healthcare quality. USP standards describe specifications and tests
for identity, strength, quality, and purity. USP standards are
enforceable by the U.S. Food and Drug Administration (FDA) for
medicines and their ingredients imported into or marketed in the United
States and have been used in more than 140 countries. Such standards
also assist industry in the development, manufacturing, and testing of
medicines. USP standards are developed by independent experts through a
transparent scientific process, with input from stakeholders and
federal agencies such as FDA and the Centers for Disease Control and
Prevention.
USP's Promoting the Quality of Medicines Plus (PQM+) program improves
access to quality-assured priority medicines and addresses the
proliferation of poor-quality medical products in low- and middle-
income countries. PQM+ strengthens medical product quality assurance
systems in low- and middle-income countries through cross-sectoral and
systems strengthening approaches and the application of international
quality assurance standards across the pharmaceutical system.
USP is implementing a comprehensive program to support the public
health response to the COVID-19 pandemic. Our immediate work is focused
on facilitating the supply of quality medicines across the global
supply chain--especially for those medicines that treat symptoms
associated with the virus--by working closely with regulators,
manufacturers, and other stakeholders around the world. We are also
engaging in middle- and long-term activities to assess vulnerabilities
in the global supply chain for medicines, advocate for greater
transparency and more diversity in the sources of medicines and their
ingredients, and ultimately help build a more resilient supply chain.
______
Atttachment 2
June 3, 2020
U.S. Department of Health and Human Services (HHS)
Office of the Assistant Secretary for Preparedness and Response (ASPR)
Division of the Strategic National Stockpile (DSNS)
Re: RFI # 75A50120NEXTGENSNS
Dear Sir/Madam,
The United States Pharmacopeia (USP) appreciates the opportunity to
provide comments in response to the request for information (RFI) from
HHS/ASPR/DSNS on the Strategic National Stockpile (SNS). USP is an
independent, scientific, nonprofit public health organization founded
in 1820 that works to improve health through the development of public
standard s and related programs that help ensure the quality, safety,
and benefit of medicines and foods.
USP's public standards define quality expectations for medicines and
are developed by Expert Committees and Panels, which are comprised of
over 1,000 independent, scientific experts and include the
participation of over 100 government liaisons from the Food and Drug
Administration (FDA). The United States Pharmacopeia-
National Formulary (USP-NF) includes over 5,000 documentary quality
standard s for drug substances and drug products.\1\ Material reference
standards are used in conjunction with these documentary standards to
verify that a medicine and its ingredients can pass tests to ensure
adherence to quality requirements. USP standards are legally recognized
in the United States and are used in more than 150 countries.
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\1\ USP standards are developed through an open, transparent,
expert-based process, offering the ability to respond to public health
emergencies, adapt to new industry practices, and support evolving
science and technology.
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Response to Section 1/Question 1--``Do you agree with the stated
objectives of the SNS? Have we missed anything
major in articulating our vision?''
USP supports the objectives of the SNS and the expansion of public-
private partnerships. USP believes that a contempora1y SNS will need to
include an appropriate volume of the most critical medicines,
manufactured and maintained to quality expectations. To ensure the
quality of these medicines, as well as any that are manufactured and
purchased by the U.S. government during a crisis, the SNS should also
include the USP material reference standards required to test these
medicines.
As explained in more detail below, enabling readily available access to
USP reference standards would: (1) help industry and government-funded
programs expand manufacturing capacity of medicines associated with
pandemics, such as COVID-19; (2) allow government agencies to evaluate
the quality of medicines purchased to respond to a pandemic, regardless
of the manufacturer or manufacturing process; and (3) help the
government evaluate and ensure the continued quality of medicines in
the SNS.
Response to Section 1/Question 3--``How can your organization
contribute to achieving the vision for the SNS?''
USP stands ready to help ensure that the medicines in the SNS are
quality assured. Specifically, we propose that USP reference standards
be part of a managed initiative that makes reference standards for
stockpiled medicines available to test medicines in the SNS for their
quality.\2\ Readily available standards will enable regulators to
evaluate and ensure the quality of medicines in the SNS. Moreover, a
managed SNS invento1yof reference standards would support industry and
government-funded programs to expand the manufacturing capacity for
quality medicines during a crisis. It is essential for public health
and patient safety that the quality of drugs in the SNS is ensured, and
reference standards are necessary to do this.
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\2\ USP also recommends including in the SNS items such as
chromatography equipment and substances (e.g., reagents) for use in
conducting tests and analyses with reference standards.
As stated above, USP public quality standards include two components
that work together: documenta1y standards and reference standards.
Documentary standards are substance-specific or product-specific that
articulate the quality expectations for a medicine, including its
identity, strength, and purity. Documentary standards also describe the
tests to validate that a medicine and its ingredients meet these
criteria. These are included in the USP-NF online platform in the form
of monographs. A USP physical standard, also known as a reference
standard, is a highly characterized specimen of a drug substance or
ingredient that facilitates testing to the specifications outlined in
the USP-NF. Reference standards are used in conjunction with
documentary standards to verify that a medicine and its ingredients
adhere to quality requirements.\3\ They are rigorously tested and
evaluated by multiple independent commercial, regulatory, and academic
laboratories to confirm accuracy and reproducibility.
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\3\ Additional information on the use of reference standards can be
found in guidances from the Food and Drug Administration (FDA) and
International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use (ICH). See ``Analytical
Procedures and Methods Validation for Drugs and Biologics,'' at https:/
/www.fda.gov/files/drugs/published/Analytical-Procedures-and-Methods-
Validation-for-Drugs-and-Biologics.pdf; ``Q6B Specifications: Test
Procedures and Acceptance Criteria for Biotechnological/Biological
Products,'' at https://www.fda.gov/media/71510/download; and ``Q7 Good
Manufacturing Practice Guidance for Active Pharmaceutical
Ingredients,'' at https://www.fda.gov/media/71518/download.
In addition to being required for quality testing, reference standards
and access thereto in a time of crisis facilitate the expeditious
production of quality medicines for the SNS. USP reference standards
support manufacturer's ability to test its products during the drug
manufacturing process. Ready access to standards--both documentary and
reference--is especially needed, and in greater quantities, when drug
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manufacturing is increased to meet a surge in demand.
In response to increased demand for pa1iicular drug products related to
the current pandemic, USP has taken steps to ensure continued
operations of essential services, including the production of reference
standards, to minimize disruptions and support the medicines supply
chain. Looking ahead, however, it is difficult to predict all rapid
increases in demand. Setting aside specific reference standards
maintained at USP facilities in Ma1yland to support the SNS will help
secure capacity and support production of critical medicines,
particularly in a time of crisis. USP can work with HHS/ASPR/DSNS to
determine which reference standards, and the volume of each standard,
are needed for the current and evolving stockpile.
* * *
Thank you again for the oppo1iunity to comment on this RFI. USP stands
ready to work with HHS/ASPR/DSNS to help support manufacturer capacity
to produce drugs that meet quality standards. For more information,
please contact Carrie Harney, Senior Director, Government Affairs,
Policy and Advocacy, at [email protected] or (202) 239-4136.
Sincerely yours,
Anthony Lakavage, J.D.
Senior Vice President, Global External Affairs
Secretary, USP Convention and Board of Trustees
[email protected]
(301) 816-8334
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