[House Hearing, 113 Congress]
[From the U.S. Government Publishing Office]
21ST CENTURY CURES: INCORPORATING THE PATIENT PERSPECTIVE
=======================================================================
HEARING
BEFORE THE
SUBCOMMITTEE ON HEALTH
OF THE
COMMITTEE ON ENERGY AND COMMERCE
HOUSE OF REPRESENTATIVES
ONE HUNDRED THIRTEENTH CONGRESS
SECOND SESSION
__________
JULY 11, 2014
__________
Serial No. 113-158
Printed for the use of the Committee on Energy and Commerce
energycommerce.house.gov
________
U.S. GOVERNMENT PUBLISHING OFFICE
91-848 PDF WASHINGTON : 2015
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COMMITTEE ON ENERGY AND COMMERCE
FRED UPTON, Michigan
Chairman
RALPH M. HALL, Texas HENRY A. WAXMAN, California
JOE BARTON, Texas Ranking Member
Chairman Emeritus JOHN D. DINGELL, Michigan
ED WHITFIELD, Kentucky Chairman Emeritus
JOHN SHIMKUS, Illinois FRANK PALLONE, Jr., New Jersey
JOSEPH R. PITTS, Pennsylvania BOBBY L. RUSH, Illinois
GREG WALDEN, Oregon ANNA G. ESHOO, California
LEE TERRY, Nebraska ELIOT L. ENGEL, New York
MIKE ROGERS, Michigan GENE GREEN, Texas
TIM MURPHY, Pennsylvania DIANA DeGETTE, Colorado
MICHAEL C. BURGESS, Texas LOIS CAPPS, California
MARSHA BLACKBURN, Tennessee MICHAEL F. DOYLE, Pennsylvania
Vice Chairman JANICE D. SCHAKOWSKY, Illinois
PHIL GINGREY, Georgia JIM MATHESON, Utah
STEVE SCALISE, Louisiana G.K. BUTTERFIELD, North Carolina
ROBERT E. LATTA, Ohio JOHN BARROW, Georgia
CATHY McMORRIS RODGERS, Washington DORIS O. MATSUI, California
GREGG HARPER, Mississippi DONNA M. CHRISTENSEN, Virgin
LEONARD LANCE, New Jersey Islands
BILL CASSIDY, Louisiana KATHY CASTOR, Florida
BRETT GUTHRIE, Kentucky JOHN P. SARBANES, Maryland
PETE OLSON, Texas JERRY McNERNEY, California
DAVID B. McKINLEY, West Virginia BRUCE L. BRALEY, Iowa
CORY GARDNER, Colorado PETER WELCH, Vermont
MIKE POMPEO, Kansas BEN RAY LUJAN, New Mexico
ADAM KINZINGER, Illinois PAUL TONKO, New York
H. MORGAN GRIFFITH, Virginia JOHN A. YARMUTH, Kentucky
GUS M. BILIRAKIS, Florida
BILL JOHNSON, Missouri
BILLY LONG, Missouri
RENEE L. ELLMERS, North Carolina
Subcommittee on Health
JOSEPH R. PITTS, Pennsylvania
Chairman
MICHAEL C. BURGESS, Texas FRANK PALLONE, Jr., New Jersey
Vice Chairman Ranking Member
ED WHITFIELD, Kentucky JOHN D. DINGELL, Michigan
JOHN SHIMKUS, Illinois ELIOT L. ENGEL, New York
MIKE ROGERS, Michigan LOIS CAPPS, California
TIM MURPHY, Pennsylvania JANICE D. SCHAKOWSKY, Illinois
MARSHA BLACKBURN, Tennessee JIM MATHESON, Utah
PHIL GINGREY, Georgia GENE GREEN, Texas
CATHY McMORRIS RODGERS, Washington G.K. BUTTERFIELD, North Carolina
LEONARD LANCE, New Jersey JOHN BARROW, Georgia
BILL CASSIDY, Louisiana DONNA M. CHRISTENSEN, Virgin
BRETT GUTHRIE, Kentucky Islands
H. MORGAN GRIFFITH, Virginia KATHY CASTOR, Florida
GUS M. BILIRAKIS, Florida JOHN P. SARBANES, Maryland
RENEE L. ELLMERS, North Carolina HENRY A. WAXMAN, California (ex
JOE BARTON, Texas officio)
FRED UPTON, Michigan (ex officio)
C O N T E N T S
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Page
Hon. Joseph R. Pitts, a Representative in Congress from the
Commonwealth of Pennsylvania, opening statement................ 1
Prepared statement........................................... 2
Hon. Henry A. Waxman, a Representative in Congress from the State
of California, opening statement............................... 3
Hon. Fred Upton, a Representative in Congress from the State of
Michigan, prepared statement................................... 5
Witnesses
Janet Woodcock, M.D., Director, Center for Drug Evaluation and
Research, U.S. Food and Drug Administration.................... 6
Prepared statement........................................... 8
Answers to submitted questions............................... 123
Pat Furlong, Founding President and CEO, Parent Project Muscular
Dystrophy...................................................... 53
Prepared statement........................................... 55
Answers to submitted questions............................... 132
Robert J. Beall, Ph.D., President and CEO, Cystic Fibrosis
Foundation..................................................... 58
Prepared statement........................................... 60
Answers to submitted questions............................... 137
Richard F. Pops, Chairman and CEO, Alkermes...................... 68
Prepared statement........................................... 70
J. Leonard Lichtenfeld, M.D., Deputy Chief Medical Officer,
American Cancer Society........................................ 77
Prepared statement........................................... 79
Marshall Summar, M.D., Director, Scientific Advisory Committee,
National Organization for Rare Disorders....................... 85
Prepared statement........................................... 88
Submitted Material
Statement of the National Health Council, submitted by Mr. Pitts. 114
21ST CENTURY CURES: INCORPORATING THE PATIENT PERSPECTIVE
----------
FRIDAY, JULY 11, 2014
House of Representatives,
Subcommittee on Health,
Committee on Energy and Commerce,
Washington, DC.
The subcommittee met, pursuant to call, at 9:00 a.m., in
room 2322, Rayburn House Office Building, Hon. Joseph R. Pitts
(chairman of the subcommittee) presiding.
Present: Representatives Pitts, Burgess, Shimkus, Murphy,
Blackburn, Gingrey, Lance, Cassidy, Guthrie, Griffith,
Bilirakis, Ellmers, Upton (ex officio), Pallone, Engel, Capps,
Schakowsky, Green, Barrow, Castor, Sarbanes, and Waxman (ex
officio).
Also present: Representative DeGette.
Staff Present: Clay Alspach, Chief Counsel, Health; Gary
Andres, Staff Director; Mike Bloomquist, General Counsel; Sean
Bonyun, Communications Director; Leighton Brown, Press
Assistant; Paul Edattel, Professional Staff Member, Health;
Brad Grantz, Policy Coordinator, O&I; Sydne Harwick,
Legislative Clerk; Robert Horne, Professional Staff Member,
Health; Carly McWilliams, Professional Staff Member, Health;
Macey Sevcik, Press Assistant; Heidi Stirrup, Health Policy
Coordinator; John Stone, Counsel, Health; Jean Woodrow,
Director, Information Technology; Ziky Ababiya, Minority Staff
Assistant; Eric Flamm, Minority FDA Detailee; Karen Lightfoot,
Minority Communications Director and Senior Policy Advisor; and
Rachel Sher, Minority Senior Counsel.
OPENING STATEMENT OF HON. JOSEPH R. PITTS, A REPRESENTATIVE IN
CONGRESS FROM THE COMMONWEALTH OF PENNSYLVANIA
Mr. Pitts. The subcommittee will come to order. We are
going to have early votes, so we are going to have to start. We
understand the minority members are on their way.
The chair will recognize himself for an opening statement.
Today's hearing provides us with an opportunity to examine
perhaps one of the most important aspects of the 21st Century
Cures Initiative. What does medical innovation or faster cures
mean for patients? Keeping our work centered on the patient and
understanding the patient perspective will bring much needed
focus on results for patients who may lack adequate treatment
options. Remember, there are only effective treatments for 500
of the 7,000 known diseases impacting patients today.
While FDA has developed an enhanced structured approach to
benefit risk assessment in regulatory decisionmaking for human
drug device and biologic products, the committee recognizes the
value of considering patients in decisionmaking about therapy
development and access. Assessment of a drug or device's
benefits and risk includes an analysis of the severity of the
condition treated and the current treatment options available,
and getting the patient's unique perspective should be a part
of that assessment.
One of our witnesses today, Pat Furlong of the Parent
Project Muscular Dystrophy, PPMD--and I must say Pat is
accompanied by Mary Bono Mack, a distinguished former member of
this committee. Welcome, Mary. And Pat will explain how this
organization was founded to create opportunities for families
waiting for therapies to stop Duchenne muscular dystrophy from
claiming young lives. To quote Pat Furlong, ``Patient-focused
drug development acknowledges the need to gather input from
patients and their caregivers to create a more complete
assessment of the benefit-risk equation, encouraging
predictability, and increased flexibility within the review
process. The clock is ticking for patients who need and deserve
access to promising therapies.''
I would like to applaud her tireless work drafting guidance
PPMD recently released that actually quantifies patient
priorities and preferences. This guidance will serve the
Duchenne community and every other patient community because it
provides a path for other patient groups to follow. This was an
enormous undertaking, and I am confident it will make a
substantial contribution to the entire medical community.
I would like to welcome our witnesses today and look
forward to learning more about the assessment of benefits and
risks central to medical product development, regulations, and
healthcare decisionmaking and the tradeoffs between desired
benefits and tolerable risk. Thank you.
Any member on the majority side seeking recognition?
[The prepared statement of Mr. Pitts follows:]
Prepared statement of Hon. Joseph R. Pitts
The Subcommittee will come to order.
The Chair will recognize himself for an opening statement.
Today's hearing provides us with an opportunity to examine
perhaps one of the most important aspects of the 21st Century
Cures Initiative: what does medical innovation or faster cures
mean for patients. Keeping our work centered on the patient and
understanding the patient perspective will bring much needed
focus on results for patients who may lack adequate treatment
options. Remember, there are only effective treatments for 500
of the 7,000 known diseases impacting patients today.
While FDA has developed an enhanced structured approach to
benefit-risk assessment in regulatory decision-making for human
drug, device and biologic products, the Committee recognizes
the value of considering patients in decision-making about
therapy development and access. Assessment of a drug or
device's benefits and risks includes an analysis of the
severity of the condition treated and the current treatment
options available and getting the patient's unique perspective
should be a part of that assessment.
One of our witnesses today, Pat Furlong of Parent Project
Muscular Dystrophy--PPMD--will explain how this organization
was founded to create opportunities for families waiting for
therapies to stop Duchene muscular dystrophy from claiming
young lives. To quote Pat Furlong, ``Patient focused drug
development acknowledges the need to gather input from patients
and their caregivers to create a more complete assessment of
the benefit-risk equation, encouraging predictability and
increased flexibility within the review process. The clock is
ticking for patients who need and deserve access to promising
therapies.'' I would like to applaud her tireless work drafting
guidance PPMD recently released that actually quantifies
patient priorities and preferences. This guidance will serve
the Duchene community and every other patient community because
it provides a path for other patient groups to follow. This was
an enormous undertaking, and I am confident it will make a
substantial contribution to the entire medical community.
I want to welcome our witnesses today and look forward to
learning more about the assessment of benefits and risks
central to medical product development, regulations, and
healthcare decision-making, and the tradeoffs between desired
benefits and tolerable risks.
Thank you, and I yield the remainder of my time to --------
------------------------------------.
Mr. Pitts. The chair recognizes the vice chairman, Dr.
Burgess for the remainder of time.
Mr. Burgess. And thank you, Mr. Chairman.
And Dr. Woodcock, thank you for joining us again. It is
always good to see you, always good to have you as a witness.
You always provide valuable testimony. And our second panel
representatives. I also want to acknowledge just as the
chairman did, many of the patient organizations that you
represent have worked well with our office and myself over the
last several years.
Mr. Chairman, the laudable goals of the 21st Century Cures
Initiative, and they are indeed laudable, but we got to
remember, at the end of the day, it is all about patients.
Doctors want to heal. We want to cure. That is why we entered
the profession. No doctor ever wants to tell a patient there is
nothing more we can do. The good news is that the golden age of
medicine is really right around the corner. The doctors of
tomorrow will have tools at their disposal unlike any before in
human history. The ability of tomorrow's doctor to alleviate
human suffering is going to be unparalleled and unmatched in
history. Yet every day that goes by where these tools are not
realized is a day that patients and their families have to
struggle through the pain and suffering of their condition.
Every day counts for these Americans and for their
families. For those who struggle with rare diseases, their
struggle is only compounded by the lack of biomedical research.
For those patients, it is difficult to see over the horizon. We
have much work to do on this committee, and we have done a lot
in the past. We particularly celebrate the 2-year anniversary
of the Food and Drug Reauthorization Act that was just a few
days ago. That was a good template. It was a good method for
moving forward, and I appreciate that the Cures initiative is
following that template, but there is no doubt that we can do
much more.
I welcome the testimony of our witnesses, and I will yield
back my time.
Mr. Pitts. The chair thanks the gentleman.
And I now recognize the ranking member of the full
committee, Mr. Waxman, 5 minutes for opening statement.
OPENING STATEMENT OF HON. HENRY A. WAXMAN, A REPRESENTATIVE IN
CONGRESS FROM THE STATE OF CALIFORNIA
Mr. Waxman. Thank you very much, Mr. Chairman.
This hearing is a fitting followup to Wednesday's hearing
on clinical trials. After all, it is patients who live with the
diseases and conditions for which treatments are being sought,
and this hearing, which is called ``21st Century Cures:
Incorporating the Patient Perspective,'' illustrates that we
should take every opportunity to understand their experience.
Congress has a long history of listening to concerns of
patients. That is what I did in 1983 when I wrote the Orphan
Drug Act. That law came up when I heard from a constituent,
Adam Seligman, who had a rare disease called Tourette's
Syndrome. Adam was forced to take a drug that he could only get
from Canada because, at that time, there were no effective
treatments available in the United States. When his drugs were
ceased at the border, his mother made a desperate call to my
office begging me to do something.
I set out to figure out why there were no drugs in the U.S.
for Adam's condition. We discovered that Adam was not alone.
There are 134 drugs for rare diseases but only 10 had come to
market solely as a result of industry. We knew we had a problem
on our hands, and we set out to solve it.
The Orphan Drug Act has been a resounding success. Today,
there are over 400 drugs for rare diseases, and I want to
welcome the National Organization for Rare Disorders here today
and look forward to their testimony.
I am telling this story about the Orphan Drug Act not only
as an example of how Congress has listened to the concerns of
patients and acted on them, I tell it because it is an example
of appropriate use of legislation. In the case of rare diseases
in the early 1980s, there was very clear evidence of a market
failure in need of congressional action.
In the context of the 21st Century Cures Initiative, we
need to assure that both FDA and the drug and device companies
are listening to the concerns of the patients. FDA has a long
history of engaging with patients, both in the context of
advisory committees and in its review of drugs and devices. In
the 2012 FDA Safety and Innovation Act, Congress pushed FDA to
do even more to hear patients' concerns, and I look forward to
hearing more from FDA today.
From what I can tell, the agency has taken that mandate
seriously and is engaged extensively with the patient
community. We should ask today whether FDA has adequate
resources to continue to do this work.
As I mentioned on Wednesday when we had our last hearing,
when it comes to legislating in complicated scientific areas,
like the conduct of clinical trials, we need to proceed with
great caution. For example, one issue in the area of clinical
trials that is likely to come up today is how to incorporate
so-called patient reported outcomes. As I understand it, this
is an area that is multifaceted and scientifically complex.
Congress should ensure that FDA has the flexibility and
authority to make use of these outcomes but not dictate how and
when that occurs.
I hope FDA will tell us about how it is applying other
novel approaches to clinical trials in their regulation of
drugs and devices. I would also like to know whether the agency
believes it has the authorities necessary to adopt new
approaches and whether other new statutory powers are
necessary.
Mr. Chairman, thank you for holding this hearing. I look
forward to the witnesses' testimony. I must say in advance that
there is another subcommittee scheduled at the very same time
as this one, so I will try to be back and forth to participate
in both of them.
Thank you, and yield back my time.
Mr. Pitts. The chair thanks the gentleman.
I now recognize the chairman of the full committee, Mr.
Upton, 5 minutes for opening statement.
Mr. Upton. I yield back my time. I will just submit my
statement in order to----
[The prepared statement of Mr. Upton follows:]
Prepared statement of Hon. Fred Upton
The entire purpose of our 21st Century Cures initiative is
to accelerate the discovery, development, and delivery of safe
and effective treatments to America's patients. We are here
today to better understand how we can incorporate the most
important perspective--that of patients and their families--
into the conversation.
Patients should and need to play a key part of this process
if we are to be successful. As one of our witnesses, Dr. Beall
has noted, ``Congress should work to ensure patients have a
seat at the table, because no one understands a disease better
than the people who suffer and fight every day.''
I would like to issue a special welcome to Pat Furlong who
has continued to fight after losing her two boys, Christopher
and Patrick, to Duchene. We are very humbled that you are here
to help with the cures initiative. I'd also like to welcome to
Dr. Marshall Summer--a parent of a child with Down's Syndrome.
Parents are tireless advocates of their children and we are
pleased that you are here today. Thank you and all of our
witnesses for being here today.
I also would like to thank Dr. Woodcock for testifying
today. Unfortunately, prior obligations prevented her from
coming to Wednesday's hearing so today she will provide her
expertise on both modernizing clinical trials and incorporating
the perspective of patients.
As I'm sure Dr. Woodcock will explain, FDA has taken steps
to incorporate the perspective of patients in the drug
development process. FDA's work with Parents Project Muscular
Dystrophy is a good example of collaboration, and we look
forward to hearing about next steps on the guidance they put
together.
However, much work remains. We would like to learn how we
can leverage the successful examples of agency-patient
collaboration and what other steps we can take to ensure the
patient's perspective on the benefit-risk framework is
thoroughly considered and incorporated throughout the cycle of
the drug review process.
At our first 21st Century Cures roundtable, we learned that
there are treatments for only 500 of the more than 7,000 known
diseases affecting our nation's patients. Our work will not be
done until we can close this gap in cures. I look forward to
hearing how we can incorporate the voice of patients in this
process.
I yield the balance of my time to ------------------------
--------.
Mr. Pitts. The chair thanks the gentleman.
We have two panels today.
On our first panel, we have Dr. Janet Woodcock, director,
Center for Drug Evaluation and Research, U.S. Food and Drug
Administration.
Thank you for coming again today. And you will have 5
minutes to summarize your testimony. Written testimony will be
placed in the record.
So, at this time, the chair recognizes Dr. Woodcock 5
minutes for opening statement.
STATEMENT OF JANET WOODCOCK, M.D., DIRECTOR, CENTER FOR DRUG
EVALUATION AND RESEARCH, U.S. FOOD AND DRUG ADMINISTRATION
Dr. Woodcock. Thank you. We are here to discuss how drug
development better meets the needs of patients. Decades ago,
healthcare was very physician-centric and actually very
paternalistic. We all recognize that today. It was kind of
``The doctor knows best; don't ask any questions.''
Today, the model is collaboration between the patient and
the healthcare team. These changes, though, have evolved slowly
in our society, and the thinking and drug development has
slowly changed in parallel.
The FDA Safety and Innovation Act of 2 years ago took
significant steps in this direction of patient-centric
development. It contained agreements under PDUFA that FDA would
sponsor at least 20 patient-focused disease-focused meetings
over 5 years. Eight of these meetings have been held to date,
and they have been very impactful. The first one we held on
chronic fatigue syndrome, we have issued a draft guidance on
drug development in this area of very serious unmet medical
need. Also, under PDUFA, were agreements to advance the
development and use of patient-reported outcome measures. These
are measures that the patient can fill out to say from their
point of view how well they are feeling, how well the treatment
is working, what adverse events they are experiencing.
We are having an expert meeting next week and will continue
to work in collaboration consortiums to try and advance the
science of patient reported outcomes. This is very important to
really scientifically incorporate the patient's perspective
into clinical trials.
Additionally, under FDASIA, FDA was to advance the
development and use of a structured benefit risk framework in
drug approval decision, and this work is under way, and it
really explicitly provides for considering the burden of
disease, the impact of current therapies, both for good and for
ill, and the tolerance of risk from the patient's point of
view, and this is an extremely important set of factors that
need to go into the benefit-risk decision, but we need to do
this in a scientific manner and a structured manner and we are
rolling out the structured benefit risk framework.
Now, we know that for people with very serious diseases who
may lack good therapy or actually lack any therapy, access to
new treatments is their number one priority, and that is why
expediting drug development programs in these areas is so
important. If you look at the diagram that we have here that
was provided, these data and the diagram were actually
developed by the Pharma organization, talks about, shows the
drug development process, and it is starting on the left, it
shows you start with many thousands of compounds, up to 10,000
compounds at one end, the beginning, and after 9 to 13 years,
you may end up with one safe and effective drug on the market.
The clinical development phase, which is the gray phase,
the middle phase on this diagram, is the longest and by far the
most expensive phase.
In contrast, the FDA review phase, of which much attention
has been paid to, is actually the very small slice there, the
white slice toward the end of the process, right before the
drug gets on the market and is typically at this time less than
a year in duration.
So FDA has made strenuous efforts, really, to help reform
and modernize the clinical development phase of drug
development because that is the major bottleneck. Not only is
it expensive and long, many products fail in this phase, and
there is a tremendous opportunity cost there where other
treatments could have been developed.
Now, the FDASIA included several innovations to this
process and the most striking being the breakthrough therapy
designation program, so if we could have the next diagram.
Thank you. This was mandated by Congress and was specifically
directed at that clinical development phase, so that we could
help when therapies were particularly promising and were
designated, we could help move them through that phase more
quickly. The BT designation has been enthusiastically
subscribed. We have had over 160 requests in the 2 years since
the legislation was passed. We have actually--and this is the
really surprising part, we have granted 52 designations. So
what Dr. Burgess said about we are on the verge of a new era in
therapeutics, I think, is reflected by this. We would not have
seen this a decade ago, and we have approved six products: four
new products and two new indications.
Now, it is too early to judge really the impact of the
breakthrough designation program; is it really going to be able
to speed up drug development? However, I will say the four
products we approved, their clinical development time was 4.5
years, so much shorter than what I showed in the earlier
diagram.
Also, in FDASIA were clarifications of the application
accelerated approval, and we issued a final expedited draft
guidance in May that includes, in response to stakeholders'
requests, examples of rare diseases and includes more
information on the use in rare disease. However, it is clear
much more needs to be done to modernize the clinical trial
process. That is the big bottleneck now in getting discoveries
to patients. This can't be done, though, by FDA alone. We don't
execute this process. All the stakeholders need to participate,
and I think the series of hearings that have been held and the
21st Century Initiative can help provide the framework for
significant reform in this process.
Mr. Pitts. The chair thanks the gentlelady.
[The prepared statement of Dr. Woodcock follows:]
[GRAPHIC] [TIFF OMITTED]
Mr. Pitts. I will begin the questioning, recognize myself 5
minutes for that purpose.
Dr. Woodcock, what is FDA's plan to advance biomarkers and
the use of patient reported outcomes data during the drug
development process and post-market setting?
Dr. Woodcock. Many years ago, a decade ago, we recognized
that there was no structured scientific process to provide the
evidentiary basis for use of a biomarker in decisionmaking, and
so doctors and biomedical researchers would float new
biomarkers, but there was no rigorous process by which they
could be evaluated to see if they were really useful. So we
actually established a process for this. It is not really in
our mission, but we established it, and it is called the
Biomarker Qualification Process. And we also work with the
European medicine agencies and the Japanese regulators so that
this would be a worldwide activity. And consortia can come into
the FDA and propose a biomarker, a new biomarker, and we give
them advice on what needs to be done, and then--and also for
patient-reported outcomes. And if, in fact, that evidence is
developed, then we will publish a letter that is public, and so
will the EMA if they accept it and so forth, and then any
developer can use that biomarker or measure in a development
program and will rely on it for the context of use.
We have 79 projects by different consortia in different
phases of this process right now.
Mr. Pitts. Good. Describe your plans for implementation of
the structured benefit-risk framework you mentioned that--
transparent to the public and the sponsor so that the
assessment of data from clinicals trials and other studies by
FDA reviewers can be better understood and acted upon.
Dr. Woodcock. Yes. Well, this is an iterative process. We
have had public meetings. Then we went back, and we are
piloting this in the different drug review divisions and having
the medical officers work through this framework that we have
developed and see what the results are. Then when we have those
results, we will go back through a public discussion and get
input on how this can be improved, so this is not something
that can happen overnight.
It is a scientific process, and actually, we feel that we
don't have the tools right now. They exist out in society in
science, but we haven't applied them, these rigorous analytical
tools to the benefit-risk decision, and so we have had
workshops on this, various scientists come in and advise us, so
we will have a public process once we have gathered more
experience.
Mr. Pitts. I have been hearing a lot about FDA's efforts to
improve the quality of pharmaceutical manufacturing. Where do
U.S. drug manufacturers currently stand when it comes to
producing quality medicines? Can you tell me a little bit about
your plans in this area?
Dr. Woodcock. Well, I think the major problem here is that
many of our essential drugs are not made in the United States,
and they are made all around the world, and sometimes they may
only come from a single source, and this is, I think, a real
vulnerability to medicine. And in addition, we used to be a
manufacturing powerhouse in drug manufacturing, but those jobs
have moved offshore. And I think now we have an opportunity,
with new modern manufacturing methods, such as continuous
manufacturing, to actually build a high-tech industry in the
United States that actually will make the drugs we need here in
this country. And FDA has been collaborating with this
manufacturing community to help bring this about, and we are
very interested in seeing this happen.
Mr. Pitts. Now, we have recently heard a lot about Lung-
MAP, the Lung Cancer Master Protocol trial. There are other
examples of similar innovative trial designs, like I-SPY for
breast cancer. What else needs to happen before these types of
trials are no longer front-page stories?
Dr. Woodcock. That is a good question. We also have been
advocating for this for many years, and it is wonderful to see
it start to become a reality. The concept, I think, in drug
development needs to be turned on its head in clinical drug
development, and instead of, for each investigational drug,
there is a whole clinical trial program developed with
different clinical trials that take a very long time, as you
heard on Wednesday, to get started and so forth, that there are
networks that are available that investigational drugs can be
plugged into. This will provide independence of an assessment
but also really decrease the time and expense of assessing
whether these drugs are safe and effective.
But what needs to happen, I think, is we need to expand
this to more diseases. The NIH is very interested in
antimicrobials in setting up a network, and other groups are
looking into this, and I think you may hear today from some
patient groups say Cystic Fibrosis has really successfully set
up the infrastructure to have cystic fibrosis drugs rapidly
evaluated once they reach the clinic.
Mr. Pitts. The chair thanks the gentlelady.
Now recognizes the ranking member of the subcommittee, Mr.
Pallone, 5 minutes for questions.
Mr. Pallone. I am going to have to--since I just got here.
Mr. Pitts. OK. You want to yield to Green?
Mr. Pallone. Yes.
Mr. Pitts. All right. Mr. Green.
Mr. Green. Thank you, Mr. Chairman.
Dr. Woodcock, welcome back. I want to thank our chairman,
ranking member, and Dr. Woodcock for testifying. In a time
where revolutionary science and technological development, we
have an opportunity to target specific patient populations,
advance personalized medicine, and transform how we approach
the prevention and treatment of disease, one of the goals I
think is particularly worthy of exploration is the idea of
personalized medicine, in which a patient may be able to
receive more tailored drugs and treatment suited to his or her
specific condition.
Our understanding of the human genome is the key to that
goal. Academics and researchers tell me, another piece is the
potential for researchers and developers to discuss these drug
and device innovations with patients during the development
phase.
Dr. Woodcock, can you give us your views on the upsides and
downsides of any increasing permissibility of communication
between patients and developers during the clinical trial phase
of development?
Dr. Woodcock. It is a very interesting question. We have
seen from the 1990s, where only 5 percent of drugs were
targeted; in 2013, 45 percent of the drugs we approved were
targeted in some way. There are barriers to locating patients
and joining up patients who have specific conditions, subsets
with appropriate investigational therapy, and these diseases
are fragmented into smaller and smaller subsets. It is harder
and harder to find these people who might be eligible for a
given therapy.
The Lung-MAP trial is one way of doing that where it has
multiple investigational arms in one trial, so people can come
in, and they can be spread out. But there is great interest, of
course, with more patient activism in using social media and
other ways to actually match up the right patients with the
right investigational drugs, and I think this is one of the
challenges right now of the clinical trial enterprise.
Mr. Green. Well, increasing patient involvement in FDA's
decisionmaking surrounding drugs, devices is a significant yet
challenging endeavor. Can you provide your suggestions on how
mechanisms need to be developed to accurately measure what
meaningful outcomes for patients are, both in the clinical
outcomes and the quality of life? Can we do that?
Dr. Woodcock. Yes. That is what I was referring to with
Chairman Pitts is that there is a science of measurement, and
patient-reported outcomes is one science. How do you measure
how a patient feels from their point of view? And there are
ways to do this, but these measurements have to be developed.
We approved many drugs based on their impact on quality of
life, so that is completely possible, but what needs to be done
is this science needs to be developed, and we are participating
in that. As I said, we have an expert meeting next week on
patient-reported outcomes.
Mr. Green. Well, and the patient involvement process has to
be data driven and improve the overall efficiency of drug
development and maintain FDA standards of safety and
effectiveness. How can Congress support the FDA in
incorporating patient perspectives in regulatory decisionmaking
in a way that helps deliver that innovative, safe, and
effective medicines to the patients sooner?
Dr. Woodcock. Well----
Mr. Green. Do you need statutory authority, or do you think
you already have it?
Dr. Woodcock. To my knowledge, we have the authority to do
this, and I think you will hear from the next panel, for
example, how patient groups can develop draft guidance, submit
it to the FDA. They can run processes that actually incorporate
all their points of view and those of the expert scientists, so
more of that needs to be done, but I don't know that it needs
more statutory authority.
Mr. Green. Can you do it within current resources, because
again, you are specializing, instead of a broad brush--and I
assume it costs more when you do an individual?
Dr. Woodcock. Yes. Well, when you have 7,000 diseases that
need good treatments and most of them don't have them, it would
be very difficult for FDA alone to develop the standards for
patient reported outcomes in each one of those diseases, much
less the clinical outcomes. So much more participation of the
medical and patient community is needed in drug development,
and we need to find better ways to do that, but I am not sure
that is through legislation.
Mr. Green. OK. And without a doubt, our greater resources,
but again, our committee has worked over the years to try and
provide those resources----
Dr. Woodcock. Yes.
Mr. Green [continuing]. To the FDA and look forward to
working with you.
Thank you, Mr. Chairman. I yield back.
Mr. Burgess [presiding]. The gentleman yields back.
I recognize myself for 5 minutes for the purposes of
question.
Dr. Woodcock, again, good to see you, good to have you back
in the committee. So you have talked about how the FDA
routinely works with sponsors to apply flexibility, including
the use of biomarkers, surrogate endpoints, and nontraditional
trial designs, and other available tools to expedite the
development of products to treat both common and rare diseases.
With respect to the common diseases, how is the FDA working
with sponsors to apply these innovative development and review
methods?
Dr. Woodcock. Well, for example, hypertension is a common
disease. We approve drugs for hypertension based on a surrogate
measure, blood pressure, that is very well accepted, and for a
number of years ago, we looked at automated blood pressure
monitoring, and we decided it was unbiased, and so we decided
that you really didn't need a control group in the same way
that you would for most other diseases because you have an
unbiased measure, and so we issued new approaches to studying
hypertensive medicines. So that is an example.
Mr. Burgess. What could happen so that the FDA could use
this more frequently?
Dr. Woodcock. Well, 45 percent of the drugs that we
approved over the last several years used a surrogate endpoint.
So we do use that when it is appropriate and it is available.
For many diseases, we don't know what the right surrogate is,
and that is why many of the accelerated approvals have been
confined say to cancer and HIV is because the science, a great
deal of science has been driven in those conditions, and we
understand the biomarkers. But for other diseases, there needs
to be more scientific development, and that is why we are using
this, for example, biomarker qualification process to try and
get more biomarkers developed that we can use, but we can't
just dream them up and use them.
Mr. Burgess. I thought that was your job. Well, let me ask
you this. Are there situations where a majority of the
scientific or research community believes that a certain
biomarker sufficiently predicts the clinical outcome, but the
FDA has yet to accept that?
Dr. Woodcock. There may be. I think there is a lot of
controversy around use of these. You heard some of that on
Wednesday. There are two sides to this. If you rely upon a
surrogate, often, especially when it isn't well validated,
there is more uncertainty about whether or not the drug is
actually going to work or not, and so there are different
points of view. And as we have all been saying, the community,
the patient community really ought to have--and treating
community ought to have--a lot of input into how much
uncertainty should be tolerated, given the circumstances of
that disease.
So there are situations where there is disagreement amongst
various parties, external and internal, about the use of a
surrogate.
Mr. Burgess. Are you able to give us any examples of that,
of a surrogate that the FDA may not right now be willing to
accept?
Dr. Woodcock. Well, for example, raising good cholesterol,
all right. We had a series of trials on that. Everybody thought
raising good cholesterol would be really good, and in fact, it
turned out to be either neutral, or in one case, it actually
increased mortality, so we no longer accept that surrogate.
That is the kind of example where--and there are many others
like that.
In bone density, for osteoporosis, estrogens do a very good
job and they decrease fractures. Although they have other
liabilities. But some other agents were tried, and actually,
they increased bone density, but they also increased fractures,
and so we have to be careful when we use these surrogates to
make sure that we are getting the intended results, clinical
results.
Mr. Burgess. Thank you for that.
Let me ask you a question that is a follow-up from when we
visited in April.
Do you have an update on the status of the FDA's guidance
on biosimilars naming and when that guidance will become final?
Dr. Woodcock. Well, I certainly would like to get that
guidance out as soon as possible. We are working diligently on
that, and I don't have any further update.
Mr. Burgess. But that was submitted as a question in April,
and we are awaiting an answer.
Now, also, along with that, I asked if anyone in the
administration, outside of the FDA, had provided the agency
with suggestions or recommendations with respect to this
guidance.
Can you, if the answer to that is yes, can you provide us
with the name or names of those individuals?
Dr. Woodcock. We would have to get back to you on that.
Mr. Burgess. And again, we anxiously await your answer.
My time is expired.
I will recognize the gentleman from New Jersey, the ranking
member, 5 minutes for questions.
Mr. Pallone. Thank you.
Mr. Chairman, you asked a lot of my questions, so I am
going to have to move on to other things.
But Dr. Woodcock, we heard a lot at Wednesday's hearing
about the accelerated approval program at FDA, and as you know,
the program allows for earlier approval of drugs that treat
serious conditions and fill an unmet medical need, and the
drugs are approved on the basis of surrogate endpoints which we
also learned about on Wednesday, and of course, a critical
requirement of the system is that companies conduct studies to
confirm the clinical benefits suggested by the surrogate
endpoint, and these studies are called phase 4 confirmatory
trials. So a critical part--I want to ask about the phase 4
trials. What challenges has FDA faced with respect to phase 4
trials? Do sponsors complete in a timely manner?
Dr. Woodcock. Well, it is sometimes difficult to complete
these trials, and the reason is that if you had a serious and
life-threatening disease and we approved a treatment for it,
you probably would be somewhat reluctant to enter a trial where
you had a maybe 50 percent chance of not getting the treatment.
So what we often do is ask that trials be conducted in a
different stage of disease or something where it actually
hasn't been studied yet, so then we can get the results since
that might take time.
So I think in the early years of the program, we didn't
track this as well as we should, and we did have a lot of
trouble getting these trials completed. But in the current era,
we are on top of this, and generally speaking, the sponsors are
diligent in trying to get them completed, generally, but they
have difficulty sometimes enrolling patients in these trials.
Mr. Pallone. Another important component of the program is
that when the surrogate endpoints do not ultimately show the
anticipated clinical benefit, FDA could be faced with needing
to remove the indication or take the drug off the market, and I
imagine that is also no easy task.
Can you describe what is involved with removing the
indication or taking a drug off the market and what challenges
does the FDA face there?
Dr. Woodcock. Yes. Generally, if the confirmatory trial
failed to show benefit, the first thing we ask is the sponsor
to voluntarily withdraw the drug or the indication from the
market. It is only if the sponsor does not agree to do that,
then we go into a long administrative process, which includes
hearings and formal findings and so forth, and this can take a
long time if the sponsor can test our finding that the drug
isn't effective.
Mr. Pallone. Now, just a couple of years ago, we included
some provisions to improve upon the accelerated approval
program, and the FDA Safety Innovation Act of 2012. For
example, the law made it clear that FDA could rely upon
evidence developed using biomarkers or other scientific methods
or tools when assessing surrogate endpoints. Can you describe
what impact those legislative changes had on the program, and
are there any other changes that you feel are necessary to
allow you to make full use of the most recent scientific
developments with respect to surrogate endpoints?
Dr. Woodcock. I think the legislation was very helpful. We
have taken it quite seriously. We have issued guidance, final
guidance on expedited programs, and probably the biggest change
that the legislation brought about was its focus on
intermediate clinical end points, and we had to have quite an
internal discussion about what that means, and I think you will
see us approving more products under accelerated approval based
on these intermediate clinical endpoints.
Mr. Pallone. All right. Well, thanks.
Again, it is clear to me that this is an extremely
complicated area and one that is not necessarily conducive to
further legislation, but I wanted to ask last about the master
protocol.
At the hearing on Wednesday, some panelists described some
of the inefficiencies that exist in the way that clinical
trials are currently conducted, and one of the suggestions for
addressing those inefficiencies is to create a master protocol.
So I just wanted to ask, first, can you tell us more about
this, what is a master protocol? How would it help to improve
the way we conduct clinical trials? Has FDA been involved in
the development of a master protocol, and are there particular
diseases that the master protocol is more appropriate for than
others, and if so, which ones, and are there other areas where
it might be expanded?
Dr. Woodcock. Well, master protocol is one version of using
clinical trial networks or standing clinical trials to evaluate
investigational therapies where the drug development program
isn't just for one therapy. It is for any therapy for that
disease. So master protocol, though, has to be somewhat disease
specific. You can't just have a general overall master
protocol, right. It has to be focused on one disease.
For example, the Lung-MAP trial is on squamous cell cancer
of the lung that is advanced but five different agents right
now are being studied all at once within that protocol, and
that is a huge efficiency. But there are other versions of
standing trials or trial networks that also could be used in
other diseases. And as I said, the Cystic Fibrosis Foundation
has a kind of network of clinical excellence where they
actually sequenced the genome of all their patients, and so
they are ready when a targeted therapy comes along. They are
ready. They can put those patients into the protocol, and that
tremendously improves the efficiency.
So it is a long conversation that probably can't be had in
5 minutes, but I have long advanced this concept and tried to
push this concept because the current clinical trial paradigm
is not sustainable.
Mr. Pallone. All right. Thank you very much.
Thank you.
Mr. Burgess. The gentleman's time is expired.
The chair recognizes the gentleman from Pennsylvania, Dr.
Murphy, 5 minutes for questions, please.
Mr. Murphy. Thank you.
And good morning, Doctor. It is always good to have you
here.
Let me start out by asking about it is important for the
medications and research to advance those but also for those
that are already approved, and so let me ask you, we had passed
the PDUFA laws a while ago, certainly that was supposed to help
us get more generic drugs in the queue, but what has happened
is we got 1.5 billion authorized over 5 years, what has
happened is approval times have gone up, and there are fewer
approvals, even though the law was supposed to reduce all
those.
Can you give me some indication of what is going on and
what FDA is going to do about that?
Dr. Woodcock. Certainly. We are well aware of these issues.
In June, we received 625, I believe, generic drug applications,
so the rate of submission is well above what was projected in
the negotiations that we held.
However, on October 1, the deadlines kick in for timelines
for review of generic drugs, and we are fully prepared to meet
those timelines as well as deal with this large backlog of
pending.
We had to hire a large number of people and totally revise
our processes, reorganize the generic drug review offices and
conduct many other changes, and that is what we have done over
the past 2 years in preparation for the deadlines coming into
effect on October 1.
Mr. Murphy. Thank you. Another question here about some
labeling issues. The abbreviated new drug application that
would allow generic manufacturers--this is a proposal for FDA
to change a label without FDA's prior approval but then come
back later on, and the FDA itself has recognized, and say,
quote, ``consistent labeling will assure physicians help
professionals and consumers that a generic drug is as safe and
effective as its brand name counterpart,'' unquote. But there
is a concern out there that allowing these changes take place
and then go backfill them later on can cause a lot of confusion
in studies that have asked pharmacists and physicians this, so
I am wondering where this issue stands in clarifying this.
Dr. Woodcock. Well, we have received comments on the
proposed rule. It was a proposed rule, and we received many
comments. We are analyzing the comments, and subsequent to
that, we will have to go forward with a rulemaking process.
The proposed rule contemplated that we would actually have
less disparities of labels in the marketplace on this because
of this proposal because we would put up a Web site, and we
would also require conformance of labels, which we cannot carry
through right now, given the current systems.
Mr. Murphy. A lot of us back in January asked to meet with
Commissioner Hamburg and others about this, and I am not sure
those things have taken place yet, so I hope this gets
expedited and that these issues are addressed because I think
it still leads to some confusion. So I am not clear yet in
understanding even why this proposed rule was set up there to
allow individuals to change the label and then come back later
and ask permission.
Dr. Woodcock. Well, currently, generic labels do not always
match the innovator and they do not change their label in a
timely manner, and so there will be labels out there for quite
a bit of time, even with serious safety issues like new box
warnings that don't conform to the innovator label, so we are
trying to address this situation. And also, as generics are now
85 percent of all drugs dispensed to consumers--that they
should have the opportunity, since their drugs are the ones
that people are being exposed to, to submit their findings of
adverse events and suggest label changes, proposed label
changes and actually execute them.
Mr. Murphy. Well, I just hope that you will meet with the
committee staff members and the companies to help clarify this
because it still is not clear to me why this would be allowed,
and I think it would end up confusing.
I want to bring up one last thing just while you are here.
I had sent a letter a few weeks ago to Dr. Hamburg. I am sure
you didn't see this, but one of the things that is out there,
too, is complications that are oftentimes reported in the media
about caffeine, whether it is--and sometimes toxic levels
people take.
Dr. Woodcock. Yes.
Mr. Murphy. Through over-the-counter things, pure caffeine
or some of these supplements out there for athletes, et cetera,
and yet it is also in everything from chocolate to coffee and
other things we promote all the time, so I am hoping, at some
point, FDA can also give some recommendations in terms of
individual levels per drink, per dose, per day, per male,
female, the genders, for weight, age, whatever that is.
Dr. Woodcock. Yes.
Mr. Murphy. Because it is still pretty confusing, whatever
those products are that they can be beneficial, but I hope you
will expedite that.
Dr. Woodcock. Thank you.
Mr. Murphy. Thank you.
I yield back.
Mr. Burgess. The gentleman's time is expired.
The chair recognizes the gentlelady from California, Mrs.
Capps for 5 minutes for questions, please.
Mrs. Capps. Thank you for holding this hearing, to our
chairman and ranking member.
Thank you, Dr. Woodcock, for your testimony.
This is an issue very dear to me, and as you know, I am
incredibly concerned about our Nation's history of excluding
minority groups, especially women, from all levels of medical
research, from the lab rats to the most advanced clinical
trials. And reports have shown that even when these groups are
included in trials, there are often too few participants in the
groups to analyze the effects on them or the analyses are
simply not run or reported.
I am sure you are familiar with the case of Ambien,
commonly prescribed medication that recently had its label
changed because it metabolizes differently in women than men,
meaning that women had been receiving an inappropriately high
does of this drug for over 20 years.
In addition, in spring, a report entitled ``Sex-Specific
Medical Research Why Women's Health Can't Wait'' was released,
which provides evidence for the further inclusion of sex and
gender in scientific research. And the FDA's own August 2013
report, which was initiated by the inclusion of My Heart for
Women Act in the FDASIA legislation, showed that there is still
much work to be done to make sure that women are fully
represented in clinical trials and that the safety and
effectiveness of the information is readily available.
I know the FDA is continuing to work on an action plan to
address these disparities, so Dr. Woodcock, can you give us an
update on where the agency is on this?
Dr. Woodcock. Certainly. I would expect that that would be
released, we would be timely in its release. I believe there
was a statutory deadline or not, or there is some expectation,
so we are working diligently on the action plan, yes.
But I will say for drug development, which is what I am
discussing here, that we did a study, for example, the class of
2010, the product that we approved, we found that about 45
percent of the participants were male, all right.
And we found that almost all the submissions included the
required gender analysis, which has been required for drugs for
20 years, because I oversaw that when I first joined the Center
for Drugs in 1994. So it is by regulation, so we do have these,
but I think the transparency of the information is the problem,
and we are working on that, and I really am committed to making
that information more transparent so people understand what we
know and what we don't know.
Mrs. Capps. I think you put your finger on something, and I
want to highlight a bipartisan letter I led, signed by the
women of the House of Representatives, urging this agency to
include clear and actionable strategies. And I think what you
said about transparency and the reporting in the action plan is
a way to address this issue once and for all.
At Wednesday's hearing this week, I also asked the panel
about the tools FDA is developing that could supplement our
knowledge base, especially in the light of less robust clinical
trial designs. The FDA Sentinel system, which I understand is
making progress, if slowly, to conduct post-market passage
surveillance of drugs and devices, could help spot issues like
adverse drug interactions more quickly. I believe the Sentinel
program holds great promise, and that is why I worked to get
the Sentinel Assurance for Effective Devices Act included in
FDASIA to continue progress on the program and ensure the
design for both drugs and devices. Could you update us on the
development of the Sentinel program, please, and what other
resources or authorities do you need to get the system up and
running to protect consumers more effectively and
expeditiously.
Dr. Woodcock. Well, I think use of electronic health data,
which is rapidly becoming available, and the electronic health
records and so forth, has tremendous promise for actually
finding out what happens in the real world for medical
products, both that are approved recently and those that have
been on the market a long time, and that is what the Sentinel
system is intended to do.
We have run a mini-Sentinel network for 5 years, and that
was between drugs and biologics. We paid for that out of our
money that we have, and we are recompeting that to put up the
Sentinel system, so that contract proposal is out on the
street, and we hope to establish the real Sentinel system,
which will be a large-scale system for surveillance.
Now, as far as medical devices, we require a unique
identifier or some kind of identifier in the medical record
electronically so that we are able to capture that because the
Sentinel system uses those electronic records to get the
information, and I will repeat for everyone that it does not
take any personnel information and move it to some central
database. It strictly runs those analyses within the healthcare
system and then the results only are combined.
So that has tremendous promise. We feel very good about
that. We actually are piloting running active surveillance on
there, so when we approve a drug and we have a question about
it, we can watch over time and see what actually happens. And
as more and more people get on electronic health records, we
can really have more insight in what is happening.
So that is where we are with that, and it is resource
limited. I have to pull resources from other activities to fund
that, but I believe very strongly that this is the future.
Mrs. Capps. Thank you. I appreciate that.
Mr. Pitts [presiding]. The chair thanks the gentlelady.
Now recognizes the gentleman from Georgia, Dr. Gingrey, 5
minutes for questions.
Mr. Gingrey. Mr. Chairman, thank you.
Dr. Woodcock, thank you for appearing. It is always good to
see you.
I understand that a number of the challenges that have led
to the duration and cost of conducting clinical trials in the
U.S. to increase essentially are outside of FDA's purview. That
being said, clinical trials are conducted to generate evidence
used in the application for FDA approval, so my first question,
how early do you typically communicate with these
pharmaceutical companies, to discuss their trial design before
the investigational new drug application is submitted?
Dr. Woodcock. Well, we have agreements under PDUFA, that
prescription drug user fee program, and for novel products or
novel indications, say they are testing a disease that really
doesn't have any treatment, companies can come in and have a
pre-IND meeting. That meeting is before they start their
clinical trials, their first in human studies, and we talk
about that development program so they can start thinking about
how that is going to be done.
We do have information, it is preliminary, but looking at
our information, it seems that companies that have more
interactions with the FDA are able to get their products
through more quickly, through the entire clinical trial process
than companies that haven't had interaction with the FDA during
the development process. But there are formal meetings that are
held at different times under the user fee program, and those
minutes are tracked, and we track the meetings and so forth, so
there is quite a process for interaction during drug
development.
Mr. Gingrey. So you, as a manager, would be, maybe at that
particular time, you make sure that your reviewers are not
requesting overly burdensome data that really is not necessary
so that the process can be speeded up?
Dr. Woodcock. Well, there is always a push and pull.
Scientists of all stripes always want more data, and that is
scientists in the companies and scientists in the FDA, and so
we have to walk that path between getting more data and
actually the cost that is generated. And we have made a number
of efforts under the CITI collaboration that we do with Duke
University and many, many, many other partners to try and
figure out how to streamline clinical trials as far as data
collection, for example. But it is difficult.
We have 1,600 meetings a year under the PDUFA, and when we
meet with companies, the supervisors are there, the senior
medical officials are also at these meetings.
Mr. Gingrey. Well, that is the whole purpose of 21st
Century Cures, of course, and as we get to the second panel and
we hear about the associations and from the families, I am sure
they are going to talk about how we can speed this process up.
The last question. At our first 21st Century Cures hearing,
we heard that only 19 drugs, outside of cancer and HIV space,
have been approved by the accelerated approval pathway since
1992, and I understand that you wrote a blog post after that
hearing about how a number of drugs that were being considered
under accelerated approval ultimately received traditional
approval, so these statistics, according to your blog, were
somewhat misleading. Can you provide some examples of when that
occurred as well as the process involved?
Dr. Woodcock. Certainly. Well, for certain rare diseases,
we may decide, for example, that the surrogate is fine, OK, and
it correlates with clinical benefit. Then the term
``accelerated approval'' is a little misleading. It sounds like
it is faster than regular approval, but actually, if we give
regular approval on a surrogate, it is just as fast as
accelerated approval, but you don't have to do confirmatory
studies afterward because we already believe the surrogate.
So, for a lot of, say, rare deficiency diseases where there
is something missing, you may be able to show that you
actually, when you replace that protein in the body, you give
the activity back to the person, right, and so you may not have
to show clinical outcomes. It is still a surrogate, but we feel
it is good enough because we understand the problem that
something is missing, and you deliver an active drug to the
site of action of where the problem is, and that would be
enough.
So, in many cases, we are able to do traditional approval
with the surrogate; that means that the patients and the
sponsor don't have to go through all these confirmatory trials.
I described the difficulties of that when you have a serious
disease; you have approved a drug; and then you ask people to
be randomized after approval.
Mr. Gingrey. Dr. Woodcock, thank you.
And my time is expired. Mr. Chairman, thank you, and I
yield back.
Mr. Pitts. The chair thanks the gentleman.
I recognize the gentlelady from Florida, Ms. Castor, 5
minutes for questions.
Ms. Castor. Well, thank you very much.
Thank you, Dr. Woodcock, for everything you are doing to
ensure safe and effective drugs are available for the American
public and those with health challenges.
This is a hearing about the patient involvement in FDA drug
approvals, and I think we can agree, they deserve a seat at the
table when companies are developing drugs and medical devices
within the clinical trial process. I have long been a supporter
of the Department of Defense's Congressionally Directed Medical
Research Programs known as the CDMRP. CDMRP funds peer-reviewed
research into breast cancer, autism, ovarian cancer, prostate
cancer, and other diseases. And since 1993, the patients have
been involved and have been a part of CDMRP, and they have a
consumer reviewer as part of a peer-review panel to represent
the stakeholder community, and it has been very successful in
combining patient perspectives and needs with scientific
research and bringing those perspectives together.
Has FDA, as you begin to consider improving patient
involvement, have you looked at CDMRP to see if there is
anything you can borrow from that in the drug approval process?
Dr. Woodcock. We have not, and that is a good suggestion,
so we would be happy to do that.
Ms. Castor. OK. You mentioned previously that the Patient-
Focused Drug Development Initiative that was included in PDUFA
was designed to allow FDA to hear from patients on how a
disease impacts their life, and I understand you are scheduled
to hold 20 public hearings. Share with us who FDA has met with
so far. Have you started those hearings? If so, what have you
learned already?
Dr. Woodcock. Well, we have learned the devastating impact,
I think, of the diseases, of these different diseases on
people's lives it just incredible. We had one on chronic
fatigue syndrome--that was our first one--HIV, lung cancer,
narcolepsy, sickle-cell disease, fibromyalgia, pulmonary
arterial hypertension, and inborn errors of metabolism, and we
plan to have 16 of these meetings completed by the end of 2015,
but we recognize this is just a drop in the bucket of what
people suffer from.
So what we are trying to do is really model how people can
do this, and hopefully, it could be done more--not put on by
the FDA but by the patient groups themselves in the medical
community that serves them so that they can assemble more of
this information and kind of multiply the effect of this, and
we are already seeing some of that. NORD, for example, has
offered to help with rare diseases, for example, to have more
input that way because our resources are limited. We are not
going to be able to cover all the different diseases.
Ms. Castor. Good. So I expect we will hear from the patient
organizations later today and their view on how they can be
helpful and we can be effective.
I think the wave of the future really is the information we
will be able to gather through the electronic health record, so
it is interesting to hear what you have done already with the
Sentinel initiative. I heard from research institutes back home
that are doing so much in genomics and personalized medicine
that they think these larger networks are the wave of the
future. You say you don't need additional legislation to
continue, but you are having to borrow resources from this and
that.
Dr. Woodcock. Yes.
Ms. Castor. So is your advice to the committee that we need
to do more in technology when it comes to improving timelines
on clinical trials by focusing on these networks and the
electronic health record?
Dr. Woodcock. The electronic networks have much promise in
doing clinical trials.
If we could move clinical trials more out into the
community and have people out in the community, like most
cancer patients in the U.S. who have diseases that are
untreatable don't get into trials because they are being
treated at places that aren't running trials. So we need to
move this out into the community, make those folks eligible.
And I am on the Steering Committee of the Lung-MAP trial,
and I really urged that we make sure that we are out there in
the community so that anyone who has lung cancer has an
opportunity to participate in this research and perhaps have a
more effective therapy.
So I think the electronic health records, that is a huge
different area that we are working on in how to do clinical
trials utilizing that infrastructure that is emerging.
Ms. Castor. Great. Thank you very much.
Mr. Pitts. The chair thanks the gentlelady.
I now recognize the gentleman from New Jersey, Mr. Lance, 5
minutes for questions.
Mr. Lance. Thank you very much, Mr. Chairman.
A portion of your testimony has focused on the FDA's
efforts on patient engagement. It is my understanding that
ClinicalTrials.gov was intended to be a resource that provides
clinical study information for patients, for healthcare
providers, and for researchers. But it seems to me that the
site lacks considerable information and has proven to be
difficult to navigate.
Dr. Woodcock, would you please comment on the current
utility of the ClinicalTrials.gov.
Dr. Woodcock. Well, I think that it has provided, along
with the requirement of the medical editors of the journals
that things be registered before they are going to be
published--provided tremendously more transparency into what
clinical trials are ongoing in the United States.
And that has been a big achievement. All right? So we know,
the issue of publication bias and everything is minimized
because we know what trials have been done.
However, I agree that, certainly for patients, I think that
initiation of trials and understanding where there might be a
trial that might be ongoing that might be available to them has
also been effective, although, as you said, there are
technological issues that remain. So it has made tremendous
progress in transparency.
Mr. Lance. Is there a way that you and we can work together
to improve it? And I am not suggesting that you are in any way
responsible for the challenges that remain. But moving forward
for the better health of the American people, how together can
we improve it?
Dr. Woodcock. Well, the FDA Amendment Act required that
regulations be issued around the results----
Mr. Lance. Yes.
Dr. Woodcock [continuing]. Section of this and that they
consider whether to require the submission of clinical trial
results for unapproved products, because much of the lag in
getting results in there is that the products still are not on
the market.
So NIH is the lead for this rulemaking and I think they
would be in the best position, and, also, they operate the
infrastructure for this database.
Mr. Lance. Thank you.
In another area, in the past several hearings, we have
discussed the difficulty of various institutions communicating
one with another and a lack of coordination often leads to
inefficiencies.
What methods are currently in place to reduce redundancies
in clinical trials? And what steps can we take together to
ensure that we are not doubling up on research or making the
same mistakes over and over?
Dr. Woodcock. Hopefully, most things would eventually come
out and be published. But certainly in the drug development
area, there is interest in more sharing of earlier data and
sharing of failures.
But this has proven to be very a intractable area----
Mr. Lance. Yes.
Dr. Woodcock [continuing]. For transparency. All right?
Mr. Lance. Yes.
Dr. Woodcock. But we have continued to work on that.
Mr. Lance. Yes.
Dr. Woodcock. As far as some of the things that were
referred to in the prior hearing, which I was able to listen to
some of, they were talking about some of the inefficiencies,
say, of IRBs, where you might have to have 100 IRBs that looked
at----
Mr. Lance. Yes.
Dr. Woodcock. And I believe that there are efforts to try
and address this. It is not an FDA issue. But, really, we came
out a number of years ago in saying that central IRBs would
really be preferable in these large multi-center trials.
And then the contractual agreements that take so long to
set up with each specific site is something that has been taken
on. They have tried to develop model agreements and so forth.
But that is something that the standing trial addresses
because you sign this contractual agreement once and then you
can do multiple investigational agents.
Mr. Lance. Are we moving in the direction of central IRBs,
in your judgment?
Dr. Woodcock. Yes. There is certainly a consensus, I think,
in the clinical trial investigator community that that is
desirable, but various universities, naturally, are legally
concerned about their own----
Mr. Lance. Of course.
Dr. Woodcock [continuing]. Liabilities and so forth. And so
there is a push and pull about that.
Mr. Lance. I think this is an area that we should engage in
further investigation to make sure that we move forward in a
manner that does not result in redundancies.
Thank you, Mr. Chairman. I yield back the balance of my
time.
Mr. Pitts. Chair thanks the gentleman.
Now recognize the gentlelady from Illinois, Ms. Schakowsky,
for 5 minutes for questions.
Ms. Schakowsky. Thank you, Mr. Chairman.
Thank you, Dr. Woodcock. I think you are really an
excellent witness. I appreciate your answers.
Dr. Woodcock. Thank you.
Ms. Schakowsky. I wanted to go a little bit further on the
problem that Congresswoman Capps raised about the
underrepresentation of women.
I know you said that you found that, actually, women were
overrepresented, but recently the Congressional Caucus for
Women's Issues sponsored a meeting with leading women heart
experts--both clinical and research experts, physicians.
Those experts raised concerns that the lack of
representation from women in clinical trials is limiting our
ability to effectively treat women with heart disease. They
were focusing in on heart disease.
And according to those experts, for the last 50 years,
women's heart treatment has largely been based on medical
research about men.
And even today, despite that fact, what they said is that
women make up more than 50 percent of the U.S. population, that
women comprise only 24 percent of participants in all heart-
related studies.
And, additionally, scientists from the Women's Health
Research Institute at Northwestern--that is in my district--
have raised concerns about the disproportionate number of
adverse drug effects that occur in women due to the lack of
sex-based clinical research.
And, as you know, the biological, physiological, hormonal
differences in males and females impact the rate of drug
absorption, distribution, metabolism, elimination and,
ultimately, affect the drug's effectiveness.
According to those experts, the lack of requirement for
drug manufacturers to take this into account and document any
sex variability early in the drug development pipeline before a
drug has been released places consumers, especially female
patients, at an increased risk of adverse drug effects.
So I want you to respond to that.
Dr. Woodcock. Certainly.
Ms. Schakowsky. Many of us were really left with a very
disturbing feeling because heart disease is the major killer of
women right now.
Dr. Woodcock. Right. Well, I think we have to--what are the
facts on the ground. All right? One of the reasons for the
disparities that they are mentioning is actually the fact that
men suffer heart disease earlier in life than women.
Ms. Schakowsky. Although, let me just point out, they also
said that the growing number, even though it is lower----
Dr. Woodcock. Yes.
Ms. Schakowsky [continuing]. Is younger women getting heart
attacks and heart diseases.
Dr. Woodcock. Yes. Yes. So that the reason for maybe
maldistribution in the trials is because there is an age
cutoff, and there always has been.
In our survey, we found that there were--19 percent of the
people in the trial in these 147 studies we looked at were over
65, which is more than in the general population, obviously,
but of sick people, that is still low representation, right--to
save people with heart disease.
Generally speaking, there is often a cutoff--age 75--and we
are trying to eliminate those cutoffs for age and concomitant
conditions so that the population will be more representative.
But to your original point, we have always required male
and female animals in the toxicology studies. All right? We
require what we call population pharmacokinetics, PK/PD, early
in drug development.
And our clinical pharmacologists look at blood levels and
exposure in men and women and we understand that, usually, and
that is modern drug development.
So there are multiple trials that are done that look at
exposures, in other words, achieve blood level by gender and
other factors, liver failure, kidney failure and so forth.
And we can look at the phase 3 trials to see if they are--
there has been a requirement in the regulations since, I think,
1994 that sponsors submit a gender analysis with their
application.
Ms. Schakowsky. Is this incorrect, then? It says women
comprise only 24 percent of participants in all heart-related
studies.
Dr. Woodcock. Well, that may be true. And that may also
include medical devices. It also may have to do with this age
disparity when onset of disease.
Ms. Schakowsky. I really hope that you will look at that
because it is a great concern. It is a growing problem for
women.
And let me just give you an example of what--she said
women, because we have different symptoms of heart disease--she
said, if you have some of these symptoms of nausea, dizziness,
go to the emergency room, but say, ``I am having chest pains''
because, without that, you may not get an electrocardiogram and
you may be misdiagnosed. We need to help women.
Thank you. I yield back.
Mr. Pitts. Chair thanks the gentlelady.
Now recognize the gentleman from Louisiana, Dr. Cassidy, 5
minutes for questions.
Mr. Cassidy. Hello, Dr. Woodcock. I always enjoy your
testimony.
Dr. Woodcock. Thank you.
Mr. Cassidy. I mean that as a big compliment.
So, next, real quickly--because I want to talk about
something else--but does FDA--you mentioned that some
institutions may be nervous about their liability if they refer
their IRB activity to a centralized IRB.
Dr. Woodcock. Correct.
Mr. Cassidy. Except so many do, we know that is a false
argument.
Is there any way FDA can reassure those institutions?
Because the gentleman from Mayo suggested it is a cultural
issue. He didn't mention anything about legal. Thoughts?
Dr. Woodcock. Right. Yes. I heard his testimony.
In my experience, that there are legal--there are concerns
of the--counsel of the various----
Mr. Cassidy. Attorneys are always nervous. Right? I mean,
they don't make money if they are not nervous. I hate to be
cynical, but----
Dr. Woodcock. Yes.
Mr. Cassidy. Is there any way FDA can send reassurances
regarding that?
Dr. Woodcock. Well, we have tried. In guidance and so
forth, we have encouraged this. And in the city initiative, we
had a whole discussion and dissemination of information about
central IRBs. But possibly there is more that we can do to
encourage this.
Mr. Cassidy. OK. Let me then bring on--you mentioned
something intriguing earlier, that there may be some at high
risk for disease; so, therefore they will be more risk-
tolerant.
Dr. Woodcock. Yes.
Mr. Cassidy. Now, I have a family member, a nephew, with
Down syndrome. And I am looking on the alzheimers.org Web site,
and they mention how virtually 100 percent of adults with Down
syndrome by age 40 will have evidence of the tangles associated
with Alzheimer's.
Dr. Woodcock. Yes.
Mr. Cassidy. Now, what are the issues regarding--wow. This
is a group of adults who are 100 percent at risk for a terrible
condition.
Dr. Woodcock. Right.
Mr. Cassidy. But there are other issues involved as well.
What are your thoughts about this? How do we make stuff
available for folks incredibly at risk for such a terrible
disease?
Dr. Woodcock. Yes. Well, with Alzheimer's, there are a
number of problems. The basic problem is we still don't
understand the disease well enough and the interventions that
have been tried, which have been in late-stage disease when
people are already demented, have failed to work.
Mr. Cassidy. Now, as I gather, though, the problem is
predicting at an earlier stage those at risk. Correct?
Dr. Woodcock. That is correct. If you want to intervene
early. We recently issued a draft guidance saying that, OK, if
you want to intervene earlier, we would accept an end point
that is subtle cognitive testing.
Mr. Cassidy. I accept that.
But how do you decide which population is at such high
risk? Because, if you have a control group--you follow what I
am saying--only 10 percent are really going to be at risk.
Dr. Woodcock. Right.
Mr. Cassidy. You with me? This is a really expensive study.
Dr. Woodcock. That is right. And so we advocate techniques
called enrichment, which you try to use biomarkers or other
tests to figure out. There are genetic conditions that increase
your risk for Alzheimer's disease.
Mr. Cassidy. So speaking of Down syndrome as one example?
Dr. Woodcock. That would be one example. Yes. There are
others.
Mr. Cassidy. And can you give us the progress of that. So
if you accept these, are people now using these?
Dr. Woodcock. Well, we need agents to use them in. So that
is part----
Mr. Cassidy. And I am sorry. ``Agents,'' you mean as in----
Dr. Woodcock. I am sorry. Investigational interventions
that we can test in the people.
And that is part of the problem. The science of
understanding what causes Alzheimer's and what you can
intervene in that would actually delay or prevent the disease
is not mature enough.
And we have approved a couple imaging agents for
Alzheimer's, but they aren't 100 percent. And you would maybe
be kind of advanced----
Mr. Cassidy. But, for example, I know hyperinsulinemia is
thought to be a potential risk factor.
Dr. Woodcock. Yes. I know that.
Mr. Cassidy. And I think there are some studies suggesting
that Actos might give some benefit.
Dr. Woodcock. Yes.
Mr. Cassidy. Presumably, it would be at an earlier stage,
not a later stage, would be a non-metabolic syndrome indication
for the use of Actos. Fair statement?
Dr. Woodcock. Yes.
Mr. Cassidy. So there is at least some of that. I guess I
pose that to ask the degree to which that has been, again, the
current state. I will go back to what is the current state of
using that sort of thing?
Dr. Woodcock. Right. So the current state, if someone
decided to do a trial--and I believe there have been some
intervention trials, not of Actos, but an earlier intervention
at high-risk--in higher-risk people--they might identify people
they felt were high risk for one reason or another, randomize
them to this intervention or not, and then we would allow use
of neurocognitive testing even before they had symptoms, if
they had subtle changes, and if the treatment group did better
than the placebo group, we could give accelerated approval.
Mr. Cassidy. So I guess you have got the framework. It is
just a question of someone coming forward to take advantage of
it.
But how long would such a study, do you imagine, take to
complete its course? Twenty years?
Dr. Woodcock. No. No. But we need to have better
measurements that stick to these biomarkers and other
measurements, like of subtle cognitive function, where we--the
NIH and us and others are working on this.
Because the earlier you can intervene--if you have a very
targeted test that can identify people early, they don't have
any symptoms, but you can tell their brain isn't working as
well as it should, and then it will decrease over time. So that
is kind of the rate-limiting step.
But I agree. Prevention is very difficult because there you
want to intervene on people who are well and treat them for a
long time and expose them to something with the hope that, at
the end of the day, they are not going to get whatever bad
outcome.
Mr. Cassidy. We are out of time. Thank you very much.
Mr. Pitts. Chair thanks the gentleman.
Now recognize the gentleman from Virginia, Mr. Griffith, 5
minutes for questioning.
Mr. Griffith. Thank you very much, Mr. Chairman.
Dr. Woodcock, as others have said today and, also, what I
have heard in some of our informal conversations is that you
not only do a good job as a witness, but that you are doing a
good job overall.
Dr. Woodcock. Thank you.
Mr. Griffith. And so I appreciate that, and thank you so
much for being here today.
You and Dr. Cassidy had a little conversation about
lawyers. Some lawyers are always nervous. Other lawyers are
always looking for a way to solve the problem.
And so maybe we need to get some of those lawyers on your
team and some of the corporate teams to solve the problem,
figure out how we can make these things work, because I do
think it is important.
As you probably know, I am one of those who advocates that
we try to move a little quicker in those areas where we have
problems that we don't have solutions for currently and, also,
favor what is known in some State laws as right to try when you
have a situation where doctors have tried everything and folks
are given a diagnosis they have got months to live or their
condition is going to be fatal.
I am one of those people who believes that we ought to let
them go ahead and try whatever it is they are willing to pay to
do because the FDA can't protect you if you are going to die
from something that might kill you.
Dr. Woodcock. Right.
Mr. Griffith. I mean, it is going to happen one way or the
other. You might as well have the right to try something.
That being said, I know there are a lot of issues
surrounding that. I am not sure we have time for for that
discussion today.
And I know that there is another panel, and I want to hear
from the patients as well because they are involved in this
process.
So respecting you greatly, I yield back my time.
Mr. Pitts. Chair thanks the gentleman.
Now recognizes gentlelady from North Carolina, Mrs.
Ellmers, 5 minutes for questions.
Mrs. Ellmers. Thank you, Mr. Chairman.
And thank you, Dr. Woodcock, for being with us again today.
This is such an important issue. As you know, we had our
panel on Wednesday. And it seemed to me that it was a general
consensus that everyone is looking for ways to expedite this
and to make it more efficient and get those drugs to market
sooner so that we can be taking care of our patients more
effectively.
In your testimony and in the discussions that we have had
today, you have touched on the biomarkers and targeted drug
development to benefit disease populations, obviously.
As all of our representatives here, we all have
constituents with rare diseases, heart-breaking. Especially
right now in my community, I have a very good friend with ALS.
And as I am learning more and realizing, we have had a number
of members of our community diagnosed with ALS. So this is
something that is very important to me right now.
And I am just looking at the idea--as far as the target
approval process being appropriated and applied through the
FDA, it seems to be that we are looking at cancer and HIV.
Where do some of those rare diseases fall within that?
And you had mentioned and there was discussion about the
master protocol and that seems to be applied more to cancer or
HIV. Where can some of the rare diseases fall in there? And
what can we do to help make that happen?
Dr. Woodcock. Well, any rare disease would be a great
candidate for a standing network, a network of experts--and I
think you may hear more about this from the next panel--where
they are ready to evaluate any therapy that advances through
the early, the nonhuman, stages.
So they could pick that up right away and test it quickly.
In the meantime, until that happens, they can get what we call
natural history, which I know sounds very wonky.
But people are asking--just now Mr. Cassidy--like how long
does Alzheimer's progress from presymptomatic to symptomatic.
Well, we need to know that so that we can design the trial
correctly.
In rare diseases, even more difficult because nobody knows.
And, usually, they get experts together and say, ``Well, in my
opinion, it takes this long.'' Right? And they are usually
wrong because they have only seen a few people.
So we are encouraging these natural history studies, these
networks. First, they look at the people and they can look at
the biomarkers, too.
So what changes in ALS? What can we measure? Could we
measure something that gives us indication that treatment might
be working? Right?
And then, as soon as a therapy becomes available, then you
can rapidly get people into a trial and there would be no
delays because there is no delaying an ALS.
Mrs. Ellmers. Right. Exactly.
And that is obviously part of the concern. And certainly I
agree with my colleague in talking about right to try. This
would be a perfect example of decisions that families and
patients can make.
I do want to talk about--you had also mentioned listening
carefully to patients and families.
Dr. Woodcock. Yes.
Mrs. Ellmers. And do you consider and give more weight--
that is one of our questions, is how much weight are you giving
to the patients and families? And there again, from our
perspective in Congress, what can we do?
You know, as we have heard everyone agreeing that we need
to make a difference here and we can move things forward, how
open is the FDA to this possibility? And what can we do right
now to make this happen?
Dr. Woodcock. Well, as I said in my testimony in the
beginning, medical culture has changed over the years. It used
to be very doctor-centric and now it is patient-centric. And
the FDA culture and drugs is a medical culture. And so that has
changed at the same time, but slowly.
So we have been working, though, very diligently with
patient groups and so forth to try to get the patient point of
view more central to the evaluation of benefit and risk and
what it means to the person who actually has the disease, is
going to take the drug.
To answer your question what can be done, I think a lot of
this needs to be done out in the community. The patient groups
need to get organized and develop these. Some of them are
working with PCORI and trying to use that mechanism to get more
information available and so forth.
We have gotten draft guidances from different groups,
including Muscular Dystrophy, that really are a statement of,
``This is what we care about. This is what we value. This is
what we want you to look at.'' And we will pay extremely close
attention to those, and those are extremely valuable.
Mrs. Ellmers. Thank you, Dr. Woodcock.
And I yield back the remainder of my time.
Mr. Pitts. The chair thanks the gentlelady.
We are voting on the floor. We have 10 minutes left in the
vote. We have three more questioners.
Mr. Guthrie recognized for 5 minutes for questioning.
Mr. Guthrie. Thank you, Mr. Chairman. I will try to be
brief.
I will echo what the others said about your testimony.
Appreciate it.
But since we started this 21st Century Cures and--
everybody's excited. Both sides are trying to see how we can do
this better.
And I have heard from a lot of groups and I have heard
several times that the oncology division seems to be one people
really like to work with and it works well. Some of the other
divisions in expedition is not as well to work with.
And I have always believed--Jack Kemp used to say, ``Don't
study failures and point out the problems. Let's look at
successes and see how it can be replicated.''
So within your own agency, you are having wonderfully
successful programs, at least according to the feedback I have
gotten, and some not as fun as the ability to work with.
So I guess my question is: Is there any impediment to
saying, ``Hey, this''--the oncology is what we hear about more,
not that the others aren't, but we hear more--is there any
impediment to taking what is happening there and transferring
to other agencies? Is there something Congress can do to make
it easier or is it just learning and moving forward?
Dr. Woodcock. Let me tell you that 10 years ago, I heard a
lot of negative comments about our oncology group. All right?
And now we have therapies that are so effective. They are
really on fire.
They see that, for their patients they took care of--they
are all oncologists, hem onc doctors--that these new treatments
would really have made a difference for those people. And so
they are doing everything they can to get those treatments out.
And I think what we need, we need the same kind of
inspiring therapies in these other areas. And I do think the
doctors--they are doctors. They are physicians. They care about
patients in their disease area.
And this breakthrough--I don't know whether you can see it
here, but you see that other disease areas are coming up and we
are designating--in neurology and anti-infectives and
psychiatry, we are designating potential breakthroughs. And so
this type of thing will really help.
But, also, of course, we try to have a management
structure, multiple mechanisms whereby we have consistency and
uniformity of our approach and our procedures, and I think we
do quite well in our procedures.
But I think the attitude may have something to do with the
underlying science. We had a war on cancer. It is starting to
pay off. And we need to really expedite that.
Mr. Guthrie. Well, thanks.
And I have a bill particularly to put the same professional
budget judgment status for Alzheimer's, which we are going to
spend in 2050 $1 trillion. This is not loss of income, loss of
productivity.
Dr. Woodcock. Right.
Mr. Guthrie. That is $1 trillion spent on that disease.
That is when I am 86. So that is when my children and our
grandchildren will be taking care of us. So, hopefully, we can
have the same inspiration and do that, particularly in
Alzheimer's.
Dr. Woodcock. I can assure you that, if they were promising
treatments for Alzheimer's, we would jump right on them.
Mr. Guthrie. Appreciate that. Thank you very much.
And I will yield back.
Mr. Pitts. Chair thanks the gentleman.
Recognizes the gentlelady from Tennessee, Mrs. Blackburn, 5
minutes for questions.
Mrs. Blackburn. Thank you so much, Dr. Woodcock. I have
basically one question that I do want to get to.
Looking at the QIDP and the moving forward of that, it can
give up to 5 years of additional data exclusivity. Bipartisan
effort. We were all for it.
What I want to know from you is: How many QIDPs has the FDA
designated to date? How many products have actually been
approved to date? And do you believe that the QIDP is an
important designation?
Dr. Woodcock. It is absolutely important.
Mrs. Blackburn. OK.
Dr. Woodcock. We have granted 50 designations for 34 unique
molecules. And in the last several weeks, we have approved the
first two medications that are designated, the first two
antimicrobials.
Mrs. Blackburn. Excellent.
Dr. Woodcock. So that is making a difference. We do feel,
though, that probably more needs to be done.
Mrs. Blackburn. And in that ``more needs to be done,'' give
me a couple of examples of what you think the next step should
be. I would be interested in that.
Dr. Woodcock. Well, we are very interested in the pathway
that people call limited population antibacterial drugs or
other streamlined pathways for development that would be
matched with some sort of symbol or logo that would enable
doctors and other prescribers to recognize that it was from a
limited program. We think that would also allow us to
streamline the development program.
Mrs. Blackburn. Excellent.
And for the second panel, I want to welcome a fellow
Tennesseean, Dr. Marshall Summar, who is going to be speaking
on behalf of the National Organization of Rare Diseases.
So welcome. We are delighted you are here.
And I would yield back.
Mr. Pitts. Chair thanks the gentlelady.
Now recognizes the gentleman from Florida, Mr. Bilirakis, 5
minutes for questions.
Mr. Bilirakis. Thank you, Mr. Chairman. I appreciate it.
And thank you for your testimony, Dr. Woodcock.
I asked these questions a few months ago and I didn't get a
response. So I am going to see if I can get a response this
time. Appreciate it if you can answer.
Can you tell me how many treatments were approved with
novel biomarkers used for the first time?
Dr. Woodcock. No. I don't have that in the----
Mr. Bilirakis. Can you get that information to me as soon
as possible?
Dr. Woodcock. I would be happy to. It is a very interesting
question. Yes.
Mr. Bilirakis. And then next question: Have any accelerated
approval occurred within novel biomarker in never-before-
treated disease?
Dr. Woodcock. Oh, yes. All the time. And I can get that for
you. I don't have it, again.
Mr. Bilirakis. Please.
How many new biomarkers did the FDA accept for a first-time
use in the last 5 years?
Dr. Woodcock. Certainly.
Mr. Bilirakis. Can you get that for me?
Dr. Woodcock. Absolutely.
Mr. Bilirakis. OK. Very good. Thank you very much.
I know we don't have a lot of time; so, I will yield back.
Thank you, Mr. Chairman.
Mr. Pitts. Thank you.
There is 2 minutes left in the vote on the floor; so, we
are going to recess. There are two votes. As soon as we have
the second vote, we will come back and reconvene with our
second panel.
Again, Dr. Woodcock, thank you for coming. You have been a
terrific witness.
Dr. Woodcock. Thank you.
Mr. Pitts. Members will have follow-up questions. We will
send them to you. We would ask that you please respond.
Thank you. And thank you for your patience.
The subcommittee stands in recess.
[Recess.]
Mr. Pitts. Time of recess having expired, we will reconvene
the subcommittee on Health and introduce our second panel.
In our second panel, we have five witnesses. I will
introduce them in order of their presentation. First, Ms. Pat
Furlong, Founding President and CEO of the Parent Project
Muscular Dystrophy; second one, Mr. Robert Beall, President and
CEO of Cystic Fibrosis Foundation; third, Mr. Richard Pops,
Chairman and CEO of Alkermes; fourthly, Dr. Leonard
Lichtenfeld, Deputy Chief Medical Officer of American Cancer
Society; finally, Dr. Marshall Summar, Director of Scientific
Advisory Committee, National Organization for Rare Disorders.
Thank you all for coming. You will each be given 5 minutes
to summarize your testimony. Your written testimony will be
placed in the record.
Ms. Furlong, we will start with you. You are recognized for
5 minutes for your opening statement.
STATEMENTS OF PAT FURLONG, FOUNDING PRESIDENT AND CEO, PARENT
PROJECT MUSCULAR DYSTROPHY; RICHARD F. POPS, CHAIRMAN AND CEO,
ALKERMES; MARSHALL SUMMAR, M.D., DIRECTOR, SCIENTIFIC ADVISORY
COMMITTEE, NATIONAL ORGANIZATION FOR RARE DISORDERS; ROBERT J.
BEALL, PH.D., PRESIDENT AND CEO, CYSTIC FIBROSIS FOUNDATION;
AND J. LEONARD LICHTENFELD, M.D., DEPUTY CHIEF MEDICAL OFFICER,
AMERICAN CANCER SOCIETY
STATEMENT OF PAT FURLONG
Ms. Furlong. Thank you.
Good morning, Chairman Pitts and members of the committee.
My name is Pat Furlong. Twenty years ago I joined other
parents to form Parent Project Muscular Dystrophy to end
Duchenne, one of the many forms of muscular dystrophy and the
most common lethal genetic disorder diagnosed in childhood.
In 1984, I received the horrific diagnosis on my two sons,
Christopher and Patrick, and both of my sons are gone now. I
wage this crusade in their honor.
Much has happened over the past 15 years to transform the
Duchenne clinical and research landscapes, and much of this is
a direct result of the actions by Congress and this committee,
notably the enactment of the Childs' Health Act in 2000, and
the Muscular Dystrophy CARE Act 1 year later. Since the MD CARE
Act was enacted, we have seen about 10 years added to the
lifespan of patients with Duchenne.
There has been an improvement in quality of life driven
largely by the development and dissemination of care standards
so that all patients can be diagnosed accurately and as early
as possible and provided with the highest quality of care.
The MD CARE Act also transformed the Duchenne research
landscape. What was just 12 years ago a near-barren field has
evolved into a robust area of research where multiple potential
therapies are in clinical testing and several others are in
early stages of development.
Despite these advancements, Duchenne remains a fatal
disease without any FDA-approved therapies. Most boys end up in
wheelchairs by their mid-teens, and only a few live beyond
their late 20s.
Our community needs therapies and we need them fast to. To
achieve this goal, PPMD has led groundbreaking efforts over the
past year to address two major impediments in our request to
end Duchenne.
One is a lack of regulatory understanding of patient and
parent perspectives on benefit-risk; and, two, a lack of clear
guidance or direction to the biopharmaceutical companies
designing these clinical trials.
PPMD partnered with Johns Hopkins University to conduct the
first-ever scientific survey on benefit-risk perspectives. The
survey involved 120 parents of Duchenne children. It validated
what we have known anecdotally for years.
Because Duchenne is 100 percent fatal at a young age, many
patients and families are willing to accept higher levels of
risk in return for the prospect of potential benefit.
The data has been shared with the FDA and was recently
published in an academic journal. Now the FDA must ensure its
reviewers apply this evidence to their decisionmaking process.
Another impediment to drug development, particularly in
rare diseases, is the absence of a clear guidance from FDA when
it comes to designing clinical trials. Small patient
populations, limited knowledge about the condition and a lack
of accepted or validated biomarkers are some of these
challenges.
At the invitation of the FDA, PPMD led a comprehensive 6-
month effort to convene key stakeholders--patients, parents,
clinicians, researchers and industry--to write a draft guidance
document that would address trial design and many other issues.
This was submitted to the FDA last month, marking the first
time a patient group has led the development of such a product.
Now the FDA must step up promptly to review the draft,
gather stakeholder input and issue a guidance document under
the Agency's name.
While each of these projects is focused on Duchenne, each
also offers a template or a model that could be applied to
other diseases or other conditions, particularly rare diseases,
and I hope other organizations will take on similar programs.
So what can Congress and Federal agencies do moving ahead?
First, you can make sure that the patient perspective on
benefit-risk and other issues is considered by reviewers of the
FDA.
One way to do so could be by establishing a nonburdensome
step where reviewers would disclose how they did or did not
take such information into account making their decisions on a
drug application. This would shed light on for what many
considered a mysterious process and could be done in a very
simple manner.
Second, I suggest an even greater focus on regulatory
science so the FDA keeps pace with the breakneck speed of
innovation. Specifically, NIH could bolster support for
regulatory science research and infuse that into clinical and
translational awards. Incorporating a regulatory perspective
earlier in the pipeline can maximize the likelihood that
candidate therapies will be ready for the rigor of the FDA.
Finally, I would encourage greater flexibility in clinical
trials, particularly rare fatal conditions like Duchenne that
have small populations. Business-as-usual trial designs simply
do not hit the mark when working with these populations.
The Duchenne community has traveled a great distance over
the past 15 years, thanks in significant part to the leadership
of this very committee, leadership that will continue on Monday
with action by the full committee on the MD CARE Act
amendments.
For far too many families, my own included, this journey
has not been fast enough. We stand ready to work with your
committee to make sure the 21st Century Cures Initiative ends
Duchenne and so many other rare diseases.
Thank you.
Mr. Pitts. Chair thanks the gentlelady.
[The statement of Ms. Furlong follows:]
[GRAPHIC] [TIFF OMITTED]
Mr. Pitts. Mr. Beall, you are recognized for 5 minutes for
your opening statement.
STATEMENT OF ROBERT J. BEALL, PH.D.
Mr. Beall. Thank you very much for this invitation to
present this testimony.
The story of cystic fibrosis is clearly a story of
determination of hope and optimism. The progress that we have
documented in our submission really shows what is possible when
a system works well, when patients, when stakeholders and the
regulatory agencies collaborate to develop life-changing
treatments.
Cystic fibrosis is clearly a life-threatening genetic
disease that affects about 30,000 individuals in the United
States. There has been tremendous progress in life expectancy
over the decades.
In the 1950s, people with cystic fibrosis barely lived to
elementary school. But there are people that are living today
with cystic fibrosis in their 30s and 40s, and some are even
going beyond.
But we still lose too many patients at very young ages. The
increase in life expectancy is due in large part to
groundbreaking advancements and treatments made possible
because of the Cystic Fibrosis Foundation, our patient
community and our industry collaborators.
Two years ago the FDA approved Kalydeco, the first drug to
treat the underlying causes of cystic fibrosis in a small
subset of people with the disease. Hailed as a game-changer, it
has transformed the lives of those taking this drug.
It is a perfect example of personalized medicine. I might
mention that the FDA approved this drug in near record time, 3
months before the prescribed PDUFA date and months before the
EMEA.
Just 2 weeks ago we saw another breakthrough in cystic
fibrosis. It happened when--the positive data from a phase 3
clinical trial for a new therapy that is targeted at 40 percent
of the CF population.
This data was released by Vertex Pharmaceuticals Company.
These products would not have been possible without the
breakthroughs that have taken place in basic research, in all
the efforts that our foundation has made over the years.
The CF community was thrilled to learn that the trial
participants showed a significant improvement in lung function,
weight gain, and 30 to 40 percent reduction in exacerbations.
That is the time that they would have to go to the hospitals or
have IV infections.
So this is clearly a game-changer for these patients.
Obviously, Vertex plans to submit the new drug application to
the FDA by the end of the year for this treatment.
What is exciting about this progress is that these drugs
would not have been possible were it not for the Foundation and
our patient community. Our commitment to scientific discovery
and drug development is at the root of our success, but it
hasn't been easy and it hasn't occurred overnight.
In 1965, we created the first patient registry in the
United States, now a model for chronic disease. Because of this
registry, we have a documented natural history of cystic
fibrosis.
We have the mutation analysis on most of these patients, as
Dr. Woodcock referred to this morning, and we have the ability
to have post-marketing phase 4 follow-up on these new drugs as
they are introduced to the community.
The same year, 1965, we created a care center network. 90
percent of all patients seen in the United States are seen at
these CFF-accredited and funded care centers.
In 1989, through our support, the CF gene was discovered,
12 years before the human genome was completed.
In 1998, we established a Clinical Trials Network, the
first Clinical Trials Network founded solely by a nonprofit
organization like the Foundation. It is a critical component of
our ability to conduct CF clinical trials efficiently and
effectively.
In 1999, the CF Foundation pioneered a successful venture
philanthropy model to derisk companies from investing in CF
research drug development.
It was our initial investment of $42 million in a small
biotech company in San Diego that ultimately led to Kalydeco.
Vertex would not have had Kalydeco and the other drugs
announced last week were it not for the Cystic Fibrosis
Foundation.
The CF Foundation spearheads collaboration across all
sectors, and this same collaborative spirit extends to the
Foundation's strong partnership with the Food and Drug
Administration.
With the FDA, we are committed to collaboration and
bringing strong data to the table. As often has been stated,
the CF Foundation comes with data, not demands.
Just last week we met with FDA officials to discuss
strategies for clinical research design that may not occur
until 5 years from now.
However, curing a disease is never easy, and even more
risky is the approval of drugs without sufficient data to
assure efficacy and safety.
If this happens, you place patients immediately at risk and
you risk losing the opportunity to test drugs that could have a
real impact and beneficial effect.
So, in closing, what can Congress do for us? Congress
should make sure that patients have a seat at the table, as was
just referred to.
Congress must provide the necessary resources so that the
FDA can attract the best and the brightest. And Congress must
provide the NIH and FDA sufficient resources for regulatory
sciences, as also mentioned.
But, finally, Congress may also encourage that they look at
the CTSA program, a network of care centers that are funded by
the NIH, and see how they might use these to be able to
facilitate Clinical Trial Network and the development of
patient registries in other rare diseases.
So, once again, thank you for this opportunity to add the
CF community's perspective to this important discussion.
Mr. Pitts. Chair thanks the gentleman.
[The statement of Mr. Beall follows:]
[GRAPHIC] [TIFF OMITTED]
Mr. Pitts. Mr. Pops is recognized 5 minutes for an opening
statement.
STATEMENT OF RICHARD F. POPS
Mr. Pops. Thank you very much.
I would like to thank you, Mr. Chairman, Ranking Member
Pallone and all the members of the committee for inviting me to
testify.
I just want to thank Chairman Upton and Congressman DeGette
for spearheading the 21st Century Cures Initiative.
I would also like to express my respect for and
appreciation for the folks on this panel and for Dr. Woodcock.
We are all partners in this together, and it is an credibly
important mission.
The simple and powerful concept of incorporating insights
from patients is centrally important to the future of the
Nation's healthcare system. And it is also one of the great
opportunities for us all to have a transformative impact.
I have served as the CEO of Alkermes for over 20 years. Our
company develops medicines for people living with chronic
debilitating diseases, such as opioid addiction, schizophrenia,
and depression. Our approach is entirely dependent upon
considering the patient perspective early and consistently
throughout the drug development process.
I also serve on the Boards of both BIO and PhRMA and was
deeply involved in the PDUFA V negotiations, as well as the
preparations ongoing for PDUFA VI, where elevating the patient
voice has already emerged as a key theme for that initiative.
Today I would like to propose a new framework for patient
involvement in developing new medicines, which requires
engagement from all three of the major parties involved,
innovative biopharmaceutical companies like ours, FDA, and the
patients who stand to benefit from these medicines.
And the framework is based on three core principles.
First is that interactions must be data-driven, based on
science and separate from powerful and passionate advocacy
messages that patient groups otherwise deliver.
Second, the engagement framework should be actionable, not
theoretical. It should improve the overall efficiency of the
process rather than adding new steps in a process that is
already incredibly complicated. This is particularly important
for young biotechnology companies who are developing their
first drugs on limited resources.
Third, the approach should preserve and enhance FDA's gold
standard of safety and efficacy, which is really one of our
great national treasures. I believe deeply, personally, that
increased patient input can coexist with efficiency and the
highest level of scientific rigor.
So from industry's perspective, there is clearly no
consistent way to incorporate patient-generated input. This
input would have a really meaningful impact on a range of
critical decisions we and our researchers make specific to
particular product candidates and certainly to the way we
design clinical trials and implement them around the world.
This is an important missing link.
As Dr. Woodcock mentioned and the FDA, patient engagement
is not a new concept. Several provisions included in PDUFA as
well as FDASIA have resulted in meaningful new expansions in
patient engagement.
FDA has also been open to and has taken initial steps to
include patient input into their reviews, and we can build on
this. The proposed framework I am considering would build on
all of these things.
The historical paradigm of drug regulation as a bilateral
process between FDA and the industry is outdated. Science and
society have continued to advance. Patients are organizing in
new ways, and their critical role in driving innovation is
becoming more the rule than the exception. We have 20th-century
regulatory framework for 21st-century drug development.
To tackle these increasingly complex scientific and
regulatory issues as we look to treat and cure complex
diseases, all three parties can work together to develop
improvements to their existing regulatory framework.
These would include new clinical trial designs, more
efficient clinical trial enrollment methods, advancing FDA's
evaluation of risk and benefit, and more sophisticated post-
market data collection. These are incredibly exciting areas for
future consideration.
We would need to evolve the way we work together, all the
different parties, recognizing our shared responsibility to
improve the efficiency of the development process and our
accountability to assure the medicines are safe and efficacious
for patients.
There will be a number of challenges to this as we move in,
and these could include establishing a common threshold for
data and scientific rigor that is shared by patient industry
groups and FDA, modifying existing regulations to accommodate
this new framework, protecting intellectual property and data,
which is essential to enabling innovation and maintaining this
gold standard of safety and efficacy.
As next steps, I propose that Congress, industry, FDA and
patient groups come together to develop and implement this new
framework, building on existing patient-focused provisions of
PDUFA and FDASIA. We should also analyze existing statues and
regulations to identify impediments and opportunities.
In conclusion, the concept of a new and comprehensive
patient-inclusive framework is both ambitious and, at the same
time, it is quite modest.
It is ambitious as it could result in a dramatic change in
the way we discover and develop medicines. It is modest because
it is not a new regulatory pathway or authority, but it builds
on an existing foundation.
And we at Alkermes and all of our colleagues in the
biopharmaceutical industry are standing by to help you in that
effort. We really thank you very much for your leadership.
Mr. Pitts. Chair thanks the gentleman.
[The statement of Mr. Pops follows:]
[GRAPHIC] [TIFF OMITTED]
Mr. Pitts. Dr. Lichtenfeld, you are recognized for 5
minutes for your opening statement.
STATEMENT OF J. LEONARD LICHTENFELD, M.D.
Dr, Lichtenfeld. Good morning, Chairman Pitts, Ranking
Member Pallone, and members of the subcommittee.
I am Dr. Len Lichtenfeld, and I am Deputy Chief Medical
Officer for the American Cancer Society and truly appreciate
the opportunity to be with you today to testify. The American
Cancer Society is pleased to contribute to the dialogue around
the committee's 21st Century Cures Initiative.
Today I would like to focus on three critical areas for the
committee's consideration. One is the need for greater
investment in research; secondly, expedited approval processes
that continue to ensure safety and efficacy of approved drugs;
and, third, making patients active partners in all aspects of
research development and regulation of new therapies.
We are fortunate and blessed that today we have 14 million
cancer survivors in the United States. It is a remarkable
number, and it is due to more effective treatments and improved
screening tools that have been made possible through research.
We must continue and expand our steadfast commitment to
research, and we must continue to support researchers working
on finding the next generation of cures.
Just as important, we must ensure that expedited approval
processes for drugs and devices are appropriately safe,
effective and accessible to patients. The goal of the 21st
Century Cures Initiative is to accelerate the development and
approval of new medical treatments.
There are a few other areas that can match the research and
development activity in the field of cancer. It is, in fact,
and has been a model of innovation.
The FDA's Office of Hematology Oncology Products has
aggressively used the tools provided by Congress to speed new
drugs to patients and has encouraged drug companies to be
innovative in clinical trials.
In the past 8 months, three cancer drugs have been approved
using the accelerated pathway. One approval was based on a
trial of 111 patients, an example of research approvals
happening faster and with smaller clinical trials as has been
the case in the past.
Small-sized trials and accelerated approval do have
drawbacks. They may not include a diverse population, which may
yield an incomplete picture of how a drug might work in a
broader population. Small trials and accelerated approvals also
tend to be seen in deadlier cancers where there are no other
good therapeutic options.
And I want to stress that the risk-benefit tolerance of a
cancer patient facing a poor prognosis may be much different
than for those with other available treatment options.
And, therefore, the same acceptance of reduced data on
which to base FDA approval may not be appropriate in other
fields or for other diseases.
Finally, I want to stress the importance of researchers,
pharmaceutical companies and the FDA in engaging widely and
meaningfully with patients.
The Food and Drug Administration Safety and Innovation Act
requires greater patient involvement throughout the drug and
device approval process. ACS CAN championed provisions to
expand the FDA's patient representative program to maximize
patient input during the drug development process.
We need to continue to build on that progress. Patients can
provide important perspectives at various stages of medical
product development and regulation.
They know more than anyone what is most important to
patients, to themselves: Symptom reduction, risk tolerance and
design elements that might affect trial recruitment or
retention.
This kind of patient involvement should be reinforced and
supported and, to this end, the FDASIA provisions requiring FDA
to address challenges that have hindered patient involvement
must be fully implemented.
We urge the committee to consider examining opportunities
for providing greater funding to support the FDA patient
representative program as well as broader continued engagement
with the patient community.
Another important way patients' perspectives can inform
development of therapies is through the design and use of
patient-reported outcomes.
Measures of cancer therapy effectiveness sometimes include
functional status, pain or quality-of-life measures, but these
may be reported by the physician rather than by the patient.
Quality-of-life measures like pain or nausea should come
from patients themselves, and patients should help prioritize
the importance of these side effects in the overall response to
a disease and the associated treatments.
When quality-of-life outcomes are vigorously measured and
supported by the FDA, they should be included in a drug's
labeling and they should be considered for a drug's approval.
The FDA should also be encouraged to work with industry and
researchers to incorporate self-reported symptom measurements
as a regular part of clinical trials.
In closing, we appreciate the opportunity to contribute to
the dialogue around the committee's 21st Century Cures
Initiative and look forward to working with the subcommittee
and its staff. I am happy to take any questions.
Thank you very much for this opportunity.
Mr. Pitts. Chair thanks the gentleman.
[The statement of Dr. Lichtenfeld follows:]
[GRAPHIC] [TIFF OMITTED]
Mr. Pitts. Dr. Summar, you are recognized for 5 minutes for
your opening statement.
STATEMENT OF MARSHALL SUMMAR, M.D.
Dr. Summar. Thank you, sir.
Good morning, Chairman Pitts, Ranking Member Pallone and
members of the subcommittee. And thank you for inviting me
today.
My name is Marshall Summar. I have the good fortune to be
the Chief of Genetics and Metabolism at Children's National
Medical Center here in Washington, D.C.
I have been working in the field of rare diseases for the
last 29 years, and I am here today in my capacity as a member
of the Board of Directors of the National Organization of Rare
Disease and Chair of the Scientific Advisory Committee of NORD.
On behalf of the estimated 30 million individuals with rare
diseases, NORD thanks you in the Energy and Commerce Committee
for your continued strong support of the rare disease
community. You have made a huge difference for us.
NORD's a unique federation of over 200 patient advocacy
groups, clinicians, researchers, dedicated to helping people
with rare diseases.
NORD provides resources, research advocacy, education,
community and infrastructure support to the rare-disease
community that small individual organizations cannot. It is the
nature of rare diseases. They are small.
NORD was founded in 1983 and played an active role in the
passage of the Orphan Drug Act, which is a successful model of
how to incentivize the development of treatment that saves
lives.
Data show that years of life lost to rare diseases declined
at an annual rate of 3.3 percent after the Orphan Drug Act due
to the development of new treatments.
Without these new drugs, if you take them out of the
equation, the number of years of lives lost should have
increased at about a 1 percent rate per year. So it has made a
real impact on our patients.
Speaking personally, without these treatments, many of my
patients would not be here. I thank you for what you have
already done.
These efforts represent a good beginning, but there is much
more we can do to improve the lives of our patients, and NORD
views the 21st Century Cures Initiative as a great way to do
this.
NORD's long advocated increased involvement of patients in
the drug development process. We appreciate the commitment by
many at the FDA to increase patient involvement, but believe
much more needs to be done to make patients feel they are
partners in the process. NORD will continue to work with the
FDA to advance the patient role in the development and approval
process.
We have developed a series of recommendations that we
believe will advance not only the development of new orphan
drugs and devices, but non-orphan ones as well. We look forward
to discussing these ideas with the committee as the 21st
Century Cures Initiative continues.
Permit me to focus on two of our recommendations.
First, we support the establishment of a commission and
national plan to determine priorities, methods, resource needs
and a consistent agenda on rare-disease registries and natural
history studies.
They have got a lot of variation. They tend to be all over
the map. To assess the drug's efficacy, we need the information
on the existence, frequency, and severity of clinical findings.
This information is needed before a clinical trial can begin.
We encourage the creation and maintenance of programs to
create, curate, and standardize registries and national history
studies which can generate this needed data.
This could be one of the most important accelerators of the
treatment development and monitoring process. These registries
can also be used in the post-approval process as well.
This is an area where patients can have a major and cost-
saving impact on the process. Patient-entered data has been
shown to be accurate and useful when collected properly.
Creative hybrids using physician-, patient- and other
health professional-collected data can greatly speed the
understanding, discovery, approval and monitoring process.
In collaboration with the NIH and FDA, NORD has built and
is in the process of testing a rare-disease patient-driven
registry national history program. The NIH's Rare Disease
Clinical Research Network has already demonstrated the benefits
of this approach.
In a registry I have been involved with, we have had
approval of three drugs over a 10-year period with only 700
patients. So it definitely has accelerated the approval process
for us.
The Patient Centered Outcomes Research Institute is
developing these statistical methods and models to use data
from rare-disease patient studies that will further refine this
process.
They are also involved in patient-driven registries through
PCORnet and will begin working with NORD on our rare disease-
focused registry program. So we should have good input from
multiple agencies.
All of these efforts will help our patients, but a national
plan and standards would help prevent duplicated effort and
resources. This is what we truly need.
The other thing we advocate is significant reform to the
Institutional Review Board system. I have been working with
this system for the last 30 years; so, I am pretty familiar
with all of its manifestations.
Currently, all clinical trials for new treatments, whether
a drug, biologic or medical device, must receive approval from
an IRB.
Each institution and study site typically requires approval
and protocol adjustment by its own IRB. With a large number of
sites needed for rare-disease study, this is one of the
greatest impediments and cost to clinical trials.
NORD recommends that Congress develop legislation that
would de-risk the process and foster the creation of an IRB
system that is portable across institutions.
The de-risking of the IRB process and the encouragement
requirement of reliance agreements between institutions
receiving Federal funding would save cost and time while
accelerating the clinical trials and clinical research process
greatly. This will significantly increase the pool of study
sites and allow greater patient participation.
These are just two of our recommendations. My written
testimony includes the rest.
And I on behalf of NORD, I thank the committee for allowing
us to testify today.
Mr. Pitts. Chair thanks the gentleman.
[The statement of Dr. Summar follows:]
[GRAPHIC] [TIFF OMITTED]
Mr. Pitts. Thanks to all the witnesses for your opening
statements. And we will now begin questioning.
I will recognize myself 5 minutes for that purpose.
Ms. Furlong, we will start with you.
Do you believe your guidance collaboration with industry is
a scaleable model that can be used in other conditions,
specifically, where there are unique factors that make Duchenne
muscular dystrophy guidance a special case in the multi-
stakeholder effort that you led with encouragement from the
FDA?
Ms. Furlong. Thank you, Chairman Pitts, for the question.
I certainly think that this methodology and process is
exportable to other rare conditions. How we started the
guidance or initiated the guidance was to develop a steering
committee that was representative of the stakeholders, which
included patients, academia, as well as industry.
From there, the steering committee identified several
areas, seven working groups, actually, of things that they felt
were relevant, to include diagnosis, biomarkers, clinical trial
design, natural history, and benefit-risk.
And then we further developed a CAB, which is the Community
Advisory Board, so that would be--incorporate the entire
patient voice and any individual or patient group that wanted
to contribute to the development of the guidance.
The standardization for the guidance was that it would be a
reference document and that it would include documented
evidence that was published or accepted for publication by the
end of July.
So we felt--and we are writing up the methodology--that
this methodology is exportable. It was certainly an
investigation and a thorough, thoughtful, reasoned look at the
community and the nuances of Duchenne.
But I believe that most rare diseases could do the same.
Their issues may be slightly different and their progress to
date might be slightly different, but it is certainly
exportable.
Mr. Pitts. Thank you.
Dr. Beall, communication with patients to make sure they
can make informed decisions about clinical trial participation
is critical.
How does the cystic fibrosis community communicate with
patients about the various options? And how do you think we can
best translate your good practices into the Cures Initiative?
Mr. Beall. Thank you very much.
First of all, because 90 percent of all of our CF patients
are seen in a network of care centers and that we also have a
Clinical Trials Network, there is a very close relationship
between our physicians and the patients that are involved.
And that is critical for the recruitment of patients in the
clinical trials. It is critically important for showing them
the value and the risk of participating in clinical trials.
And it is that close association between the physician and
the patient and the recruitment process in a very closed
network that is critical. That is why I think Clinical Trials
Networks are critically important.
So we also have established within our Clinical Trials
Network a data safety monitoring board independent of the
Cystic Fibrosis Foundation, but it is made up of experts.
And that provides a degree of assurance to every single
patient that there is somebody looking out for their continuing
interest and for any risk that may be inherent in any single
trial.
So I think all of these things, plus we have worked very
hard to try to create a culture of participation and a
responsibility that each patient, when you have a small patient
population, needs to participate in the process. So I think it
is that reassurance that is so important.
Mr. Pitts. Thank you.
Mr. Pops, what stage of drug development could most use the
assistance of patient insight about benefit expectations and
risk tolerance?
Mr. Pops. Thank you for the question.
It is actually the most exciting part of the whole
opportunity, that it is every stage, actually from
identification of new drug candidates, all the way through to
determination of the value of the medicine after the completion
of the pivotal clinical trials.
And I think that is the whole idea of this framework, is
creating a structure where we can get that input on a
continuous basis, and I think it could fundamentally transform
the way we approach these development programs.
Mr. Pitts. Thank you.
Dr. Lichtenfeld, you have discussed examples of cancer
drugs that have recently been successfully approved by FDA
through an accelerated approval process.
Are there best practices that we can learn from cancer and
how FDA is expediting the approval process for particular
drugs?
Dr. Lichtenfeld. Thank you, Mr. Chairman.
When we talk about best practices, I think the question
really came up with Dr. Woodcock earlier today: What is the
oncology community doing that is different than other
communities?
Let's understand it is a complex process in the sense that
we have research that has been building literally for decades
that has produced very exciting results that is actionable and
companies are standing up to create drugs for the targets that
we are finding for the new immunotherapies for genetic disease,
what have you, genetic markers. So we are, in a sense, at an
interesting and turning-point kind of place.
But important, relevant to your question, the Office of
Hematology Oncology Products has also stepped up to the plate.
And as was mentioned earlier, the oncology community
appreciates the efforts of the FDA staff to reach out to the
patient community, to reach out to the pharmaceutical
community, to reach out to those who do clinical trials, to be
active participants, to be at the table.
Lung-MAP was cited several times. The American Cancer
Society was grateful to be able to have contributed to that
effort, among many other organizations.
But the FDA has become an active partner with the process.
And so I don't know if that is a best practice or a best
example. But it is that source of communication.
But let's not forget it is also the opportunity because we
are now in a place that we only dreamed of just a short while
ago.
Mr. Pitts. The chair thanks the gentleman.
My time has expired.
The chair recognizes the ranking member, Mr. Pallone, 5
minutes for questions.
Mr. Pallone. Thank you, Mr. Chairman.
My questions are of Mr. Beall.
The Cystic Fibrosis Foundation has done some great
collaborative work that has resulted not only in successful
marketing of Kalydeco, but also the recent positive test
results of a complementary drug that may extend treatment to
nearly half of all patients with CF. And, of course, I commend
you for your efforts.
But I wanted to ask you about a couple of points in your
testimony. In your remarks, you spoke about the CF Foundation's
strong relationship with the FDA and the importance of bringing
good data to the table when consulting with the FDA, which I
know is true. And I would like to hear more about that
relationship.
Obviously, we are hearing a lot today about the need for
FDA to do more to seek and incorporate patient input into its
review process.
So the basic question, Mr. Beall, is: Can you tell us more
about the CF Foundation's interaction with the FDA? And are
there any lessons that can be learned by other disease groups?
Mr. Beall. Well, I can give you a perfect example because,
on Wednesday of this week, we had three officials, including
Dr. Robert Temple, who is in the drug division at our offices,
talking about the development of clinical trial protocols of
drugs that might not enter into clinical trials until 3 to 5
years from now.
So that is a perfect example of this open discussion.
Because we have a natural history of the disease. We know that
the drugs that we have tested are treating the basic defect. We
know the mechanism of action. We have a safety profile.
And now we can start to talk about the future. And I think
it is that kind of example. And that goes back many, many
years.
Soon after we discovered the CF gene, we talked about gene
therapy and we had extensive dialogues with the FDA, not only
with manufacturers, but with the FDA and the Foundation.
So I could just say that we have always had a wonderful
collaboration. We have data. We have natural history of the
disease because of the patient registry.
And, again, we come with data and we come with experience
and we come with the networks that can make these things
happen.
So I just gave you an example. That was the example.
Mr. Pallone. No. That is fine.
We are hearing a lot about the various expedited drug
review processes at FDA, and it is clearly a push by many to
get the Agency to use these pathways more frequently and in
more disease areas. And I share the goal of speeding the
therapies to patient at the earliest possible time.
But I think we need to be cognizant of the risks that could
accompany that speed, and we especially need to be concerned
about such risks if we are ultimately thinking about somehow
requiring more frequent use of these expedited pathways through
legislation. And I know you share that concern.
Your testimony mentions the health risk that could result
from approving therapies based on early data that needs more
vigorous study, but you also describe the possibility that
these kinds of approvals could endanger progress toward the
development of other treatments.
Can you just elaborate on both of those concerns, if you
would.
Mr. Beall. Well, certainly, one of the things when you are
dealing with a small population--and now we are talking about
personalized medicine where you may only have 25 patients with
a certain genotype that may be approachable or therapeutic
opportunities for that particular drug--if those patients were
introduced to a drug that was less than effective, what happens
when the next drug that could be effective--how do you do the
clinical trial?
So I think that is really very critical because we want to
make sure that our first introduction is drugs that are
efficacious, and then we move forward to the next level.
Because then you really are depriving, if you don't have safe
drugs, of developing good drugs and effective drugs that could
move us above the therapeutic options that we have.
So I think that that is the critical thing that we always
face. There is always the risk. But now we are dealing with
small populations, personalized medicine. Maybe there is only
going to be 6, 10, 1,000 patients.
So I think you have to be particularly critical on that
issue with rare diseases.
Mr. Pallone. OK. Yes. I just wanted to echo another point
you made in your testimony about the importance of resources.
And I couldn't agree more, that, as you say, FDA needs
resources to ensure that they can rely on the best regulatory
science available and they need adequate resources to enable
them basically to meaningfully engage with the patient
community.
And we have this 21st Century Cures Initiative, which is
progressing now. We have had some sort of larger meetings and
now some hearings. And my colleagues always ask what can
Congress do.
And I think that the most effective thing we can do is
provide adequate resources to make sure that FDA, as well as
NIH, have the resources to fulfill the expectations we have for
both agencies.
And I hear not only from the agencies, but, also, from my
constituents, that they don't have enough resources. So I just
wanted to echo again what you said.
Thank you, Mr. Chairman.
Mr. Pitts. The chair thanks the gentleman.
I now recognize the vice chairman of the subcommittee, Dr.
Burgess, 5 minutes for questions.
Mr. Burgess. Just before my time starts to run, could I
make a unanimous consent request?
Mr. Pitts. You may proceed.
Mr. Burgess. I would like to move that the committee make
people aware that, if someone wishes to contact or communicate
with the Cures Initiative, it is [email protected].
I know there are many people watching who think, ``I would
like to interact with the committee staff.'' So that is the way
to do it.
Mr. Pitts. Thank you.
Without objection, so ordered.
Mr. Burgess. Very well. I knew they wouldn't deny me.
Let me ask Ms. Furlong. You were kind enough to mention the
work on the MD CARE Act, and thank you for that. As you know,
we will likely be marking that up next week. So that is a big
milestone.
Can you talk about how the MD CARE Act needs updating and
the type of updating that this committee has pursued?
Ms. Furlong. Certainly. And thank you for the question, Dr.
Burgess.
The MD CARE Act was the solid foundation that set Duchenne
and the muscular dystrophies--really galvanized their progress.
So the MD CARE Act was enacted in 2001 and reauthorized in
2008. And right now the amendments are really to look at what
we have learned in the meantime.
So the cardiac issues in Duchenne muscular dystrophy are
real and they have to be tackled in order to answer the
question. As you look at these potential therapies that were
hopeful to be approved in the next months and years, they
extend function. Will they protect or have a negative effect on
the heart?
So it is the gaps that we need to really look at with the
amendments, in addition to the fact that, when this legislation
was enacted in 2001, young boys with Duchenne didn't live to be
adults.
So now we have an adult population and we need to really
address those adults in terms of their medical care and, also,
to incentivize and understand how to treat them, how to
encourage them to have long and independent lives as they
become adults and reach for their dreams.
So I think that the MD CARE Act is now looking with the
muscular dystrophy committee from the NIH and other agencies.
Their research plan has to be updated and these amendments to
be incorporated so that we are really achieving the full effect
that the MD CARE Act was initiated for.
Mr. Burgess. Thank you.
And of course, Mr. Beall will also acknowledge that the
population of patients is changing because of some of the
successes that have happened over the past several years.
And in both of those illnesses, both cystic fibrosis and
muscular dystrophy, it is important that we keep pace with the
way the patient population is changing.
We want people to live longer and fuller lives with their
conditions and, at the same time, we don't want the legislation
then to stymie that. So it is, in my opinion, an important step
forward.
Dr. Beall, we talked--or you talked about the development
of mutation-specific therapies and the next evolution in
precision medicine and you could see the cystic fibrosis
example impacting the way we address other serious illnesses.
Is there something more you would like to add to that?
Mr. Beall. Well, again, we are clearly in the age of
personalized medicine. Fortunately, with the completion of the
human genome, we understand the genetics of so many more
diseases and genetic diseases that it is a very critical time
for us.
Mr. Pitts. Microphone.
Mr. Beall. Not on? OK.
I just saw Dr. Collins downstairs, and he is excited
because he was one of the discoverers of our CF gene.
So we live in a very unique age, and I think more and more
therapies are going to be directed towards specific mutations.
And that is one of the reasons that we have to have these
kinds of patient registries, so we can start to identify those
mutations.
When Vertex felt that they had a drug that might work on a
certain mutation, the small drug that came out, G551D, we were
willing--we were able to tell them in the United States we have
1,100 of those patients within 5 minutes after they asked us
because of a patient registry, because we have a documented
history of the disease.
So I think that is why it is very important to have
personalized medicine, therapies and the options for that, but
it is also--we have to be able to document the patients that
can participate in the trials.
Mr. Burgess. Yes. It is very powerful.
And, of course, you referenced to the 1965 registry. In
1965, you didn't know that we were going to know about the
sequence of the human genome 30 years later.
Mr. Beall. Well, but we have been able to document it.
Today we have 26,000 patients whose data is provided to our
patient registry every single year.
Mr. Burgess. Let me ask you a question. I am going to run
out of time pretty quickly. But--and this is either for Mr.
Beall or Mr. Pops.
The world is different now and you have people that are
perhaps lucky enough to enter into a clinical trial and they
are likely to perhaps have friends with the same condition.
So in the old days, a randomized clinical trial, you
wouldn't know which arm to which you were randomized, who was
getting the target or study drug, who was getting either an
older therapy or no therapy. But now people communicate.
Facebook. Twitter. They are likely to be Facebook friends.
How is that going to impact the ability to have a blind and
randomized clinical trial? Are people likely to communicate
with each other, I mean, look, ``I am getting a lot better on
this stuff. How about you?'' ``Wait a minute. I haven't seen a
darn thing''?
Mr. Pops. I think it is a real question. It is a real issue
because--and you can't pretend that it is not going to happen.
This is already happening, particularly as you get large
cohorts of patients in randomized studies in multiple
countries. They are all communicating.
So I think it is very important that we be really rigorous
in maintaining the blind to the extent that we can.
Mr. Burgess. To the extent that we can. But, also, we
probably need to embrace the fact that the information is out
there and being communicated and, to the extent that it can
further enhance what we are doing----
Mr. Pops. So let's take advantage of it.
Mr. Burgess. Yes.
Mr. Pops. Let's do more in the aftermarket. Let's approve
drugs and collect this information and get a more nuanced view
of the drugs' use in the real world and turn it to our
advantage.
Mr. Beall. And, in some cases, it is going to make it
easier to do clinical trials when you can have large networks
that exist out there, when they can report patient-reported
outcomes and things like that.
So I think sometimes it is looked at as a disadvantage, but
we ought to turn it--as Mr. Pops just said, we ought to turn it
to an advantage because I think it can expedite the ability to
do clinical trials as we move forward with the technology.
Mr. Burgess. Great. Thank you.
Ms. Furlong. And it should expedite post-hoc analysis so
that we can see the long-term effects. Because in a clinical
trial of 12 months, for instance, plus or minus, you might not
see the full effect of a drug that is multisystemic. So it will
enable us to understand the full impact on the patients' lives.
Mr. Burgess. Thank you, Mr. Chairman. I yield back.
Mr. Pitts. The chair thanks the gentleman.
Now recognize the gentlelady from Illinois, Ms. Schakowsky,
5 minutes for questions.
Ms. Schakowsky. Thank you very much.
I had a question for Dr. Lichtenfeld--actually, for anyone
on the panel that wants to comment on this.
This is about quality-of-life outcomes. I mean, obviously,
if this is a known life-threatening disease, you want to do
everything you can to make sure that the therapies match the
disease.
But there are--you would say, when these quality-of-life
outcomes are rigorously measured and supported by the FDA, they
can and should be included in drugs' labeling and can by
themselves be a basis for a drug's approval.
I certainly know people who have suffered so much from side
effects of drugs. And I just wonder, in the whole process of
drug approvals, how much are these quality-of-life issues
really looked at? As a basis for approval or just as a basis of
whether or not they are used?
Dr. Lichtenfeld. Thank you for your question.
In fact, it is a work in progress. Let's understand that
quality of life is a buzzword today, but it wasn't a buzzword
very recently.
So as we look at the issues, shall we say, of palliative
care, of supportive care, quality of life, issues that the
American Cancer Society and many others have been involved in,
it is relatively new to the table.
Having said that, there have been issues recently with one
particular drug where, had the question really centered around
was the--even though the drug may not have met the FDA
standard--and this was about 2 years ago--even though it had
not met the FDA standard, did it meet the quality-of-life
standard? Did it improve the quality of life of the--it
happened to be a breast cancer drug--for the women who took it?
Because that would have been an important consideration.
And, unfortunately, the quality of the data measuring quality
of life was inadequate.
So going forward, cancer patients have enough on their
plates, as do everyone represented at this table, as do
patients throughout this country. We need to be aware that
quality of life is an important part of the treatment process,
and we need to have tools in place.
They are not uniform yet. They are not as good as we would
like. But they have to be in place to measure quality of life,
and that has to be considered. And patient-reported outcomes
are very much a part of that process.
Ms. Schakowsky. Yes. Go ahead, Doctor.
Mr. Pops. I just wanted to make a comment as it relates to
patients with chronic disease as well. We talked a lot about
cancer and orphan, small diseases.
We work in the field of chronic disease--schizophrenia,
depression, addiction--where patients are taking medicines for
long, long periods of time.
And simple things that may seem prosaic to the researcher,
like nausea----
Ms. Schakowsky. Sure.
Mr. Pops [continuing]. Fatigue, propensity to get addicted
or dependent on the drug, these are really important inputs
that we want to hear from patients about.
Ms. Schakowsky. And is that part of the process?
Mr. Pops. It is less part of the approval process today
than I think it will be in the future. It is certainly part of
the utilization process as patients make a determination,
``Which medicine do I want to stay on for years and months?'' I
think that is a critical part of it, but it is not really
incorporated in the consideration of the approval.
Ms. Schakowsky. Especially where all things might be equal
in effectiveness, whether or not something causes nausea,
fatigue, could be really important.
Mr. Pops. That is right. Particularly if you are launching
a new medicine into a large category where there might be an
abundance of generic drugs that are safe and effective, but
might not hit all of those parameters for certain subsets of
patients for long periods of time.
And we just want people to be sensitive to the fact that,
from the patient perspective, there are differences between the
medicines.
Ms. Schakowsky. Right.
And then, also, Dr. Lichtenfeld, I wanted to ask you about
small-sized trials. And you mentioned one of the drawbacks.
I had talked about the extent to which women aren't
considered. And I would just be concerned--I understand the
plus. I do. But if we rely too heavily on them, isn't there the
real risk of excluding important populations?
Dr. Lichtenfeld. Well, the answer is yes, there is a real
risk of excluding important populations.
In fact, when you talked about women and heart disease, I
remember back in the early 1990s when the article came out
talking about the absence of women in clinical trials for the
treatment of hypertension and heart disease. So this is an
issue I am aware of.
But let's talk about the other side of the coin, and that
is, when you are sitting--I have sat in the presentations at
ASCO, at oncology meetings--and you see a presentation of 80
patients and you see what we call waterfall plots--basically,
the responses in survival that occur--and suddenly, 70 percent
of those patients are having significant responses, In a
disease where there was no treatment before, I don't think one
asks the question--they ask the question in followup, but not
at the moment.
And what has happened and what has been exciting to me is I
am now sitting in those presentations every June and I see--I
wrote about it--it took a year for one of the drugs to go from
clinical trial to approval because it was that effective in the
disease where there was no other treatment available. That is
pretty spectacular. That is new thinking. That is a new
approach.
Now, we have learned more as time has gone on. Yes. Doesn't
mean we have stopped learning, as was mentioned before about
cystic fibrosis. But when you suddenly see moments like that,
no one would want to hold back. Develop the data, yes, but
don't hold back the opportunity.
In fact, even a phase 1 trial that was presented at this
ASCO meeting in June, the company, actually--well, not the
company, but ASCO in the press release indicated the company
was willing after a phase 1 trial to put it into compassionate
use. And that is pretty amazing, a major change in the way that
traditionally we have seen cancer drugs move through the
pipeline.
Ms. Schakowsky. Thank you.
I have overstayed my time. Thank you.
Mr. Pitts. Sure. Thanks to the gentlelady.
I now recognize the gentleman from Virginia, Mr. Griffith,
5 minutes for questions.
Mr. Griffith. Dr. Lichtenfeld, let's pick up there, because
I think that that compassionate use is something that--we
really need to be figuring out how we can make it more
effective and how we can do it faster at the Federal level.
You talked about in your testimony that patients needed to
be involved both on saying what kind of nausea they had and
what the pain levels were and so forth, and I agree with that.
But I also think that, particularly when you have no
treatment, that patients need to be involved in that, too. And
as Ms. Furlong said earlier, when there isn't a treatment, you
are much more willing to take those risks than you would be if
there is some other treatment out there that might work, but
this might be a little more comfortable.
And I want to give both you and Ms. Furlong an opportunity
just to address that further.
Dr. Lichtenfeld. Well, thank you. And I appreciate the
question, and I know you mentioned it earlier.
It is a complex issue. It is not a new issue. As you may
well be aware, it has been around for some time with the number
of drugs that have gone through the pipeline, which seem to
show some opportunities. Various state legislatures are
involved.
And I am sitting here today both as a representative of the
Society, but also as an individual, and understand that there
are discussions on both sides of that issue and they are
complicated.
Bottom line is that we need to understand what drugs work
when they work. We need to understand that patients need to
have access to promising drugs as soon as possible.
Companies make those decisions as to how they are going to
handle that process. The FDA, as a matter of fact, has approved
almost all of the applications they received. And we need to
have those discussions to come to a better resolution about how
to address that issue.
Mr. Griffith. And what I would say is that whatever we can
do--I think I speak for a lot of the members of the committee--
I am probably a little more out there than some--but whatever
we can do to help by changing the law to expedite that process,
we will do.
Dr. Lichtenfeld. We would be glad to have those discussions
on behalf of the Society, sir.
Mr. Griffith. Ms. Furlong, did you want to make another
comment about risk assessment? Because, obviously, when your
boys were sick, you probably would have taken anything that had
any promise of hope.
Ms. Furlong. I think I could tell you stories about looking
in China to see some tea that you might be appalled about, but
that was long ago.
I think it really is up to the companies. FDA has always,
to my knowledge, at least in the Duchenne and other fields,
been willing to entertain and talk about compassionate use.
I think for the rare disease community this really talks
about and gets us back to trial design.
In general, trials are designed to test a small subset of
patients. In the Duchenne community, the 6-minute walk test is
the standard primary outcome measure.
So that means, as a child with Duchenne, you have to walk 6
minutes and even further, as we learn more about the testing.
It is a very narrow subset of people within a certain framework
of that 6-minute walk test, which, as you can imagine, leaves a
great number of people outside the trial.
So I think trials have to be designed that are inclusive
and welcoming of people that live with the spectrum of the
illness, both very young as well as adults with very limited
functional ability.
That way, we can test those in those populations. We can
have labels that are broad and then provide access to all. So I
think that might be a better solution.
Mr. Griffith. Thank you.
I look forward to working with you all.
And, with that, I yield the remainder of my time to Dr.
Burgess.
Mr. Burgess. I thank the gentleman.
Dr. Lichtenfeld, I just wanted to follow up with you
because your specialty has been involved in this type of
activity probably longer than any other branch of clinical
medicine, going back to 1955 when the developmental
therapeutics program was put into place at the National Cancer
Institute.
So with that breadth of experience within your specialty,
are there things that you want to share with others about what
that experience has taught you?
Dr. Lichtenfeld. Well, what we did back in 1965 or whenever
was a lot different than what we are doing today. I don't want
to take the time to really go into it. You may be aware of it.
But here is the message. It didn't happen overnight. It
took 40 years of research to get us to the tipping point where
we understood the genome and had the opportunity to take
advantage of that and move forward.
Immunotherapy, the same story. It has taken us 40 years.
That was a substantial amount--I don't want to underestimate
the value of research investment to get us to the point where
we are, where suddenly we look like we have so much to offer
and to do.
I also comment, with regard to my co-panelists, that they
have populations and they have demonstrated that finding the
patients where they are is critically important.
We have a substantial amount of work to do to understand
not only the clinical trial mechanism, but also the medical
practice system, so we can make sure that patients and
communities--I live in a small town in south Georgia--that my
friends have opportunities to get these drugs in clinical
trials and be part of that process. There is a lot of work to
do.
Mr. Burgess. Thank you, Mr. Chairman. I yield back.
Mr. Pitts. The chair thanks the gentleman.
Now recognize the gentleman from New York, Mr. Engel, 5
minutes for questions.
Mr. Engel. Thank you, Mr. Chairman and Mr. Pallone, for
holding this hearing. I am pleased to have this opportunity to
further consider how patient perspectives can best be
incorporated into the therapeutic development process.
As the author of the ALS Registry Act and the Paul D.
Wellstone Muscular Dystrophy Community Assistance Research
Education Amendments of 2008 and 2013, along with my colleague,
Dr. Burgess, I have worked to be a voice with those with rare
and orphan diseases.
I am encouraged by the advances we have made into the
causes and mechanisms of these diseases, as well as our
progress toward treatments, but, obviously, we still have a
long way to go.
One of the most striking gains we have made is for
individuals with Duchenne muscular dystrophy. As Ms. Furlong
mentioned, our efforts have added an average of 10 years to the
life expectancy of boys with Duchenne. And now, as life
expectancy increases, we face new challenges in finding
effective therapies.
The patient community brings an important perspective and
understanding to this process, and I am interested to see how
we can best use that knowledge to assist medical researchers
with therapy developments.
So, Ms. Furlong, let me ask you this. I am particularly
interested in the way the Duchenne patient community is engaged
with the FDA to help inform the benefit-risk determinations
made by agency reviewers, as well as the Duchenne community
guidance document you referred to in your prepared testimony.
Could you please comment on how you hope to see these
efforts affect the therapeutic pipeline and the various
stakeholders who are part of that pipeline.
Ms. Furlong. Yes. Thank you, Mr. Engel, for the question.
The benefit-risk really originated out of discussions with
the FDA because, in our early discussions, it was known that we
were telling anecdotal stories that the equation of benefit-
risk was different in, for instance, Duchenne muscular
dystrophy than perhaps some more common disease.
And in that the FDA suggested to us that they agreed, but
they didn't have anything they could rely on, any quantified
evidence-based document that could help them make those
decisions.
So we agreed to go out on benefit-risk and did the pilot
with 120 parents. We learned that their priority is disease
stabilization and they were willing to accept a great deal of
risk. In fact, they are living with a great deal of risk, as
they know that their child has a fatal illness.
So the FDA has now asked us to expand that study to a
greater number of patients than 120 patients and, also, to ask
these questions of the young men with Duchenne. Our hope is
that they will incorporate it into the review process and they
will demonstrate to us how and when they use it and when they
don't and what makes sense for them as they make their
decisions.
Mr. Engel. Thank you. And thank you for your advocacy and
hard work. It is very much appreciated.
Dr. Summar, can you talk about the role you think the
patient perspectives should play in developing therapies for
diseases like ALS and muscular dystrophy that have limited
treatment options and for which quality of life is, obviously,
an especially important factor to patients.
How can the FDA best consider the views of patients and
families when examining the benefit-risk calculus for these
diseases?
Dr. Summar. Thank you for that question, Mr. Engel.
This really kind of expands across the entire field of rare
diseases, but your question is particularly relevant for those
two groups.
Patients often tell us about things that they wish were
better that we never thought of. One of the things I have run
across time and time again is, when we go and ask our patients,
``What is the worst part of this disease?''--a lot of times it
is parents in the case of pediatric patients--they will list
some things. And sometimes the things we thought were most
important are number nine or ten on the list.
So I think, when we look at what our therapeutic targets
are, what our quality-of-life targets are for these diseases,
patient and family input is a huge factor, and I think it is
something we can incorporate a lot better than we have.
I think during the early stages, particularly when we are
designing our pivotal trials, clinical trials, looking at what
end points are--I think that those are going to become more and
more important.
And the other thing, of course, is the small group sizes
with these. Many times it is hard to pick one single outcome
variable that you are going to be able to achieve.
The smallest study I have been involved with was five
patients for an approval process. Getting one exact target for
that--fortunately, the effect of the drug was massive; so, we
were able to do it. But if it had been milder, I might have
needed more than one outcome variable.
So I think families can help us determine what is important
there. They can help us, also, as we talked about with some of
what risk is tolerable in those situations. It is different.
And there are 7,000 different rare diseases. Each one of these
is unique in its own regard. But there are some commonalities
like that.
Mr. Engel. Well, thank you. And thank you for your
comments, and also thank you for your interest.
And I want to thank the panel for a very interesting
discussion.
Thank you, Mr. Chairman.
Mr. Pitts. The chair thanks the gentleman.
Now recognizes the gentleman from Florida, Mr. Bilirakis, 5
minutes for questions.
Mr. Bilirakis. Thank you, Mr. Chairman. I appreciate it.
And I thank the panel for their testimony today.
I know we have been talking about this and you have had an
opportunity. I want to give you more of an opportunity to
respond on this.
On Wednesday, I asked one of the witnesses about his
statement in including patients in the clinical trial process,
but I want to make sure that you all have every opportunity to
respond to this.
If patients had a greater role in clinical trial design--
and I know you have touched upon this--if trials measured
qualitative data from patients like, ``How do you feel?'', ``Is
it less painful?'', what have you; ``How would things be
different?'' and ``What would you like to see?''
We will start with the----
Mr. Beall. I would like to start.
First of all, the patient-reported outcomes I think has
been part of every clinical trial in cystic fibrosis for the
last 10 or 15 years. Some of the tools are not the best at this
point, but we are working to refine them.
We have just spent as a Foundation a large effort to look
at the patient-reported outcomes as a kind of specific
validated tool for CF, and it is going to be submitted to the
FDA and go through a validation process. In the past, we have
used one that was generally for lung disease, but it may not be
specific.
So this is a science that is evolving. A decade ago or 15
years ago, 20 years ago, PROs were not really incorporated.
So it is a science that is evolving, and it has to be
evolved not only with the FDA, it has to be evolved with the
sponsors, too, because they have got to be willing to
incorporate those into the clinical-trial process.
So I am encouraged by the process, but I will tell you
the--just in this last trial we had where their lung function
went up and the exacerbations went down, we didn't have a
statistically significant improvement in the patient-reported
outcomes.
Because when you are starting to treat the basic defect,
you are treating the whole disease process and you are looking
at extending lives.
And the patients may not feel that from day to day, but
over years, you may have a tremendous impact on those patients.
So it is a tool that can be used, but it shouldn't be used
exclusively.
Mr. Bilirakis. Thank you very much.
Ms. Furlong, do you have a response?
Ms. Furlong. Sure.
So I agree with Dr. Beall. And patient-reported outcomes
are incredibly important, but I think this is where involving
the patients in the design and conduct of clinical trials is
really going to be important.
Because, for instance, how do we measure energy and
endurance? How do we know that turning over in bed is important
to patients as opposed to an outcome measure such as the 6-
minute walk test?
So I think things are important to patients that have a
real effect on their lives. For instance, as you can imagine,
if a boy can still text at the age of 18, that gives him
independence. If a child can walk up a single step, they can
enter buildings. If a child can roll over in bed, that makes
the families' quality of life overall, in general, much, much
better.
So I think the use of patient-reported outcomes and
including the patient voice in the discussion about what the
clinical trial looks like and what the measurements are, both
primary and secondary, is going to be incredibly important.
Mr. Bilirakis. Thank you so much.
Mr. Pops, do you have a comment or----
Mr. Pops. I think these outcomes are so critical. In the
world that we are developing drugs in, which is in psychiatry
often, in schizophrenia, depression, addiction, the end point
of the clinical trial--the hard end point is asking people
essentially how they feel.
And so how you feel is typically embodied in the set of
validated scales, but those often don't capture some of the
most important parts of how they actually feel over time.
A perfect example might be an opioid dependence or an
alcohol dependence, where a critical question the patients ask
us when they take our medicine is, ``Is my craving going to go
down? Am I going to crave this less? It may block the receptor
and keep me from drinking, but is my craving going to change?''
That was not a validated end point. That was something we
couldn't incorporate in the label, but it is essential to the
patient's perception of the disease.
Mr. Bilirakis. Good point.
Doctor?
Dr. Lichtenfeld. About 4 weeks ago at ASCO, the oncology
meeting, they showed a picture of a lady who was 96 years old
who had received a phase 1 drug--that in itself is a
fascinating point--whose cancer completely resolved.
And on the bottom end of the before and after picture--on
the after picture, you saw a trace of a little smile. And I
noticed that smile and I tweeted it, actually. I took a picture
and tweeted it and it got re-tweeted quite a bit. And then the
lecturer said, ``Yes. That really is a smile'' in front of
2,000 people.
What I am trying to say by that example is that is what we
have to be able to measure and aggregate in a scientific way to
show that the treatments make a difference.
One example of one lady in an unusual situation, but
something that I think all of us agree--I would echo the
comments that were already made--is so critical to
understanding, particularly in the oncology world, what we do
and how we do it and the goal that we have to have of improving
quality of life.
Mr. Bilirakis. Thank you.
Dr. Summar?
Dr. Summar. Yes. I will just use another example, too.
We had a new medication we were looking at. Most of the
patients with rare diseases are on the medicines they take for
life. So it is every day, day in and day out. And these care
plans are often complex and they really affect the whole
family.
So the new drug looked like it was promising from the
standpoint of maybe a little bit better efficacy, a little bit
better control, but it was five times a day instead of two or
three times a day compared to the old one.
And the families were like, ``Why would we add three more
times a day of dosing for the small effect?'' And no one had
really bothered to ask them that before we started.
So I think there is all of these things that really getting
the patient input early on is going to make a difference.
Mr. Bilirakis. Thank you so much. Appreciate it.
Mr. Chairman, can I ask one more question?
Mr. Pitts. You may proceed.
Mr. Bilirakis. OK. Thank you so much. Appreciate it.
Dr. Beall, the CF Foundation's venture philanthropy model
has produced incredible results. Congratulations. Your
foundation found your breakthrough drug when it helped
translate some of the early research through the valley of
death, and now you have the Kalydeco.
How are you able to establish this program? And how can
other groups adopt this similar model?
Mr. Beall. Well, it is a willingness to take risks. That is
what you have to do in drug discovery. And we were frustrated
by the fact that companies were not getting involved in the
orphan diseases.
So the whole concept here was to say, ``Take some of the
risk out of biotech companies or pharmaceutical companies to
get engaged in CF research.'' And, as I said, we spent $42
million initially to start a high-throughput screening that led
to Kalydeco.
I think what is the most important and gratifying thing for
the Cystic Fibrosis Foundation--and I know Ms. Furlong was in
my office a number of years ago--and what we are seeing is so
many other organizations are feeling the same impatience that
our foundation felt 14 years ago in adopting this.
One of the first times I talked about venture philanthropy
at the bio meetings, we had 10 people in the audience. And now
it is really becoming really inherent in what many voluntary
health organizations are doing.
In fact, FasterCures has been an organization that has been
central to making some of that happen. There are law firms that
specialize in it.
So we love to share our ideas. We share our ideas all the
time. And it has been very gratifying to our community that we
happen to be fortunate enough to be able to start it because we
had the resources. Bill and Melinda Gates gave us $20 million
to start our program. We had other dollars to really make that
initial investment.
Mr. Bilirakis. Can you tell us how you successfully
established the CF registry?
Mr. Beall. As I say, it goes back a long time. But Dr.
Zerhouni was here several years ago when he was the head of the
NIH, and he says one thing about the CF community, it is a
community with a culture of research.
And every patient who goes to one of our care centers is
asked, ``Do you want to participate in a patient registry?''
And I think it is 99.5 percent of the patients that say, ``Yes,
I do'' and then signs the informed consent.
So it is all part of the culture. It is part of the culture
the organization creates. It is the physicians and it is the
relationships and the recognition that it is an important part
of having a disease because we can't cure this disease without
their involvement.
Mr. Bilirakis. Very good. Thank you very much. Appreciate
it.
I yield back, Mr. Chairman.
Mr. Pitts. The chair thanks the gentleman.
Dr. Summar, I didn't get to you in my round.
On Wednesday, we heard an idea thrown out there that there
are vast amounts of data available that are not being utilized.
And we all know what an organ donor is. The idea was that we
have data donors.
Now, how would this play--and you mentioned the IRB system,
the risk enterprise. What is your reaction to that?
Dr. Summar. This is something we talk about when we are
having coffee a lot.
There are data sets all over the place. In fact, most of
them end up usually lost when someone's computer gets recycled.
We had a physician lose 15 years of data because his Excel
spreadsheet didn't update.
I think a way--find a way that balances, obviously,
people's desire for confidentiality versus the irreplaceable
and oftentimes irreproducible amounts of data that are out
there. We really do need to find that balance.
My reaction to that would be I would love to find a way
forward with that. That one is going to--you can see a lot of
sides to that question. But I definitely think it is worth
looking at.
And I think what we find is a lot of patients are like,
``Yes. I will put it out there. I am fine with that.'' There
will be a small core that won't. You can take a count for that.
But I think most folks, if you ask them, saying, ``Would you
feel OK if your data is out there so everybody can take a look
at it?'' would be fine.
You see people opening up their genomes, who had their
genomes sequenced, saying, ``I will publicly post it along with
my medical health history.'' A lot of folks want to help.
Mr. Pitts. Thank you. Thank you.
Mr. Burgess. I did that. We did that. I mean, that is a
real thing that is happening right now. And, yes, privacy is
something we all value, but it also is a voluntary
relinquishing of a portion of that for the greater good.
I think that is something we ought to not encourage--well,
not encourage, but we certainly shouldn't stand in the way if
that is an activity that----
Dr. Summar. Right.
Mr. Burgess. And unfortunately, I can't say that we don't
always respect that, that we shouldn't stand in the way. But
enough about that.
Mr. Pitts. All right. The chair thanks the gentleman.
That concludes the questions of the Members who are here.
Another exciting, informative, very important hearing. Thank
you so much for coming.
Members will have followup questions, and we will send
those to you. We ask that you please respond promptly. I remind
Members they have 10 business days to submit questions for the
record, and that means Members should submit their questions by
the close of business on Friday, July 25th.
I have a UC request, a statement for the record, from the
National Health Council. Without objection, that will be
inserted into the record.
[The information appears at the conclusion of the hearing.]
Mr. Pitts. Without objection, the subcommittee is
adjourned.
[Whereupon, at 12:19 p.m., the subcommittee was adjourned.]
[Material submitted for inclusion in the record follows:]
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