[Senate Hearing 110-293]
[From the U.S. Government Publishing Office]
S. Hrg. 110-293
FOOD AND DRUG ADMINISTRATION'S CRITICAL PATH INITIATIVE
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HEARING
before a
SUBCOMMITTEE OF THE
COMMITTEE ON APPROPRIATIONS UNITED STATES SENATE
ONE HUNDRED TENTH CONGRESS
FIRST SESSION
__________
SPECIAL HEARING
JUNE 1, 2007--SALT LAKE CITY, UTAH
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Printed for the use of the Committee on Appropriations
Available via the World Wide Web: http://www.gpoaccess.gov/congress/
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COMMITTEE ON APPROPRIATIONS
ROBERT C. BYRD, West Virginia, Chairman
DANIEL K. INOUYE, Hawaii THAD COCHRAN, Mississippi
PATRICK J. LEAHY, Vermont TED STEVENS, Alaska
TOM HARKIN, Iowa ARLEN SPECTER, Pennsylvania
BARBARA A. MIKULSKI, Maryland PETE V. DOMENICI, New Mexico
HERB KOHL, Wisconsin CHRISTOPHER S. BOND, Missouri
PATTY MURRAY, Washington MITCH McCONNELL, Kentucky
BYRON L. DORGAN, North Dakota RICHARD C. SHELBY, Alabama
DIANNE FEINSTEIN, California JUDD GREGG, New Hampshire
RICHARD J. DURBIN, Illinois ROBERT F. BENNETT, Utah
TIM JOHNSON, South Dakota LARRY CRAIG, Idaho
MARY L. LANDRIEU, Louisiana KAY BAILEY HUTCHISON, Texas
JACK REED, Rhode Island SAM BROWNBACK, Kansas
FRANK R. LAUTENBERG, New Jersey WAYNE ALLARD, Colorado
BEN NELSON, Nebraska LAMAR ALEXANDER, Tennessee
Charles Kieffer, Staff Director
Bruce Evans, Minority Staff Director
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Subcommittee on Agriculture, Rural Development, Food and Drug
Administration and Related Agencies
HERB KOHL, Wisconsin, Chairman
TOM HARKIN, Iowa ROBERT F. BENNETT, Utah
BYRON L. DORGAN, North Dakota THAD COCHRAN, Mississippi
DIANNE FEINSTEIN, California ARLEN SPECTER, Pennsylvania
RICHARD J. DURBIN, Illinois CHRISTOPHER S. BOND, Missouri
TIM JOHNSON, South Dakota MITCH McCONNELL, Kentucky
BEN NELSON, Nebraska LARRY CRAIG, Idaho
JACK REED, Rhode Island SAM BROWNBACK, Kansas
ROBERT C. BYRD, West Virginia
(ex officio)
Professional Staff
Galen Fountain
Jessica Arden Frederick
Dianne Preece
Fitzhugh Elder IV (Minority)
Stacy McBride (Minority)
Graham Harper (Minority)
Brad Fuller (Minority)
Administrative Support
Renan Snowden
C O N T E N T S
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Page
Statement of Senator Robert F. Bennett........................... 1
Statement of Dr. Andrew C. von Eschenbach, Commissioner, Food and
Drug Administration, Department of Health and Human Services... 3
Prepared Statement of........................................ 7
Statement of Dr. Raymond L. Woosley, President and CEO, Critical
Path Institute................................................. 15
Prepared Statement of........................................ 17
Statement of Dr. Jeffrey L. Anderson, Associate Chief of
Cardiology at the LDS Hospital, Co-Director of Cardiac
Research, and Professor of Internal Medicine at the University
of Utah........................................................ 19
Prepared Statement of........................................ 22
Statement of Dr. Glenn D. Prestwich, Presidential Professor and
Director, Center for Therapeutic Biomaterials, University of
Utah........................................................... 25
Prepared Statement of........................................ 28
Statement of Dr. David A. Jones, Senior Director for Early
Translational Research, Huntsman Cancer Institute.............. 31
Prepared Statement of........................................ 33
FOOD AND DRUG ADMINISTRATION'S CRITICAL PATH INITIATIVE
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FRIDAY, JUNE 1, 2007
U.S. Senate, Subcommittee on Agriculture, Rural
Development, Food and Drug Administration, and
Related Agencies, Committee on Appropriations,
Salt Lake City, Utah.
The subcommittee met at 9 a.m., at the University of Utah,
Eccles Institute of Human Genetics, Hon. Robert F. Bennett,
presiding.
Present: Senator Bennett.
statement of senator robert f. bennett
Senator Bennett. The hearing will come to order. Good
morning. We appreciate everyone being here. I want to give
special thanks to the University of Utah for allowing us to use
this auditorium, and to the Eccles Institute of Human Genetics.
This is an impressive facility, as we all realized when we
walked in it. And the staff here have been wonderful to work
with. We especially thank Kim Wirthlin and Kaye Clark as well
as Elaine Fry with the Eccles Institute. Senator Herb Kohl is
the chairman of the subcommittee, and we meet here today with
his approval. I'm grateful to him for scheduling this hearing.
I've focused on health care for quite a long time. Last
month I cosponsored the Healthy Americans Act in the Senate
with Senator Wyden of Oregon. It's our attempt to find a way to
give all Americans access to health care with some kind of
insurance coverage.
Senator Wyden and I both agree that health care discussions
should focus on health. Most of the discussions are about
payment systems and insurance companies and coverage.
Prevention is worth a pound of cure, as the old cliche says.
Like most cliches, it happens to be true.
When Americans need to go to the doctor, they should be
able to get a treatment that is safe, effective and right for
them. Often a treatment sometimes is right for one individual
but not for another. And so we have asked the Commissioner of
the Food and Drug Administration, along with some distinguished
panelists, to be here today to talk about the role that FDA can
play in keeping our treatments safe.
Now, in 2004 FDA called for a national effort to identify
specific activities aimed at modernizing the delivery of health
care, and they formally launched the agency's Critical Path
Initiative. The term ``Critical Path'' is used to describe the
way that a potential drug or biological product or device can
find its way from prototype or an idea to a viable medical
product for use in patients.
The initiative was born out of the agency's concern for the
declining number of new medical products coming to the market.
One of the strengths of the American economy has been the
constant flow of new products in this area. And when the number
starts to drop off, that is a legitimate reason for concern.
The FDA has realized that many of the tools used to develop
and review medical products today are outdated. They need to be
modernized so that new forms of scientific data, like genetic
information, can be applied to product development and
ultimately to the use of these products in patients.
There's no place where you can come and focus on genetic
information that's better than the University of Utah and the
State of Utah, which is one of the reasons why we are holding
this hearing here. I want to discuss the future of Critical
Path, and I hope we'll be able to determine which proactive
efforts FDA, the research community, and industry can engage in
to bring the Critical Path Initiative along in the way it
should go forward.
We're delighted to have the commissioner of the Food and
Drug Administration here at the University of Utah. As I say,
it's the ideal location for a discussion on these issues
because the university is currently engaged in Critical Path
research.
Now, particularly on the anticoagulant warfarin, this
research program has been extremely successful. It's described
as a good model for similar Critical Path research
opportunities. The University of Utah is a leader in the study
of human genetics. And we're going to have a panel of
university experts mixing with the commissioner.
Given the right tools the Federal Government, academia, and
industry can work together to speed the delivery of new
products to patients in need, as well as pay attention, as it
always has, to the safety and efficacy of these products, and
products that are already on the market. Then incorporate new
scientific approaches to lead to a more personalized and
targeted therapy.
We're hoping that as a result, millions of Americans now
suffering from diseases that don't respond to their present
treatment can be helped. To give you an example: targeted
research dollars can help get the right drug to the right
patient to take some of the guesswork out of medical care,
which would minimize side effects.
If you take a blanket drug, the side effects show up in
some patients and then the whole drug is challenged. But if you
can do the targeting process that we're going to talk about
today, you can maximize drug benefits, increase efficiency, and
at the same time lower costs.
Research done at the University of Utah on the
anticoagulant drug warfarin has been estimated to reduce
hospitalizations from adverse reactions and reduce health care
spending by approximately $1.1 billion annually. And this
savings is achieved through further understanding of the way in
which certain people metabolize warfarin and integrate genetic
testing into warfarin therapy.
Given this new tool, doctors can make a decision that will
get the right dose of warfarin to a patient based on that
patient's specific genetic makeup. This is an exciting new
frontier that I'm proud to say is coming out of activity here
at the University of Utah.
And it's only one example. The FDA has already started
working on 40 long-term projects to support the Critical Path
Initiative. And with appropriate resources in the right places
the agency can, through collaborative agreements, facilitate
the development and delivery of therapies for such diseases as
cancer, diabetes, and cardiovascular disease.
Those are the opportunities we're going to explore with our
panelists this morning. We'll discuss the Critical Path
Initiative and look for ways that it can lead to better medical
products, personalized medicine, and ultimately lower health
care costs.
Now, we always divide our hearings into panels. Our first
panel is one man, Dr. Andrew von Eschenbach. He's the
Commissioner of the Food and Drug Administration.
Dr. von Eschenbach, we're delighted to have you here at
Utah, and we hope you find your stay, both at the university
and in the State, successful and enjoyable.
The second panel will join with Dr. von Eschenbach, and
I'll introduce them now. Dr. Ray Woosley, who's the president
and CEO of the Critical Path Institute. Dr. Jeffrey Anderson,
associate chief of cardiology at LDS Hospital and a professor
of internal medicine here at the University of Utah.
Dr. Glenn Prestwich, he's the presidential professor and
director of the Center for Therapeutic Biomaterials at the
University of Utah. And Dr. David Jones, who's the senior
director for Early Translational Research at the Huntsman
Cancer Institute.
Dr. von Eschenbach, we will start out with you. And then
instead of having you step down, we will have the panel join
you and see if we can't make this a roundtable kind of
discussion instead of the usual congressional hearing, with
each panel just speaking back.
In this case you're speaking to the record because this
Senator probably is not going to understand most of what you
have to say. I shouldn't admit that in public, but I'm
committed to full disclosure. I will do my best to catch what
you're doing.
There is, of course, since this is an official subcommittee
meeting, a full transcript being made. And if the witnesses
wish to submit information for the record so that it can
facilitate the testimony and the panel discussion, that of
course will be acceptable.
Dr. von Eschenbach, we look forward to your testimony and
hope you will be able to stay for the discussion round with the
second panel.
STATEMENT OF DR. ANDREW C. VON ESCHENBACH,
COMMISSIONER, FOOD AND DRUG ADMINISTRATION,
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Dr. von Eschenbach. Thank you very much, Senator Bennett.
And I certainly look forward to a morning of very full and very
important discussion both with you and with the other members
of the panel and also with the audience.
I have submitted for the record written testimony that
addresses the very important role that the Critical Path
Initiative will play in the Food and Drug Administration's
commitment to protect and promote the public health and the
welfare of the American people we serve. And I'd like to take
my remarks this morning to really summarize and emphasize the
importance of this initiative, as it is a part of our
appropriations request to your committee.
And I want to begin by thanking you, Senator Bennett, for
your leadership and your willingness to convene this meeting,
this hearing, to address this specific subject. You and
Chairman Kohl have been strong and ardent supporters in support
of the Food and Drug Administration. Senator Kohl's staff is
here as well today. And it is extremely important that I
express to you and other members of the committee the gratitude
of the FDA for that support.
This particular initiative is, I think, very fitting to be
discussed at a meeting, at a hearing being held here today in
Utah. And it's not just because of the incredibly beautiful
scenery, weather, and tremendous hospitality, but most
importantly because of the setting. One might wonder why, if
this is an important meeting, is it being held here and not in
Washington, DC.
There's no better place for a meeting to talk about an
initiative to secure the future of health, health care, and our
health care delivery system than to do it here in a community,
surrounded by the people we are committed to serve. And in an
environment of academic excellence that has actually served to
provide the scientific basis upon which this new future in
health and in health care is based.
And so what I am here this morning to do is to share with
you a bit of that vision for that new future. The role that the
Food and Drug Administration can play in being a bridge to that
new future by utilizing the tools of modern science and
technology to help facilitate our ability to bring the fruits
of discovery and development to those who are desperately in
need of cures for disease, enhancement of their health, and the
hope of a better and more healthful, healthy life.
I too want to thank the University of Utah for the
hospitality in hosting this meeting. And particularly I refer
back to my past life as the Director of the National Cancer
Institute, where I had a firsthand opportunity to appreciate
the excellence of this university, particularly its cancer
center, the Huntsman Cancer Center, and the tremendous
contributions that it is making to our national effort to
alleviate the burden of a disease like cancer.
The reason why this hearing is so important and why the
initiative is deserving of the support and the investment of
the American people is because of the fact that we are
currently in the midst of perhaps the most profound
transformation to ever occur in the history of medicine.
Those of us who are physicians have inherited a profession
where, for thousands of years, our only hope of being able to
address the needs of a patient by taking care of a disease was
based primarily on what we could observe using our five senses.
We basically observed the manifestation of disease in terms of
what we could see, what we could hear with the stethoscope,
what we could perhaps feel with our hands.
And perhaps a hundred years ago we made a major step
forward in that model of observation by now having microscopes
and x-ray machines, but the fundamental principle remained the
same. We were dealing with diseases based on the observation of
the manifestation of that disease.
The recognition of disease told us very little about what
to do about it. The observation of a lump in a woman's breast
did not tell us what the appropriate therapy might be. But
because of the investment this Nation made in science and
technology throughout the latter half of the 20th century, we
began to change that paradigm.
Because of the kind of work that's going on here at the
University of Utah, specifically with the focus on beginning to
understand genetics, and the genetic basis of disease and the
genetic basis of life, we have moved from that model of
macroscopic and microscopic observation to a model of molecular
understanding of disease.
We now can recognize the genes and the molecules that are
actually at the cause of the disease process. And with that new
understanding, we have transformed our ability to now deal with
diseases. Diseases like cancer, and Alzheimer's, and many
others. We now have the opportunity, based on that
understanding of fundamental mechanisms, to envision new
solutions, new interventions, new drugs, new biologics, new
devices, that can actually intervene in those mechanisms and be
able to obtain a predictable beneficial outcome.
One specific example in my field of interest--oncology--was
the fact that for many years, decades, we could recognize a
form of leukemia called chronic myelogenous leukemia by
observing or seeing a chromosome in the cell under the
microscope. But we really could not do very much about that
until the fruits of genetics and molecular biology allowed us
to understand that what we were observing in that abnormal
Philadelphia chromosome was actually a gene relocation and
fusion that produced a cascade in a molecular pathway that was
driving the unregulated proliferation of that cell, namely
leukemia.
The knowledge of the mechanism driven by the--those
abnormal genes, or oncogenes, allowed us to immediately
recognize that if we had a drug that could intervene in that
pathway, a kinase pathway inhibitor, we would be able to shut
that cancer cell off. And in fact such a drug was developed and
was approved by the Food and Drug Administration and became, if
you will, the poster child for targeted mechanistic-based
interventions in the disease process. This is but one example
of what is now a widely growing and rapidly growing new
portfolio of opportunities. But as Senator Bennett has pointed
out already, the pathway to get the fruits and the benefits of
those observations and that development to the patients, the
people, the public, who desperately need them the most, is a
pathway that is clogged by mechanisms and processes that are
not equipped or prepared to deal with this new reality.
And so we must transform the pathway from discovery to
development to delivery. And that transformation of that
pathway is, in fact, the Critical Path Initiative. It is a
series of tools using science and technology that will allow us
to entirely revise and revamp our ability to develop and bring
to patients the fruits and benefits of these new interventions.
This will have enormous implications and benefit, not only
for improving the health and welfare of the people we serve, by
similar examples of the one I mentioned with the revolutionary
treatment of chronic myelogenous leukemia, but also other
diseases, like Alzheimer's and diabetes and a variety of
others.
Even more importantly, it will lead to a transformation in
our health care and our health care delivery system with not
only the benefits of millions of lives saved and improved but
also the reduction of costs. You will hear later about one
specific example of that opportunity.
By understanding fundamental molecular mechanisms, not only
in the disease but in the patient or the person with that
disease, and not only understanding the disease process but the
interventions and the treatments that we're using, we can now
begin to create a system of health care that is predictive,
preemptive, and much more personalized.
The drug warfarin that you'll hear about today is one
that's widely administered. But just like many of the other
drugs that I learned to use, we base that prescription on
simply an observation of a large population. The most common
prescription a physician prescribes is ``Take two aspirin and
call me in the morning.''
And the reason it's two aspirin is because we have no idea
how much aspirin any one individual should take. But two is
generally a pretty good average. And why call me in the
morning? Because I have no idea as to whether it will actually
work for you. In general, it works, but I need you to call me
in the morning.
We are embarking upon an era in which, before I ever give
you that drug, I will know whether it will work. And not only
will I know, I will know exactly how much you should take.
The problem with drugs is that when we prescribe them based
on broad populations and not based on an individual person,
some patients in that population will not be getting enough
drug, and therefore will continue to have problems. There will
be other patients who, perhaps for them, are getting too much
drug.
My mother-in-law always told me she was more sensitive to
drugs than everyone else. She was right. And now we have the
opportunity to personalize those interventions. You'll hear
about that with regard to how that actually has occurred with
one of the most common blood thinners that we prescribe.
The important corollary to that that I want to stress is
the importance of the ability for us to now not only improve
quality by getting the right patient the right amount of drug
at the right time for the right reason, but also what we'll do
in the way of elimination of waste.
By virtue of the fact that we will eliminate the waste of
giving someone a drug that was inadequate, or giving them a
drug that didn't work or was too toxic, we will have reduced
the amount of costs that are involved in our health care system
due to inappropriate therapy. And that will enable us to deploy
those savings into much more critically important areas of
health care that are currently now not able to be fully
addressed.
prepared statement
And so Senator Bennett, with that as a broad overview of
the importance of why we're here today, I along with you am
going to look forward to the specific discussions and examples,
and the ability to answer many of your questions about specific
parts and pieces of the initiative.
But suffice it to say we gather today in Utah within the
community that we're here to serve to offer an opportunity for
a new future in health care that will not only save lives but
will also save costs and eliminate waste, and bring us to a
period of time where we'll give the right patient the right
treatment at the right time for the right reason and get the
predictable right outcome.
[The statement follows:]
Prepared Statement of Andrew C. von Eschenbach, M.D.
Good morning. It is a pleasure to join you at this field hearing to
discuss one of the FDA's highest priority projects, the Critical Path
Initiative. This project has the potential to transform the way medical
products in the United States are designed, developed, tested, and
used. I want to thank the subcommittee on Agriculture, Rural
Development, Food and Drug Administration, and Related Agencies for
inviting me to Utah to discuss the benefits the Critical Path
Initiative promises to generate for the health of the American public.
I also want to thank you, Senator Bennett, for being the first to
provide funding for this important initiative while you served as
chairman of the subcommittee during the 109th Congress. Your support of
the FDA's public health mission in general--and the Critical Path in
particular--reflects your vision for and commitment to better health
care for all Americans.
Let me also thank the University of Utah, our hosts today and early
collaborators on important work already taking place under the auspices
of the Critical Path. University researchers have joined with the
Cardiovascular Research laboratory of Intermountain Healthcare in a
collaboration with FDA to improve the safe use of a widely prescribed
drug. I'll have more to say about that project momentarily.
Holding this event at the University of Utah, under the auspices of
the subcommittee and with the cooperation of Senator Bennett, is
important symbolically. In today's world of health care and medicine,
we are on the brink of unprecedented advances in our ability to
predict, diagnose, and treat diseases across the board. But we also
face unprecedented challenges in moving those products from the
laboratory to the bedside--and in providing access to those treatments.
That's why it's so important to capitalize on the synergies that
are created when public health agencies such as the FDA work closely
with stakeholders in academic research community, industry, consumer
groups and elsewhere to solve problems that affect us all.
The Transformation of Medicine
Close cooperation has become particularly important because what we
are witnessing in health care today is the most profound change in the
history of medicine. Approximately 100 years ago, our ability to
understand disease moved from the macro level, where we were limited to
what was visible to the naked eye, to the micro level--when we gained a
microscopic view of disease at the cellular plane. But in the last
decade or two, we have been able to approach disease at the molecular
level, where we now can observe and understand disease as a process.
This is what I have called the ``molecular metamorphosis in
medicine,'' because it represents a phase change similar to the
transformation of a caterpillar to a butterfly. As a result of this
metamorphosis, the future of health care will be no more like its past
than a butterfly is like a caterpillar.
The payoff is that, as our knowledge of genetic molecular
mechanisms evolves, and our understanding improves, we will be uniquely
positioned to develop interventions against disease processes at the
molecular level. The potential result is that medicine of the future
could be personalized, predictive, preemptive, and participatory.
But there's a problem. Despite an unprecedented increase in funding
for biomedical research, both in the private sector and through Federal
funding through the National Institutes of Health, this increased
research has not translated into many new medical products being
available in the medical marketplace. For example, close to nine in 10
pharmaceutical products in phase I testing are never approved for
marketing, and half of all phase III clinical trials end in failure.
There must be a way to help expedite and simplify this process.
The Critical Path Initiative
That is why in 2004 FDA advanced the notion of focusing on the
critical path which medical products must travel, from the earliest
stages of development to their use in patients. The Critical Path
Initiative is FDA's effort to stimulate and facilitate a national
effort to modernize the sciences through which FDA-regulated products
are developed, evaluated, and manufactured. The Critical Path provides
an essential a tool kit of prospects and initiatives that will enable
FDA to make regulatory decisions that will define personalized medicine
in this new age of molecular medicine.
To jump start this process, FDA has been working with the academic
community, the public, the pharmaceutical industry, and other Federal
health agencies to identify the projects most likely to modernize and
transform the development and use of medicines. After intensive
consultation with many stakeholders, last year we published our
``Critical Path Opportunities Report,'' which details 76 specific
scientific projects with great promise for smoothing the path from lab
to bedside. Last December, we followed up by announcing more than 40
very promising scientific projects that we have helped get underway.
The Critical Path Initiative presents many major opportunities for
improving the process. It includes ways of qualifying biomarkers (which
are measurements that can predict or monitor responses to therapy) for
in-vitro diagnostics, imaging, and preclinical toxicogenomics. It
represents an opportunity to modernize clinical trials to make them
more effective and efficient, and we are issuing guidances on advanced
clinical trials. It will allow us to harness the potential of modern
information technology tools, and it should help us modernize
manufacturing by building in quality up front through such systems as
quality by design and process analytical technology.
Let me provide a specific example of a Critical Path project that
is already underway. It involves work related to cancer, in which FDA
is working with a host of other organizations to identify relevant
biomarkers and--what is crucial--qualify them for use in the
development of medical products.
To achieve these goals FDA and many colleagues established a
public-private biomedical partnership supported by the Foundation for
the National Institutes of Health. Launched last October, the
Biomarkers Consortium strives to accelerate the delivery of successful
new technologies, medicines, and therapies to prevent, detect early on,
diagnose, and treat a wide variety of diseases, including cancer.
Specifically, it seeks to identify biomarkers and develop tests to
determine whether a drug is appropriate for an individual patient. It
is also working to find markers that will show whether the drug is
having the right effect in the patient.
The example of Iressa and Tarceva, two drugs used to treat lung
cancer, demonstrates the potential benefits of having appropriate and
validated biomarkers. Each of these drugs has had strikingly positive
benefits for some of the patients who have taken them, reducing tumors
by up to 50 percent and extending life expectancy. Unfortunately, only
10 percent of patients treated with the drugs actually experience these
benefits. Researchers have found that the patients who respond to these
drugs have a common genetic mutation in their tumors. This mutation can
serve as a ``marker'' to identify the patients who are best treated
with these medications. Over time, similar discoveries related to other
tumors and drugs are expected to yield a major public health impact--
and that is the point of the Critical Path.
A Critical Path Project in Utah
I would be remiss if I did not point out that one of the most
promising Critical Path projects is underway right here in Utah. The
University of Utah, the Critical Path Institute based in Arizona, and
the FDA have established the Cardiovascular Drug Safety and Biomarker
Research Program. Its goal is to establish an evidence-based framework
for determining the clinical usefulness of cardiovascular biomarkers.
For example, in the first of what we hope will be many such projects,
researchers in the program are working on ways to establish better
dosing of the widely used anti-coagulation drug warfarin. They are
attempting to identify the genetic variants in people that determine
how they respond to the drug.
This is a medical matter of no small importance to individual
patients, because the medical consequences of improper dosing can be
severe. Too much warfarin can lead to life-threatening bleeding, and
too little can result in equally dangerous blood clots. The overall
impact on the U.S. health care system is also profound. Warfarin is the
second most common drug, after insulin, implicated in visits to
emergency rooms--causing 43,000 ER visits annually.
The goal of this collaboration is to improve our ability to get the
warfarin dose right for each patient when they begin treatment with
warfarin. Last June FDA and the Critical Path Institute convened a
warfarin summit that brought together many experts in this field,
including researchers from the University of Utah. We are looking for
ways to find the genetic differences that make patients more likely to
metabolize warfarin differently.
As in so many of these Critical Path projects, the goal is to get
the right medicine to the right patient, in the right dose, and at the
right time.
Conclusion
Let me conclude simply by emphasizing that the sort of
collaboration that is occurring every day here at the Cardiovascular
Drug Safety and Biomarker Research Program, under the auspices of the
Critical Path Initiative, represents the best way, the only way, to
take full advantage transformation of modern medicine. It will make
innovative medical products available sooner, it will increase our
ability to monitor their safe use once they have reached the medical
market, it will provide for personalized diagnosis and treatment, and
it will introduce great efficiencies while reducing risk.
I should also emphasize that this transformation must take place in
the context of a health care system. That's why it is so essential to
have a thoughtful national discussion about our health care delivery
system, and why it is so helpful to have the constructive engagement of
leaders like Senator Bennett.
Finally, I want to commend the University of Utah for adopting this
collaborative model. The opportunities--and the challenges--presented
by the new age of molecular medicine are so promising and so complex
that no one agent can possibly manage them alone. As the body that
reviews information about and applications for medical products across
the board, FDA is uniquely situated to see the bigger picture. But we
are far from having all the answers about how to integrate and
capitalize on all the new understandings of medicine at the molecular
level.
We share the goal of finding the best way to get promising new
interventions to patients. That's where institutions like the
University of Utah and Senators like Senator Bennett come in. We need
the help, support, and expertise of you and many other partners like
you if we are to take full advantage of the opportunities the Critical
Path Initiative offers.
Thank you for your time and attention today, and for kindly
inviting me to be with you.
Senator Bennett. Thank you very much. Listening to you talk
about ``Take two aspirin and call me in the morning,'' that's
trial and error. During the hearing we held on your budget for
fiscal 2007 we had an exchange, and you mentioned that the
current system of delivering treatment to patients is based on
the statistical probability of success.
Obviously it will reduce the cost. But can you talk about
the cost of discovering the statistical likelihood? You spend
$500,000 to determine that this particular patient----
Dr. von Eschenbach. Yes, sir.
Senator Bennett [continuing]. Would do better if you had a
smaller dose, and then you save 45 cents by giving them a
smaller dose. Now, obviously that's absurd. But I'm taking it
to that extreme----
Dr. von Eschenbach. Sure.
Senator Bennett [continuing]. To illustrate the question
that I think we need to have addressed.
Dr. von Eschenbach. I think there are two very important
aspects of the question that you are addressing. One of which
is, first of all, the cost saving not only relates to not
giving someone an inappropriate drug. Let me address that
first.
We now have, as the most common cancer in the United States
and cause of death, lung cancer. More recently a drug was
developed to treat lung cancer that virtually was able to have
patients who are on their deathbed be able to recover. At least
for a period of time. And yet that drug only helped 10 percent
of those patients with lung cancer.
It was approved by the FDA because 10 percent is better
than zero. And basically there was nothing available for them.
Senator Bennett. I'm assuming there was no toxic effect on
the other 90 percent?
Dr. von Eschenbach. There was really very little in that
regard.
Senator Bennett. Okay.
Dr. von Eschenbach. But what was occurring was the fact
that we would be prescribing that drug at approximate cost of
$2,500 per month for everyone who fit into that category. So
approximately a 100,000 patients would get that drug, when only
10 percent of them were going to actually benefit from it. And
we'd be wasting that drug on the other 90,000.
Mark McClellan, who at that time was head of CMS, and I did
a back-of-the-envelope exercise that said what we know that
about 10 percent of patients who benefit from that drug have a
unique genetic mutation in their cancer. And if we only gave
the drug to the patients that had genetic mutation, they would
be getting the right drug for the right reason.
So if we spent $500 and did a genetic screen on all
100,000, that would cost us money to do that diagnostic test.
But then we would only be giving the drug to the 10 percent
that actually would benefit from it and we would not waste it
in the other 90 percent.
That would result in enormous cost savings, because 90,000
patients would be spared taking a drug that cost about $2,500
per month. That's where we would save money, by not wasting
that medication.
Senator Bennett. I see.
Dr. von Eschenbach. But let me add one other point to that
from my perspective. And I don't mean to belabor it. But what
was really important in that example I just gave you is we
would have not have subjected those other 90 percent of
patients to use up the last 6 months of their life getting a
useless therapy with a hope that it just might make some
difference.
We would be able to allow them to make another kind of
choice. Maybe a different kind of drug or a different way to
use their time. And that also has to be factored into the
equation.
Senator Bennett. Certainly you are right that the patient
psychological benefit is a very important part. But I can
figure out that 90,000 times 500 is a lot less than 90,000
times 2,500 a month. Ninety thousand times 500 once?
Dr. von Eschenbach. Once, correct.
Senator Bennett. Yes, okay. Are there other examples of
that same pattern? Where a test could be given to the entire
universe that could produce that kind of dramatic cost savings?
Dr. von Eschenbach. They are continuously evolving. For
example in breast cancer. Women who have a particular mutation
in a gene HER2/neu would then be appropriate candidates for a
drug called Herceptin.
You could then know that that drug would be appropriate
because it was addressing that particular genetic pathway that
was operative in that disease. There are a variety of those
kinds of strategies. Looking at estrogen receptors in tumors
and deciding which women should or shouldn't get a particular
form of hormone therapy is another way of being able to tailor
and make the treatment appropriate for a particular patient.
And what we'll hear today as part of the discussion of
critical path is one initiative that Dr. Woosley is
particularly involved in, in the development of biomarkers.
These markers that will enable us to have the ability to know,
in a particular patient, what the right intervention is for
them.
Senator Bennett. Can we go outside the universe of those
who are critically ill, like the cancer patients, and say that
by virtue of what you are doing in the Critical Path you can
have screening activities, genetic screening activities for a
wider population?
Dr. von Eschenbach. Yes.
Senator Bennett. Those who appear fully healthy?
Dr. von Eschenbach. Correct. And when I indicated that one
of the promises of this molecular metamorphosis, this movement
to this new area, is that medicine would be personalized, which
we've been discussing, predictive, which we've also alluded to,
and also preemptive.
Preemptive in that we will move to a much more preventative
strategy, rather than dealing with an established disease that
we recognize when it's fully manifested, to being able to
detect susceptibility to certain diseases by virtue of genetic
tests or molecular tests and then be able to intervene much
earlier, even before someone has the overt manifestation of the
disease, is an opportunity to secure health before a disease
ever really occurs.
And that's where biomarkers of prediction and
interventions--intervention strategies of prevention will
become extremely important.
Senator Bennett. This is probably outside the scope of the
original hearing, but as you have this conversation you get
into the issue of confidentiality of medical records. Because I
can understand a lot of people would be very reluctant to have
advance notice, if you will, that they have a predisposition to
a particular disease, and have that in a form that might be
available to a potential employer.
Say, I won't get the job, even though I'm qualified for it.
And in fact, statistically the chances that I will get the
disease are sufficiently low that I'm a good risk. But somebody
does research on me, I fall into a category that says I have a
predisposition to this, that, or the other, and the employer
says, I don't want to take the risk.
And as I say, it's outside the scope of the hearing, but
it's where we go. Could you talk for just a little bit about
confidentiality of medical records?
Dr. von Eschenbach. Yes, sir. I think this is obviously
going to be an extremely important challenge that we're going
to have to address on a societal level. And I think it's one of
the areas where, quite honestly, we're very indebted to the
kind of leadership that you are providing by looking at this
from, if you will, a health care system approach. And how we
appropriately deal with confidentiality.
We have, truth of the matter, been doing genetic testing
for decades, if not centuries. We've just called it ``family
history.'' Now we're able to take that down to a much deeper
level by actually looking at the genes themselves, rather than
just inherited susceptibilities or probabilities.
And how we protect that information and that remains the
domain of the individual and not something that then would
become publicly available is an important part of how we're
going to have to address the health care system.
Senator Bennett. Let's talk about clinical trials as they
go forward. Now, the classic clinical trial, we have a group of
blind tests. And they get the placebo and then the others get
whatever. Is that process obsolete? Does it need to be changed?
Is Critical Path going to have an impact on that?
Dr. von Eschenbach. Yes, sir. One of the important
initiatives you alluded to within the 40 that we currently have
operative and the 76 that were listed in the opportunities
report is our ability to revise and modernize clinical trials
and the clinical trial infrastructure.
The traditional clinical trials will still retain an
important place in the portfolio, but the portfolio needs to be
broadened considerably. There are new kinds of trial designs
based on new biostatistical approaches, like Bayesian
statistics.
There are what are we call adaptive trial designs in which,
instead of testing one drug against another drug or placebo and
waiting a long period of time to find out that effect, and then
doing another drug and finding that effect, we're able to
integrate multiple drugs into a trial using a statistical
method that can enable us to learn about each of them
simultaneously, and remove some that are not working as well as
others. And introduce new ones at the same time.
So it's a rolling trial process that's getting us answers
in a realtime, ongoing basis, rather than at an end point
that's measured in 5 years or 10 years or 15 years. So we have
to change the process to modernize it and use modern tools. And
we're also looking at opportunities to change the front end of
the process by using, for example, biomarkers, to select
patients to go into trials that are particularly relevant for
that mechanism.
So it's called an ``enrichment'' of the trials. You are
only testing the drug in the people that are appropriate for
that particular drug, rather than in the whole population. So
for example if we had a drug for an EGFR receptor mutation that
was similar to the one I was talking about, before we wanted to
test it we wouldn't test the 100,000 patients with lung cancer.
We'd only test the 10,000 that had the EGFR receptor mutation
to see if it worked in them. And that's an enrichment trial
design.
Senator Bennett. So the clinical trial gets results faster?
Dr. von Eschenbach. And more precisely.
Senator Bennett. More precisely. And not to fixate on it,
but as an appropriator, at a lower cost?
Dr. von Eschenbach. Yes, sir.
Senator Bennett. Okay.
Dr. von Eschenbach. And bring those drugs through the
process so that FDA would have adequate data upon which to make
a regulatory decision. And that would get the drug to patients
whose lives are depending upon it much sooner.
Senator Bennett. Okay, one last question. This all sounds
great. I have learned in life that you can have a solution at
the FDA headquarters in Washington. You can have a solution
passed by the Congress. And then you go out into the world 6
months, a year, or whatever later and nothing has happened.
The water hasn't gotten to the edge of the ditch, to put it
in terms that we understand in Utah. How far down the edge of
the ditch are we getting with this? Are we seeing this kind of
thing beginning to happen and attitudes beginning to change? Or
are you running into the force of inertia among medical
practitioners?
I've long since learned that inertia is not just a physical
force. Inertia is a very strong political force. And it's
usually inertia of motion rather than inertia at rest. A
bureaucracy in motion can stay in motion and in the same
direction.
You are discovering that now, as you take over a major
bureaucracy, that it is true of a bureaucracy in a university,
or a business, or a church, or whatever. A lot of people are in
the inertia of existing clinical trials, and they're
comfortable with it.
We're having this conversation about what's being done at
the research level. What do you see out at the end of the
ditch, is the inertia beginning to change among people who have
to deal with this with direct patients?
Dr. von Eschenbach. The inertia is changing very
significantly. What I have observed is the fact that, although
change is difficult, this change is so profound it's a
metamorphosis, in that the future of health care will look no
more like the past than a butterfly looks like a caterpillar,
it's that profound.
People have come to appreciate that we are in the midst of
that change process and it's occurring. And the question still
remains what it will be. What it will lead to. But there's no
more question about whether it's happening. It's happening.
And I think that points out the reason why it's so
important that this hearing is being held here, not in
Washington, DC. Because it's happening here. It's happening in
this university. It's happening in this cancer center.
It's happening by virtue of the fact that people who will
follow me will speak to the collaboration, the cooperation, the
integration that's occurring in which people are no longer
working in silos, but recognize the importance of
interdependence and are creating partnerships, creating
alliances. Creating entities, like the C-Path Institute, that
are pulling various parts and pieces of this together: The
private sector, the public sector, the academic sector.
And that's driving us much more efficiently and effectively
through this change process. I don't think it's a question of
inertia. I think it's a question of direction or lack of
direction as to where and what the future is going to hold.
And I think that's where leadership is going to be
required. And that's an appropriate role for an agency like the
Food and Drug Administration or the National Institutes of
Health not to do it, but to be a part of it and to help guide
and direct it.
Senator Bennett. A trigger--that was going to be my last
question, but you triggered one. Are you working with the NIH
closely on this?
Dr. von Eschenbach. Yes, sir. One of the important parts of
the Critical Path Initiative is exactly the opportunity to work
collaboratively and cooperatively with other agencies. We have
a biomarker qualification of project within Critical Path
that's looking at these biomarkers that will predict disease.
That's being done in collaboration with both the National
Institutes of Health and as well with the pharmaceutical and
biotechnology industry. And companies are participating in
that, sharing data, sharing information about what they're
learning and understanding, so that we collectively can
accelerate this progress.
Senator Bennett. Okay, thank you.
We will now take a break while we set up for the second
panel. And I have an interview. I'll be right back.
The subcommittee will reconvene. My thanks to the panel for
allowing us to have that break. We have roughly an hour left.
So I would ask the witnesses to summarize as best they can, so
that we can have the kind of exchange that we're looking for.
Again, for the record, the panelists are Dr. Ray Woosley,
president and CEO of the Critical Path Institute, an
independent nonprofit organization that has a goal of serving
as a facilitator among scientists from the government,
academia, and the private sector to develop the collaborative
research projects that we've been talking about with Dr. von
Eschenbach.
Dr. Jeffrey Anderson--raise your hand, Dr. Woosley, so
everybody knows who's who. We've got the name cards there, but
just to be sure.
And Dr. Jeffrey Anderson. He's the associate chief of
cardiology at the LDS Hospital, where he's the co-director of
cardiac research and a professor of internal medicine here at
the University of Utah. And he regularly teaches medical and
premed students, cardiology fellows, and physicians. And
because he has nothing else to do, he maintains his own private
cardiology clinical practice.
And Dr. Glenn Prestwich, presidential professor and
director of the Center for Therapeutic Biomaterials at the
University of Utah. He is a member of the Experimental
Diagnostics and Therapeutics Program at the Huntsman Cancer
Institute. The technology developed from his research has lead
to the startup of multiple drug and device companies.
And then Dr. David Jones. He's the senior director for
early translational research at the Huntsman Cancer Institute.
His research focuses on the identification of new targets for
drug discovery in colon cancer. Prior to joining the Huntsman
Institute, he was the leader of the drug discovery program for
a private company.
You are all involved in Critical Path research. And your
research focuses on finding ways to improve the development of
medical products. We will turn to you now, each one in the
order in which I have introduced you. And you can make your
opening statements, and then we'll move to a kind of open
discussion.
So we start then, Dr. Woosley, with you.
STATEMENT OF DR. RAYMOND L. WOOSLEY, PRESIDENT AND CEO,
CRITICAL PATH INSTITUTE
Dr. Woosley. Thank you, Senator Bennett. Thanks for the
invitation to be here and part of this exciting hearing today
on a very important topic. In 2005, shortly after the Critical
Path Initiative was launched with encouragement and support
from FDA leadership, we created this Critical Path Institute,
or ``C-Path'' we call it. And its sole focus is to work with
the FDA to facilitate their work on the Critical Path
Initiative.
A lot of people don't realize, I don't think, that this
response that the FDA has created is really in response to a
crisis. A crisis that exists in medical product development
today. And it was--you mentioned it earlier in your remarks.
I've been looking at the numbers on this. And over the last 10
years, our Nation has spent almost a half trillion dollars on
science and research and technology.
A half trillion dollars, yet the number of innovative new
products submitted to the FDA have fallen by one-half over the
10-year period. The failure rate during drug development has
doubled in that period of time. And every year 3 to 4 percent
of new drugs are removed from the market due to safety
concerns.
Consider how would the public respond if 3 to 4 percent of
airplanes would fall out of the sky within the first year. All
of this new science and all this new knowledge and we're less
efficient today, not more efficient. We're working harder but
we're not working smarter.
The FDA and the industry have come together and they
realize that the problem can be explained by a lack of
attention to methods development, methods improvement. We've
invested billions in basic science, and that's good, but not in
applied science.
Applied science is the research on how to better show that
a product will be safe and reliable when it's in general use,
in any part of the country, in a wide variety of people. We've
not developed these new methods to test drugs.
The Critical Path Initiative is all about new methods. It's
all about standards for testing and sharing. And sharing sounds
simple. However, the pharmaceutical industry is fiercely
competitive, and sharing has not been part of its culture.
Also, the FDA can't share. The information it receives is
proprietary. Therefore, everybody has been working in the dark.
However, the Critical Path Initiative is now creating change.
And for the first time ever, industry scientists are sharing
their methods.
A year ago C-Path formed a consortium of 160 scientists
from industry, from the 16 largest pharmaceutical companies on
the globe, to address drug safety. That was 1 year ago. These
scientists from these competing companies have been sharing
their methods to predict which drugs can cause cancer, which
drugs could injure the liver, the kidney, or blood vessels.
They work hand in hand with FDA scientists who serve as
advisors, not regulators. On May 7, this group made its first
consensus report to the FDA. Recommending new, far more
sensitive and specific tests for drug safety. The FDA will now
make this information the basis for new guidances for all of
the industry to follow.
Clearly, highly-competitive companies can and will work
together when the FDA is present. And that's an important
caveat. They have to be there for the companies' sharing to be
of any value.
Another important element in the Critical Path Initiative
was mentioned earlier: Biomarker validation. Well, what does
that mean though? Well, ``biomarker'' is simply jargon. It's a
way to measure something that has biological significance and
importance.
Blood pressure even is a biomarker, because when it's too
high people have strokes. Because the NIH has invested billions
of dollars in basic research, we now know how to measure many,
many things in biology, and almost all of these things are
potential biomarkers.
For example, Dr. von Eschenbach mentioned earlier the HER2/
neu. That's a biomarker that can predict which patients with
breast cancer will have the best response to the drug
Herceptin. Tests like this will make personalized medicine a
reality. Without these tests to define our individual
differences, doctors will have to continue to practice the one-
size-fits-all medicine that we've heard talked about.
Unfortunately though, only a few biomarkers have been
validated. That is, they've been proven to the FDA's standards
to be clinically reliable predictors. That proof is essential,
because sometimes these biomarkers haven't been as reliable as
we'd want, and patients have been harmed in the past.
So that FDA proof of validation for a biomarker must be
done. Yet we don't know how to do that. That's part of the
Critical Path Initiative. How do you validate a biomarker? The
FDA has formed--and C-Path have formed an exciting partnership
with scientists at the University of Utah, and Intermountain
Health Care, and companies in Salt Lake City to develop ways to
validate biomarkers more quickly and more efficiently.
That's the goal with the Utah Warfarin Project that Dr.
Anderson will tell us about. That project will define the path
for development of many of the personalized medicine tests by
showing us how to validate these biomarkers.
We believe that this and other Critical Path projects are
very wise investments. For example, for less than $700,000 the
Warfarin Project, as you stated earlier, will save an estimated
$1.1 billion in health care costs, and many lives.
Senator Bennett, we thank you for your leadership and your
support of the FDA. There's not a lot of that around these
days, as you know. But it's very important today that this
groundbreaking work that's being done here in Utah and the
other work of the Critical Path Initiative take place. But
there's a lot more work to be done.
As you heard, there's 76 projects on this Critical Path
Initiative, and we need for those to take place. The rate-
limiting step on every one of those projects is the number of
FDA scientists available to work with the community, work with
people like Dr. Anderson, and work with the people from the
pharmaceutical industry, not on their products, but on the
process.
PREPARED STATEMENT
Because that's neutral ground, where we all can focus. The
work cannot and will not be done without the FDA's active
participation. So I hope we can find the resources to enable
the FDA to really be able to be a more effective public
servant, the way that Dr. von Eschenbach wants and has as his
vision for that agency.
[The statement follows:]
Prepared Statement of Raymond L. Woosley, M.D., Ph.D.
Mr. Chairman and members of the subcommittee, I am Raymond L.
Woosley, MD, PhD., President of the Critical Path Institute, a non-
profit organization based in Tucson, Arizona and Rockville, Maryland. I
thank you for the opportunity to provide testimony today on the FDA's
Critical Path Initiative and Personalized Medicine.
The U.S. Food and Drug Administration (FDA), created in 1906, was
the first consumer protection agency authorized by Congress. Over the
last century, the FDA has protected the U.S. public admirably and set
the international standard adopted by most developed nations. In
response to tragic drug toxicities, Congress has expanded FDA's
authority to require that manufacturers, before marketing a new medical
product, must demonstrate its safety and efficacy. Yet, to effectively
regulate, FDA scientists must have the necessary expertise and access
to the broad scope of scientific information needed to appreciate the
strengths and limitations of new advances in biology, medicine,
biomedical engineering, genomics, etc. Also, the FDA must have a
regulatory framework that can evolve to address the changing
complexities of scientific advances. It must be ready and able to
accommodate the demands of entirely new scientific fields such as
nanotechnology, one of many that will be the basis for new medical
products in the future. The current system in which drugs, devices and
biologics are reviewed in totally separate and insular centers within
the FDA is outmoded. We agree with Commissioner von Eschenbach's vision
for the FDA of the future, i.e. one that will better serve the public
health by facilitating the development of safer medicines that can be
given to the right patient, at the right time and in the right dose.
The Critical Path Initiative
As science has advanced in recent decades, FDA reviewers have asked
drug developers to perform more and more testing. However, at the same
time, FDA also required older, sometimes outmoded, testing methods. In
response, the pharmaceutical industry, unsure what the FDA would
require for new drug approval, performed increasingly comprehensive
research before submitting applications to the FDA. Development times
(time from initiation of testing until submission for approval) have
gone from 7 to 15 years and now cost more than $1 billion for a single
drug. Despite a 250 percent increase in pharmaceutical research and
development investment over the last decade, there has been a 50
percent decline in the number of innovative new medicines submitted to
the FDA for review. Last year the number of new drugs approved was the
lowest in over a decade. The Nation's investment of over $100 billion
last year in biomedical research and development resulted in less than
twenty innovative new medications approved by the FDA. Reports from the
Congressional Budget Office and the Government Accountability Office
agree with the FDA's conclusion that the productivity of the
pharmaceutical industry is declining. The ability of this Nation's
health industry to create new medical treatments has reached a crisis
point.
The Critical Path Initiative began, in concept, in 2003, when the
new Commissioner of the FDA at that time, Dr. Mark McClellan, and his
Deputy Director, Dr. Janet Woodcock, conducted an analysis of drug
development failures and new drug submissions to the FDA. Their
conclusions and recommendations appeared in a 2004 report, ``Innovation
or Stagnation: Challenge and Opportunity on the Critical Path to New
Medical Products.'' This FDA paper called attention to the rising
failure rate of drugs during development which led to a decline in the
number of innovative new medical products submitted for FDA review. The
FDA concluded that a major cause was the absence of an industry-wide
process to reach consensus on which new methods more efficiently and
accurately test new products. An important recommendation was a call
for the FDA to work collaboratively with scientists in academia and the
industry to address the problem. FDA's 2004 report and the subsequent
list of 76 projects needed to address the problem have become known
internationally as the ``Critical Path Initiative.''
The FDA, while essential to protecting the public health, has had a
negative effect on innovation by adding increasing time and cost to new
product development. However, in the FDA's Critical Path Initiative,
the FDA has indicated its willingness to help resolve the problem and,
as a partner, enable industry to improve the process of medical product
development. There has been no effective forum among scientists from
the FDA and the regulated industry to discuss and reach agreement on
which testing methods have become obsolete and how they should be
replaced.
Yet, FDA is not equipped to accomplish this goal. It has no
significant mandate to conduct research nor does it have the necessary
funding, staff or resources to do so. Also, the FDA has lacked a
platform for effective, early and sustained interaction with academic
scientists to better inform regulatory decision making. In January of
2005, The Critical Path Institute or C-Path, was created and operates
under a Memorandum of Understanding with the FDA which has liaison
representatives on the C-Path Board of Directors (non-voting). C-Path
has received Arizona commitments of more than $10 million over 5 years
and has seeded five major projects that now have Federal and State
funding. One of these awards was made possible by appropriations
recommended by this Senate subcommittee (discussed below).
The Critical Path Initiative has transformed the relationship
between the FDA and the industry it regulates. Instead of an
adversarial relationship, it is now one that better serves the public
by enabling FDA and industry scientists to utilize the most modern
science in evaluating new products. For example, in the Predictive
Safety Testing Consortium created by the FDA and C-Path, 160 scientists
from the world's 16 largest pharmaceutical companies for the first time
ever are sharing and testing each others drug safety methods. Together,
these companies spend an estimated $25 million for in kind research
and, under a consortium agreement established by C-Path, openly compare
and report findings. FDA is represented at each meeting and is now
setting standards for all companies in the world to follow. The
companies also share their prior development failures so that others
will not make the same mistakes and possibly market unsafe drugs. In
this new relationship, scientists from the FDA and its European
counterpart, the European Agency for the Evaluation of Medicinal
Products (EMEA), participate as advisors and colleagues, not as
regulators. This successful FDA-industry collaboration model has been
extended to C-Path programs in personalized medicine to develop
industry-wide standards for the development of medical diagnostics and
treatment of stroke and cancer.
Since the announcement of the Critical Path Initiative, attitudes
within the industry and the FDA began changing. For the first time
ever, highly competitive companies are sharing their methods and their
failures. The FDA and EMEA scientists are meeting with industry
scientists to learn and better appreciate the value of the innovative
methods the industry has developed. Drug companies and diagnostic
companies have agreed to share their methods to measure biomarkers to
predict response to cancer drugs. Diagnostic companies are agreeing to
validate their diagnostic tests as a step toward setting new standards
that will be of value to all companies and patients.
The new collaborative relationships available to FDA scientists
have already achieved improvements in the drug development process that
will save lives, money and time. On May 7, 60 industry scientists
representing the Predictive Safety Testing Consortium, presented their
consensus data to the FDA that showed newly developed tests are more
sensitive and specific as predictors of drug safety. After the
presentation, Dr. Janet Woodcock agreed with their findings and
announced that the FDA will now begin to accept the new tests to
protect against kidney or liver injury and carcinogenicity. Drugs
entering clinical trials and the market will now have much more
stringent testing before exposure to humans.
Personalized Medicine: What will it take?
The biomedical community, through increased funding for the NIH,
has advanced our understanding of biology, inter-individual differences
between people and the pathologic basis for diseases. We are now
beginning to recognize the individual biological variations responsible
for differences in health and responses to treatment. We are also
recognizing that what we have previously considered to be single
diseases are likely to be more than one and have major differences
between individuals. For example, although many lung cancers may look
the same under the microscope, they are actually quite different in
their biology and therefore different in their response to therapies.
Advances in biomedical science have spawned a new generation of
promising targeted molecular therapies and molecular diagnostic tests.
Molecular diagnostics have the potential to guide the choice of
targeted therapy so that the right patient receives the most effective
therapy and at the best dose. However, the potential of this exciting
new generation of science is not being realized because therapies and
diagnostic tests are not coordinately developed in the pharmaceutical
industry and they are not reviewed and regulated in a coordinated
fashion by the FDA.
For over two decades, genetic tests have been reported in the
medical literature demonstrating their ability to predict patients'
response to drugs. However, they are not becoming part of the routine
practice of medicine. The major reasons relate to the barriers to
commercialization of the diagnostic tests. One of those barriers is the
lack of standards for such tests and concerns about the cost and
predictability of a path toward FDA approval of the tests. In order to
define the standards and demonstrate the path, C-Path developed a
partnership between the FDA and a team of scientists at the University
of Utah and Intermountain Healthcare. The goal is to evaluate genetic
tests for their ability to predict safer and more effective doses of
the anticoagulant warfarin (Coumadin). Warfarin is a generic drug
widely prescribed as a blood thinner to prevent dangerous blood clots.
The optimal dose varies from patient to patient and may range from 1
mg/day to 40 mg/day. If the dose is too high, the patient may have
serious bleeding and conversely, if the dose is too low, the patient
may suffer a stroke or embolism. In both these situations, death can
rapidly follow. The University of Utah is performing the clinical study
and C-Path will evaluate the methods used in the study to assure the
FDA that the results of the trial can be used to write dosage
recommendations for warfarin based on genetic testing. A recent Joint
Report from the Brookings/American Enterprise Institute concluded that,
if the Utah study is successful and its results incorporated into the
practice of medicine, 85,000 serious bleeding events and 17,000 strokes
can be avoided annually and $1.1 Billion in healthcare costs will be
saved each year.
For the promise of personalized medicine to be realized, diagnostic
tests that can predict an individual person's response to therapy must
reach the market and become routine components of therapy. One of the
factors that has limited widespread application of personalized
medicine test biomarkers is the lack of a clear path at FDA for
approval for such assays. By working with the FDA and the University of
Utah, the warfarin genotyping project is expected to form a path to FDA
approval and would aid pharmaceutical and diagnostic companies as they
develop new drugs and diagnostics. The new process created by the FDA
for this project could serve as a model pathway for other personalized
medicines.
The FDA of the Future
In order for the FDA to efficiently regulate the development of new
biomedical products, it needs many more opportunities to interact with
cutting edge scientists. We believe the model that C-Path has developed
with its Cardiovascular Safety Biomarker project is an excellent
example of how best to address this need. Under a cooperative agreement
with the FDA, C-Path has identified the leading scientists in the
Nation with the expertise needed to develop new genetic tests to guide
the initial dosage selection for warfarin.
I recommend that the FDA be given the resources and staff to form
collaborations to more aggressively work on the Critical Path
Initiative. We have found the concept of a ``critical path public/
private partnership'' to be an effective mechanism to leverage FDA's
limited resources to maximum benefit. C-Path's success in bringing the
Federal regulators and the regulated industry together results from its
scientific credibility and its financial neutrality. This neutrality is
only possible because of the unrestricted funding that it receives from
the Arizona community to pay for the operating costs and to seed the
Institute's programs. Congress has recognized the value of neutrality,
transparency and mutual oversight when industries work with Federal
agencies on ``process improvement.'' In the past, Congress created
Sematech for the computer chip industry, the National Center for Food
Safety and Technology for the food industry and others. Public-private
partnerships like C-Path can serve as the neutral third party for the
health product industry and the FDA and can fill a major unmet need for
the Nation by making it possible for biomedical innovations to reach
the public with greater speed and safety.
Senator Bennett. Thank you very much.
Dr. Anderson.
STATEMENT OF DR. JEFFREY L. ANDERSON, ASSOCIATE CHIEF
OF CARDIOLOGY AT THE LDS HOSPITAL, CO-
DIRECTOR OF CARDIAC RESEARCH, AND PROFESSOR
OF INTERNAL MEDICINE AT THE UNIVERSITY OF
UTAH
Dr. Anderson. Good morning. I also extend my thanks to
Senator Bennett for his long-time support of medical progress
to provide all of us with better health care. For your
particular interest in this initiative and for organizing this
field hearing. Obviously I'm biased, and I appreciate it's here
in Salt Lake City.
I also express appreciation to the FDA for its leadership
in this initiative that I believe can dramatically improve
health care.
Well, we've heard a lot about cancer. And the other big
gorilla, if you will, in health care is cardiovascular disease.
Heart and blood vessel disease. It is a leading cause of
morbidity and mortality. Almost a million Americans die each
year of cardiovascular disease.
And the importance of family history has really been
emphasized here in Utah in a classic study that showed that in
general about 14 percent of us have a family history of early
heart disease. But if you have heart disease yourself, the risk
is 50 percent. And if you have early-onset disease, three-
quarters of patients will have a family history. And, of
course, it's genetics that transmits that family history more
than anything.
And genetics not only determines predisposition and
susceptibility to disease, but also how we respond to diet.
What we eat. Environmental pollutants, that unfortunately we're
getting more of in the air here in Salt Lake City even. And
medications, which we are increasingly using, as we've heard,
in large numbers to prevent and treat disease.
Now, we've found so far in our work that genetics of
coronary disease is complex, thanks to some support from NIH.
And we'll continue that effort. But pharmacogenetics, which is
the application of genetics to the optimal use of
pharmaceuticals, is more straightforward and I believe will
likely lead the way in the initial application of genetics to
the prevention and treatment of cardiovascular disease.
And I'd like to return to an example that's been alluded to
that in just a minute. But just for a moment who you're hearing
from here, I've had the opportunity to see medicine from
several different perspectives: As a student, as a resident
trainee, as a servant in the Public Health Service for a while,
and a bench researcher in the National Institutes of Health for
a season, to an FDA volunteer on the Cardiorenal Advisory
Panel, and later as its chair a decade ago. And even for a
brief time as an executive director of the Cardiovascular
Pharmaceutical Development Program for new drugs for a large
international company.
But for most of the last 30 years I've had the wonderful
and varied experience of being an academic cardiologist,
including teaching, clinical and translational research,
applied research if you will, but most importantly serving my
patients as their physician and cardiologist. And one of the
challenges that I certainly can attest to as a physician is
that treatment is indeed geared to the crowd, if you will,
whereas I only deal with individual patients.
When I am paged to our hospital's laboratory for a critical
case, I can anticipate that quite often it will be a case for
an out-of-range for prothrombin, which is a measurement of the
effectiveness or activity of the common blood thinner warfarin
or coumadin, the brand name as we've heard about. Of course
putting that patient at high risk. And I always break out in a
little bit of a sweat, knowing that that patient for the next
few days, until we get that back to normal, is going to be at
higher risk.
And that's just one prominent example. Side effects from
several other drugs again occur in individuals and has already
been stated. This is a daily challenge. If we knew in advance,
it would be a much better situation. So individualizing
selection, and dosing, and medications to individual patients
based on genetics, I concur with the others that have spoken,
is a prime opportunity for better medicine for the future.
Now, warfarin has been mentioned, and it's certainly a
prime target for this initial application. It's prescribed to
over 2 million Americans for prevention of clotting disorders.
And unfortunately, warfarin has a very narrow therapeutic range
of balance, a tight rope, between too much causing bleeding
problems or too little allowing clotting problems to occur.
And so clinical management has been, as you've heard, very
difficult. And that's because there's tremendous
interindividual variability in warfarin metabolism, leading to
unpredictable and up to 20 full differences in the maintenance
dosing requirements. And right up until now we've only been
able to determine that by trial and, unfortunate error, and
frequent blood testing.
In recent years it's been exciting to discover two genes
that are responsible, together with age, sex, and weight, for
over half of the variability. This tremendous variability. But
clinical application of genetic testing has lacked. And it's
really minimal at the present time.
One of the reasons is we don't have good clinical
controlled trials that prove the benefit. What's the cost of
this? What are the tradeoffs? So recognizing this need, and
with encouragement and support from the C-Path Institute and
also with support from FDA in this critical pathway, we
undertook a prospective randomized trial just a little over a
year ago with a rapid genotyping assay that allows us to get
back information in about an hour. Again which is a critical, I
think, component of applying this.
And that has already been published recently. And I'm
pleased to announce that we've just completed this first major
randomized trial in 200 patients. We're involved in the
analysis. And we hope by the end of the month to submit this
for review and we hope publication in a major medical journal.
We think that this will be of great value to the National
Institutes of Health that we've been collaborating with in
setting up a major multi-institutional and much larger trial
that we hope will finally validate this approach, and allow it
then to be applied nationally to these 2 million patients who
are begun and have treated on warfarin.
Senator Bennett. Can I interrupt you there?
Dr. Anderson. Yes, sir.
Senator Bennett. We need to move along.
Dr. Anderson. Okay.
Senator Bennett. If you have another major point----
Dr. Anderson. Shall I just summarize?
Senator Bennett. If you would, please.
Dr. Anderson. I was just going to say that this is, of
course, just one example of many other drugs that we have in
mind. And so let me just conclude then by saying that I think
the C-Path Institute is a prime example of how a neutral party
can partner with FDA. And how important the C-Path initiative
is to bring together these many parties that I have mentioned.
PREPARED STATEMENT
But this early promise, of course, needs ongoing support to
really, I think, achieve the true potential of this approach.
And the result could and should be a major advance in health
care for all Americans, individualized to their personal needs.
And I thank you for your time and attention.
[The statement follows:]
Prepared Statement of Jeffrey L. Anderson, M.D.
Good morning. I am pleased to join you at this field hearing to
provide my personal insights relevant to the Critical Path Initiative.
I will testify that this high priority FDA project has great potential
to facilitate the much-needed transformation of the way medical
products in the United States are developed and applied and to take
advantage of the vast potential of modern human genomics. I want to
thank the subcommittee on Agriculture, Rural Development, Food and Drug
Administration, and Related Agencies for inviting me to participate as
a physician and medical scientist as well as a concerned and interested
citizen.
I extend my thanks as well to Senator Bennett, for his long-time
support of medical progress to provide better health care for all
Americans, for his particular interest in this initiative, and for his
organization of this field hearing.
As a graduate and faculty member, I wish to recognize the
University of Utah, for its support of genetic medicine in general and
its particular interest in the Critical Path Initiative. I express
appreciation to the FDA, for their stimulating leadership role in a
collaborative project that can dramatically improve the health of our
own and especially future generations. Finally, I wish to particularly
recognize Dr Raymond Woosley, whose passion for this initiative has led
to his formation of the not-for-profit C-Path Institute, a vehicle to
assist in applying the Critical Path Initiative to the development and
application of pharmaceuticals and new medical devices. Our own
research has been honored to serve as his cardiovascular clinical
collaborators over this past year. This role has been facilitated by
financial support from a grant awarded by FDA and funded by
Congressional mandate. I will comment on the return for this investment
later.
The Genetics Revolution and Its Implications for Healthcare.--
Completion of the Human Genome Project has launched medical science
into the ``Post-Genomics Era'', \1\ \2\ yet application to clinical
medicine is still embryonic. The human genome consists of 3 billion
base pairs of DNA, comprising an estimated 20,000-25,000 genes (``loci
of co-transcribed exons'') arranged on 46 chromosomes (22 autosomal
pairs plus XX or XY). The human genetic map is remarkably constant,
with interindividual differences occurring on average at only 1 in 1000
base pairs, yet this 0.1 percent variance accounts for genetic-related
differences in both normal human traits and disease predisposition.\3\
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\1\ Lander ES, Linton LM, Birren B, et-al. Initial sequencing and
analysis of the human genome. Nature 2001;409:860-921.
\2\ Ventner JC, Adams MD, Myers EW, et-al. The sequence of the
human genome. Science 2001;291:1304-51.
\3\ Guttmacher AE, Collins FS. Genomic medicine--a primer. N Engl J
Med 2002;347:1512-20.
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Overall, about 10 million relatively common polymorphisms in single
nucleotides (SNPs) have been found within the human genome; perhaps
100,000 have functional consequences (are non-synonymous). Normal
diversity-determining variants can be postulated to number a few
thousand, common disease-determining genes and genes affecting the
metabolism of our major drugs, perhaps a few hundred. Thus, despite
substantial genomic variability, the search for the genetic
underpinnings of common diseases and patient interactions with
treatment, although enormously challenging, is believed to be a
realistic possibility. This search has struggled through an embryonic
stage, and the true potential of genetic medicine is as of today almost
completely untapped. Its successful application will require a
cooperative, societal commitment, including full participation by
government, academics, industry, and public interest groups at many
levels.
The Health Burden of Cardiovascular Disease and the Contribution of
Genetics.--Cardiovascular diseases (CVD) are the leading cause of
morbidity/mortality in the United States and the Western world.\4\
Coronary artery disease and its major clinical sequel, myocardial
infarction, represent the major contributors. The importance of family
history was emphasized in a large University of Utah database study,
which found a positive family history of CAD (onset in first degree
relative at age <55 in men, <65 in women) in only 14 percent of the
general population, but 48 percent among those with CAD and 72 percent
(almost three-quarters) of those with premature onset of disease.\5\
Twin studies and other family history evidence suggest that heredity
and environment contribute approximately equally to CAD disease
etiology. The genetic contribution to CAD is believed to be multigenic
and complex.\6\
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\4\ Thom T, Haase N, Rosamund W, et-al. Heart disease and stroke
statistics--2006 update: A report from the American Heart Association
Statistics Committee and the Stroke Statistics Subcommittee.
Circulation 2006;113:85-151.
\5\ Williams RR, Hunt SC, Heiss G, et-al. Usefulness of
cardiovascular family history data for population-based preventive
medicine and medical research (the Health Family Tree Study and the
NHLBI Family Heart Study). Am J Cardiol 2001;87:129-35.
\6\ Hopkins PN, Hunt SC, Wu LL. Family history and genetic factors.
In: Wong ND, Black HR, Gardin JM, eds. Preventive cardiology, a
practical approach. New York: McGraw-Hill; 2005:92-148.
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It has been said ``genetics loads the gun, and environment pulls
the trigger''. Genetics not only determine disease susceptibility but
also the response to the diet, environmental pollutants, and
medications, ever increasing in number, used to prevent and treat
disease. Given the complexity and slow progress in determining genetic
susceptibility to CVD, pharmacogenomics, the application of genetics to
the optimal use of pharmaceuticals, can lead to the way in the
application of genetics to prevention and treatment of CVD.\7\
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\7\ Anderson JL, Carlquist JF, Horne BD, Muhlestein JB.
Cardiovascular pharmacogenomics: current status, future prospects. J
Cardiovasc Pharmacol Therapeut 2003;8:71-83.
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Insights from a Personal Journey through the Healthcare System.--My
personal journey through medicine has included many stops along the way
after medical school, including residency training in internal medicine
and speciality training in cardiology, bench research at the National
Institutes of Health, with an appointment in the Public Health Service,
many years in the practice of cardiology, volunteer service for the FDA
on its Cardiorenal Advisory panel, which I also chaired, and even a
brief adventure in industry as Executive Director of Cardiovascular
Clinical Research for an international pharmaceutical company, as a
Cardiology Division Director, and, as a practicing cardiologist seeing
patients. For 28 of the past 30 years, I have particularly enjoyed the
varied experience of academic cardiology, including teaching, clinical
and translational research, and, importantly, serving my patients as
their physician and cardiologist. This varied experience has brought me
an appreciation of the wonderful potential of modern medicine but also
pointed out its challenges and deficiencies.
One of these challenges is that our treatments are geared to the
crowd, whereas I deal only with unique individuals. I am on call 24
hours a day for my own patients and cross-cover for my academic
partner, Dr. Brent Muhlestein, and share Wednesday call with colleague,
Dr. Robert Fowles, for the large Utah Heart Clinic and the cardiology
needs of the LDS Hospital Emergency Ward. When paged to the LDS
Hospital laboratory for a ``critical value'' when on call, I can
anticipate that an ``out-of-range'' value for the common blood thinner
``warfarin'' (or Coumadin) is often the reason, putting that patient
at high risk for a bleeding event. Rare to more common side effects of
other drugs, again which occur in individuals, is a daily challenge.
Individualizing selection and dosing of medications to individual
patients, based on genetics, is a prime opportunity for better medicine
for the future.
Pharmacogenomics: Its Bright Promise for Now and the Future.--
Currently, all patients are treated with the same drugs and doses, yet
safety and efficacy vary depending on genetic background. The promise
of pharmacogenomics is to customize therapy by determining in advance
who will be responders to usual dosage (e.g., 60 percent of a patient
group), responders at higher dosage (e.g., 10 percent), responders at
lower dosage (e.g., 15 percent), non-responders (who need alternative
therapy, e.g., 10 percent), and those at adverse risk (idiosyncratic
or toxic, e.g., 5 percent).\7\ Pharmacogenetic applications represent
a very promising first major venture into the application of genetics
to personalized medicine, and a golden opportunity for efficient use of
resource and research efforts today.
Pharmacogenetic-Guided Dosing of Warfarin: Applying Genomics to
Medicine Today.--A prime target for the initial application of
pharmacogenetics to broad application in CV medicine is the orally
active anticoagulant warfarin. Warfarin is prescribed to over 2 million
patients in the United States for prevention of clotting disorders
(``thromboembolic disease'') associated with such conditions as atrial
fibrillation, prosthetic heart valves, orthopedic surgery (e.g., knee
or hip replacement), venous thrombosis, and pulmonary embolism.
Unfortunately, warfarin has a narrow therapeutic index, and
clinical management is difficult. Recurrent thromboembolism, due to
inadequate anticoagulation, and serious bleeding events, due to
excessive anticoagulation, are relatively frequent. Substantial inter-
patient variability in warfarin metabolism leads to variable (up to 20-
fold) and unpredictable dosing requirements.\8\ Oral anticoagulation
trials for non-rheumatic atrial fibrillation have determined the
optimal range of the blood test, prothrombin international normalized
ratio (INR), to be 2-3 with ratios <2 increasing thrombotic events and
those >4 increasing hemorrhagic events and with a marked increase in
intracerebral and other serious hemorrhage at INRs >5.\9\ \10\ Careful
clinical follow-up and frequent blood testing for INR are required to
ensure effective anticoagulation while avoiding over-anticoagulation
and serious bleeding events.
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\8\ Voora D, McLeod HL, Eby C, Gage BF. The pharmacogenetics of
coumarin therapy. Future Medicine 2005;6:503-13.
\9\ Hylek EM, Skates SJ, Sheehan MA, Singer DE. An analysis of the
lowest effective intensity of prophylactic anticoagulation for patients
with nonrheumatic atrial fibrillation. N Engl J Med 1996;124:970-9.
\10\ Oden A, Fahlen M, Hart RG. Optimal INR for prevention of
stroke and death in atrial fibrillation: a critical appraisal.
Thrombosis Research 2006;117:493-9.
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Variants in 2 genes affecting warfarin metabolism (CYP2C9, VKORC1)
recently have been discovered by us and others to conjointly determine
stable warfarin dose.\11\ \12\ Together these genotypes plus certain
clinical characteristics predict approximately one-half of inter-
individual dose variability.\11\ \12\ These recent studies suggest that
CYP2C9 and VKORC1 genotyping may be of substantial interest for
clinical application. Indeed, the Clinical Pharmacology Subcommittee of
the FDA Advisory Committee for Pharmaceutical Science has recommended
CYP2C9 and VKORC1 genotyping to optimize warfarin dosing. However,
clinical application has been limited, in part because of cumbersome
assays and the lack of clear demonstration of an incremental advantage
on outcomes of genotype-guided dosing algorithms by prospective,
controlled trials.
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\11\ Carlquist JF, Horne BD, Muhlestein JB, et al. Genotypes of the
cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase
complex subunit 1 conjointly determine stable warfarin dose: a
prospective study. J Thromb Thrombolysis 2006;22:191-7.
\12\ Sconce EA, Khan TI, Wynne HA, et al. The impact of CYP2C9 and
VKORC1 genetic polymorphisms and patient characteristics upon warfarin
dose requirements: proposal for a new dosing regimen. Blood
2005;106:2329-33.
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Recognizing this need, and with encouragement and support from the
C-Path Institute, and made possible in part by FDA grant funding, we
undertook a prospective, randomized pharmacogenetic (PG)-guided dosing
study. A rapid turnaround (clinical ``real-time'') genotyping assay,
one pressing need holding up clinical application, already has resulted
from these efforts.\13\ Using this assay and a predictive algorithm,
developed from recent work by our group, we have completed the first
major randomized study of PG-guided dosing, ``CoumaGen'', in 200
patients initiated on warfarin therapy, and plan to analyze and submit
our written report to a major clinical journal this month for review
and publication. These results should play an important role in the
planning of a much larger, multicenter study to be sponsored by NIH, to
validate the PG-guided approach to warfarin dosing in clinical
practice. The safety impact of this single effort in pharmacogenomics
could be substantial.
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\13\ Anderson JL, Hinz WA, Clarke JL, Et-al. A rapid (1 hour)
genotyping assay for polymorphisms affecting the dose-response to
warfarin therapy. J Am Coll Cardiol 2007.
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Making Cardiovascular Drugs Safer A Pharmacogenetics Initiative of
Highest Priority.--A next step with warfarin is to apply routine
genetic testing for dose-selection within the IHC system, involving
several thousand patients per year, and measure its impact on
healthcare outcomes. If positive, these efforts could rapidly be
expanded to regional and national networks with large potential health
care benefits.
Warfarin represents only one of a multitude of cardiovascular drugs
that we have identified, together with FDA input, as potential targets
for pharmacogenetic research and future clinical application. To
investigate genetic associations requires DNA samples and patient
information. Our research group has collected and banked blood for
serum samples and DNA, together with family histories and complete
medical records, from 15,000 patients undergoing coronary angiography
over the past 12 years. Information on over 2 million patients in the
Intermountain Healthcare Electronic Database also is available, with
appropriate approvals and safeguards, for expanded research efforts.
Intermountain Healthcare (IHC) has a world-class computerized
information system that allows for tracking of deaths, other
cardiovascular events, and adverse drug events. In addition, the FDA
has an Adverse Event Reporting System (AERS) for signal detection of
interest. Working in collaboration with FDA in a C-Path oriented
project would allow us to determine safety signals of interest, perform
retrospective and prospective surveillance studies within the
Cardiovascular and General IHC databases, identify patients with
events, and, with consent, obtain DNA samples and test for candidate
genes or do genome wide genetic scans to identify adverse event-related
genetic causes. Several specific projects already have been identified
as of potential interest and importance to national CV health:
--New or worsened heart failure after therapy with anthracycline
chemotherapies (doxorubicin, daunorubicin, idarubicin),
imatinib, and trastuzumab
--Rhabdomyolysis from statins
--Angioedema and ACE inhibitors
--Variability of clinical response to and safety of beta blockers
--Pharmacogenetic basis for sporadic long QT syndrome (causing
serious, unexpected heart rhythm disorders).
--Genomics and adverse response to QT prolonging drugs
--Confirm (or refute) linkage of CV adverse events with certain
drugs, including the coxibs (Vioxx, etc), the
thiazolidinediones (Avandia, etc.), and the GI motility agent
Zelnorm, and, if confirmed, identify a genetic basis.
In anticipation of these projects, we have performed a feasibility
study on the IHC database and have identified to date:
--2,300 out-of-range INR for patients taking warfarin (40 percent of
all INRs!).
--Developed a method to link databases in the Utah system to other
systems so that out of range prothrombin time (INR) values can
be validated as a surrogate for adverse events due to warfarin.
--Conducted baseline analysis of the monthly rate of INR out of range
values to enable power calculations for future intervention
studies
--23 subjects with anthracycline related heart failure
--27 patients with ACE inhibitor-related angioedema.
--102 with rhabdomyolysis while taking statins.
Implications for the Future of Medicine and why the Critical Path
Initiative is Important.--In the post-genomic era, the central role of
genetic-environment interactions on human health and disease is
unquestioned. However, genetic application in the day-to-day practice
of cardiovascular and general medicine is to date minimal. A paradigm
shift from ``treating the crowd'' (generalized medicine) to ``treating
the individual'' (personalized medicine) seems to be the clear and
single path to a better era of health care in the future. While the
complex role of genetics in polygenetic diseases such as CAD is being
sorted out, the application of pharmacogenetics to medicine is
approaching ``prime time''.\14\ To make application a reality, however,
will require a clear societal commitment, for many ethical and
practical issues, as well as scientific ones, must be overcome. The
FDA's Critical Path Initiative currently stands out as the single most
important way forward. The C-Path Institute is a prime example of how a
``neutral party'' has partnered with FDA and the C-Path Initiative to
bring together Government/Regulatory, Industry, Academics, and Public
Interest groups, to overcome barriers, and to address common problems
for the public good. This early promise of C-Path is a direct result of
Congressional support; its ongoing success and true fruits can only be
realized with expanded support and with a long-term commitment. The
result could and should be a major advance in health care for all
Americans, individualized to their personal needs and characteristics.
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\14\ Roden DM, Brown NJ. Pre-prescription genotyping: not yet ready
for prime time but getting there. Circulation 2001;103:1608-10.
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I thank you for your time and attention today, and for inviting me
to be with you.
Senator Bennett. Thank you.
Dr. Prestwich.
STATEMENT OF DR. GLENN D. PRESTWICH, PRESIDENTIAL
PROFESSOR AND DIRECTOR, CENTER FOR
THERAPEUTIC BIOMATERIALS, UNIVERSITY OF
UTAH
Dr. Prestwich. Thank you. I'll do my best to move things
right along. Senator Bennett, again thank you, with the other
panelists, for the opportunity to present our testimony. I
think I'm here because I'm an academic who's also an
entrepreneur, and so I want to present the point of view that
that, that that embodies.
I have started companies that develop tools for
pharmaceutical drug discovery. And in fact have been part of
discovery of anti-cancer and anti-infective drugs. In addition,
more recently I've been involved with starting companies that
make medical devices for wounding--for improved wound care. And
also now for tissue engineering, which is part of cellular
therapy, which will be one of the new regenerative medicine
techniques of the future.
That's a separate issue with the FDA, and I won't go there,
because we're going to focus on, on the personalized medicine
focus. But let me, let me convey my impressions in the area of
new biomarkers and disease models, which is one of the Critical
Path six priority areas for improving health care in the United
States.
So specifically my testimony will address the use of tissue
engineering technologies to improve both upstream and
downstream potential to unplug the drug discovery pipeline.
What we've been talking about is a pipeline that's plugged. The
water is not getting to the side of the ditch.
So let's--I'm going to look at it at two different areas:
upstream and downstream. So upstream in the drug discovery
pipeline, I think, as Dr. von Eschenbach points out, we need to
develop safer treatments faster and more cost effectively. I've
got some ideas on that.
Second, at the downstream end we need to see how tissue
engineering technologies not only can cure people better, but
maybe they offer a better potential for individualizing--
individualization of treatment options. And I have an example
that I'd like to present in that regard.
We haven't talked much about the actual cost of individual
drug development. Right now in the pharmaceutial industry the
estimate is about $1.2 to $41.4 billion to develop a new drug
entity, and it takes about 12 years to accomplish that.
The problem is that only one out of seven or eight
compounds gets through the pathway--through Phase III clinical
trials and gets approved for market. That means that seven out
of eight, or six out of seven, depending on which numbers you
believe, are failing.
Of those, at least a quarter of them or more are failing
because of hepatotoxicity. That's toxicity to the liver. And
that's happening only in large-scale Phase III studies. Right
now you can only find it out that way.
So one of my feelings for unplugging the drug discovery
pipeline would be to improve the rate at which we can eliminate
kidney toxic or liver toxic compounds early in the drug
discovery pipeline, upstream, before they get into the very,
very expensive and potentially life-threatening Phase III
studies.
This can be accomplished or is now being worked on in
research laboratories translationally with tissue engineering
technologies. So, for example in my lab, we develop materials
that allow us to culture small versions of the human liver that
are functional. And we can grow those small liver organoids and
test drugs, thousands--hundreds of thousands of them in a
couple of weeks against a functioning version of the human
liver.
Well, that's one way to do it. That would be the high
industrial-strength version of it. But what you really want is
that construct to represent a functioning liver in a rodent
model. So you take a rat and you take out the rat's liver and
you put in a human liver.
Now you've got an organism that's going to be your best
equivalent of a human. Which is that it has the liver
metabolism of a human. It's got all the circulation. Things are
moving around. Things are getting broken down. You can find
some of those things that are called ``idiosyncratic
toxicities,'' which are compounds that become toxic after the
liver activates them.
So it's being able to find those toxicities that normally
you wouldn't find until you were in a large human population.
We can find those earlier. That's going to unplug the pipeline
at the upstream end. Make it safer, quicker, cheaper.
So coming to personalized medicine, that's still sort of
genetic, right? Because it's upstream. So my take on
personalized medicine is summarized in what I call my slogan.
Which is it's all about ``Drug and Dosage--Getting it Right for
Dick or Jane.'' If you can't distinguish between Dick and Jane,
then you can't get it right for either the drug or the dosage.
So really there are two levels. Everything that we've heard
about so far is at the genetic level. That's the gene. Those
are the programs, the blueprints that encode everything that
we're made out of. But I want to address a different area,
which is the phenotype.
The phenotype is who we actually are. It's what's actually
built from those blueprints. It's not the stuff that's on the
architect's desk, it's the stuff that you're actually walking
through the door of when you move into your home. So I think
that the phenotype, the individual phenotype, is equally
important for looking at opportunities in personalized
medicine.
And so let me talk about one specific example in the idea,
the concept that I have for individualizing anti-cancer drugs.
So the technology at one of my companies here in Salt Lake
City, Glycosan, consists of an injectable material that you can
load up with cells. And so we've done this now, not just for
engineering of livers, and kidneys, and bone repair, and things
like that, but also for engineering tumors.
So this seems like the wrong thing to do. Growing a better
cancer seems like a really dumb thing to do. But in fact it's
not. It's not so dumb, because most of the anti-cancer
compounds in the clinic right now will fail. And they'll fail
because they've only been tested in animal models. And animals
are really, really bad predictors of what's going to happen in
a human.
So we want to put human tumors in a more human context. And
you want to be able to go further than that but test a specific
drug for Mrs. Anderson or Mrs. Jones and make sure that, that
patient gets the right drug.
So here's how we've used this model. Let's take breast
cancer. So we've injected breast cancer cells. And it could be
Mrs. Jones' or Mrs. Anderson's own tumor cell that we inject in
the real setting of this. We take those cells and inject them
in the mammary fat pad. That's essentially the breast-like
tissue of the mouse. And then we grow tumors. We grow breast
tumors.
Now you have mice that are growing--in this case, it could
be Mrs. Anderson could have her own set of mice, and Mrs. Jones
could have her own set of mice. And then you would go with a
particular set of drugs. Mrs. Jones has failed cisplatin, her
drug--her cancer is resistant to cisplatin and Taxol and
doxorubicin. Now what are we going to try?
Well, you can go to the pharmacy and pull out a whole bunch
of things and try one after the other or try them all at once
on Mrs. Jones. But that's using the patient herself as the
experimental animal. Why not take cancer out of the patient,
put it in the animal. And then use animals, with that patient's
own cancer, determine which is going to be the best treatment
for that particular patient.
So that hasn't been possible in the past because everything
has used tumor cell lines. And most of them don't work very
well anyway. But we can personalize that by taking Mrs. Jones'
and Mrs. Anderson's tumor cells, put them into a mouse, couple
of mice. Try this set of drugs with that mouse, try this set of
drugs with that other mouse.
And pretty soon you say, this mouse is living; the tumors
are regressing, let's go with that combination. That would take
about 4 weeks. And then you have 4 weeks in the cancer
decision-making process as to when you want to decide what to
give as the next therapy.
So rather than drone on about that, that's my feeling for a
downstream approach to phenotype-driven personalized medicine.
Senator Bennett. Okay.
Dr. Prestwich. So in my concluding remarks----
Senator Bennett. Right.
Dr. Prestwich [continuing]. I want to emphasize that
academic research, to be translated to the clinic, has to be
commercialized. And so the academic entrepreneurial investor
interface is extremely important. And we must recognize that we
need to build things, not for our own publication lists, but
for patients and physicians who are going to use things in the
end.
PREPARED STATEMENT
And so this Critical Path Initiative is part of that
process to get translational research more emphasized and more
on the minds of academics so that we actually do translate
things--to individualize therapies. And to use the best tissue
models, the best animal models, the best safety testing that we
can possibly do to get better, faster, cheaper drugs.
[The statement follows:]
Prepared Statement of Glenn D. Prestwich
Executive Summary
The FDA Critical Path Initiative has identified ``Better Evaluation
Tools--Developing New Biomarkers and Disease Models'' as one of the six
priority public health challenges to be considered as a major
opportunity in improving health care in the United States. This topic
includes biomarkers that could facilitate the development of
personalized medicine strategies. It also includes the development of
more predictive preclinical models for drug efficacy and safety. My
testimony addresses strategies and technologies in tissue engineering
with both upstream and downstream potential. First, at the upstream end
of the drug discovery pipeline, improved models based on tissue
engineering can help the pharmaceutical industry discover safer
treatments faster and in a more cost-effective manner. Second, at the
downstream end of the pipeline, tissue engineering offers the potential
for individualized treatment models for drug selection using biopsy
samples. Such methods would allow a physician to customize a treatment
before administering it to a patient.
What is the Underlying Question?
One of the six priority public health challenges for improving
health care in the United States was identified in the FDA Critical
Path Initiative as ``Better Evaluation Tools--Developing New Biomarkers
and Disease Models.'' This topic includes the discovery and use of
genetic and phenotypic biomarkers that could facilitate the development
of personalized medicine strategies. It also includes the development
of preclinical models for drug efficacy and toxicology that have better
predictive value for clinical usage.
The fundamental problem is the long time required and the high cost
of drug discovery. A second problem that exacerbates this fundamental
problem is the high failure rate in Phase III clinical trials. As a
result, drug discovery strategies are overly conservative in the
molecular targets explored and are designed to identify
``blockbusters''--single drugs that treat millions of patients and
yield over $1 billion annual sales. The blockbuster paradigm is
fundamentally at odds with the concept of personalized medicine, which
strives to achieve a patient-oriented treatment for individual
molecular disease pathologies.
In the testimony below, I describe how strategies and technologies
in tissue engineering possess both upstream and downstream potential.
First, at the upstream end of the drug discovery pipeline, improved
models using tissue engineered human organoids can make safer
treatments available more rapidly and in a more cost-effective manner.
Second, at the downstream end of the pipeline, tissue engineered
constructs made using a patient's own normal and diseased cells can be
used to individualize treatments by taking the guesswork out of drug
selection. Such methods would allow a physician to customize both the
drug and the dose before administering it to a patient.
Why are so few new Drugs Reaching the Marketplace?
Currently, it costs some $1.2 billion some 12 or more years to
bring a new molecule from the laboratory bench to the bedside. Only one
drug candidate in seven succeeds in the expensive and time-consuming
Phase III clinical trials. A significant fraction of these failures are
due to liver toxicity, and occur after hundreds of millions of dollars
have already been spent. Reducing failure at this stage could
substantially lower the overall costs of drug discovery. It has been
said that, ``The holy grail of the [pharmaceutical] industry is to be
able to predict [drug] toxicity from a cell culture.'' However, current
methods for identifying hepatotoxic drugs are far from achieving this
goal. Measuring cytotoxicity in cultured hepatocytes can predict some
instances of acute toxicity in the clinic, but this does not take into
account the many drugs (40 percent) that fail because they are
metabolized in vivo to toxic species. This idiosyncratic toxicity
cannot currently be detected until large-scale Phase III clinical
trials.
New tissue engineering technologies, including those developed in
my laboratories, offer opportunities for in vitro and in vivo liver
toxicology models by culturing human liver cells--from the immature
hepatic stem cells to mature hepatocytes--as organoids. The key is to
recapitulate the cellular microenvironment experienced by normal cells
as they normally grow and mature in the adult human liver. The ability
to grow metabolically competent engineered liver tissue is an important
``growth industry'', and the Utah technology allows growth of
engineered human liver constructs for toxicological studies.
One step beyond ex vivo organotypic models is the development of
whole-organism pharmacokinetic and pharmacodynamic models. Since drug
metabolism in rodents and humans differ dramatically, one solution
could be the production of mice with engineered human livers. This
moves from metabolic profiling in an ex vivo human organoid to the
study of how the metabolites from the organoid interact within an
intact organism. Perhaps such a system might further reduce Phase III
failures.
What is Personalized Medicine?
My philosophy on personalized medicine is summarized in this
slogan: ``Drug and Dosage--Getting it Right for Dick or Jane.'' There
are two levels at which personalized medicine can be approached:
genetic and phenotypic. Most discussions now focus on the genetic
level. A person's genome is the unique blueprints that encode the
building instructions for all the proteins in his or her body. However,
genes are not inevitable destiny, because how these blueprints are read
changes as we develop and as the environment changes. Thus, arguably
more important for personalized medicine, is the phenotype of an
individual. This is who we actually are--which proteins have been made
correctly (or incorrectly) based on those instructions. Others in this
hearing will testify about the importance of using genetic markers in
optimizing drug selection and drug dosing. My testimony will focus on
the phenotypic approach to personalized medicine.
The tissue engineering technology developed at the University of
Utah allows a vision for personalized medicine in which tissue biopsies
can be utilized for the determination of drug safety and efficacy for a
specific patient. This takes the more general approach used above for
reducing the number of hepatotoxic drugs reaching Phase III clinical
trials and makes it personal. We envision that an array of potential
pharmaceutical intervention options, could be pre-evaluated for safety
and efficacy ex vivo using a patient's own normal and diseased tissues.
The next section describes one such approach to downstream personalized
medicine.
Individualized cancer treatments: downstream personalized medicine
Current animal xenograft models used to evaluate new anticancer
therapies are limited to a small number of ``generic'' cancer cells
lines, fail to mimic the complexity of the normal human disease, and
poorly predict clinical outcomes. Our technology has generated an
injectable, in situ crosslinkable biomaterial called
ExtracelTM that can be used to deliver and grow cancer cells
in vivo by a technique we call ``tumor engineering.'' We have shown
that we can engineer breast, colon, pancreatic, and ovarian cancer in
mice by injection into the mammary fat pads, the colon, the pancreas,
and the ovaries, respectively. These engineered tumors are important
new tools to study cancer biology, invasion and metastasis, and to
investigate new therapeutic and diagnostic protocols. In fact, we have
recently used our model to validate the safety and efficacy of a new
anti-cancer drug invented at the University of Utah. This small lipid
molecule turns off a specific cell signaling pathway and causes tumors
to regress. In addition, it simultaneously suppresses metastasis, and
shows a very large therapeutic window.
To individualize the tumor engineering protocol, we would take a
breast tumor biopsy from a patient--perhaps pre-treatment, or possibly
after cancer has recurred--and obtain a heterogeneous pool of cells
that would be suspended in ExtracelTM and injected in mice
to give two to four breast tumors. In the same mouse, we would also
inject normal non-cancerous breast cells in ExtracelTM into
the fat pads on the other side. We might generate twelve mice per
patient. Approximately 2 to 4 weeks later, large tumor masses would
have formed on one side, and small normal breast organoids would be
formed on the other side. Then, a variety of treatment options could be
evaluated in order to identify a patient-specific optimal therapy. This
could be a new drug candidate, a new combination of existing drugs, or
a new treatment regimen. In this model, the patient herself is not the
test animal. Instead, a patient-specific surrogate allows multiple
options to be explored before treating the patient. This is what I
consider to be the ultimate in downstream patient-specific therapy.
Conclusions
No product of academic research reaches a patient unless it has
been the focus of an intense research and development effort by a for-
profit company. This development effort includes a rigorous evaluation
of safety and efficacy by the FDA. To be successful, products must
focus on the unmet needs of patients and their physicians, who are the
ultimate customers of the research efforts funded by the National
Institutes of Health and funding sources. I believe that it is both the
obligation and responsibility of researchers to adjust our research
priorities to meet the needs of our customers. In an analogous context,
the customers of the FDA are also the patients and their physicians.
Thus, it is my strongly-held opinion that the FDA, too, must
continuously evolve to meet the changing needs of its clientele. The
critical path initiative is indeed part of the process of change,
embodying when appropriate the best tissue models, animal models,
safety testing, and individualized therapy options that new
technologies can provide.
References
Portions of this testimony are excerpted from:
--Prestwich, G. D.; Liu, Y.; Yu, B.; Shu, X. Z.; Scott, A., 3-D
Culture in synthetic extracellular matrices: New tissue models
for drug toxicology and cancer drug discovery. Advances in
Enzyme Regulation, 2007, in press.
--Prestwich, G. D., Simplifying the extracellular matrix for 3-D cell
culture and tissue engineering: a pragmatic approach. Journal
of Cellular Biochemistry, 2007, in press; Published online as
DOI 10.1002/jcb.21386.
Biographical Sketch
Since 1996, Dr. Glenn D. Prestwich is Presidential Professor of
Medicinal Chemistry at The University of Utah, with adjunct
appointments in the Departments of Chemistry, Biochemistry, and
Bioengineering. He received a B.Sc. Honors (1970), Chemistry,
California Institute of Technology and a Ph.D., Chemistry (1974),
Stanford University. Previously, he was Professor of Chemistry and of
Molecular and Cell Biology, Stony Brook University (1977-1996) and
Director, NY State Center for Advanced Technology in Medical
Biotechnology (1992-1996). He received Alfred P. Sloan Research and
Dreyfus Teacher-Scholar Awards, the 1998 Paul Dawson Biotechnology
Award of the American Association of Colleges of Pharmacy, and is a
Fellow of the American Institute for Medical and Biological
Engineering. He received the TIAA-CREF Greater Good Award (2006), was a
Utah Business Magazine Health Care Hero (2006), and was awarded the
Governor's Medal for Science and Technology (2006). He has directed two
Centers of Excellence: the Center for Cell Signaling (1997-2002), and
the Center for Therapeutic Biomaterials (2004-2008). He co-founded and
was former CSO of Echelon Biosciences, Inc (1997-2003) and Sentrx
Surgical, Inc. (2004-2005). He is currently Senior Scientific Advisor,
Carbylan BioSurgery, Inc. (Palo Alto, CA) and a co-founder and CSO for
Sentrx Animal Care, Inc. and Glycosan BioSystems, Inc. Dr. Prestwich
has published over 590 technical papers, patents, and book chapters,
and has trained over 71 graduate students and 55 postdoctoral
associates.
Senator Bennett. Thank you very much.
Dr. Jones.
STATEMENT OF DR. DAVID A. JONES, SENIOR DIRECTOR FOR
EARLY TRANSLATIONAL RESEARCH, HUNTSMAN
CANCER INSTITUTE
Dr. Jones. Okay. Good morning. And thank you, Senator
Bennett, for the opportunity to share my view on personalized
medicine and help contribute to the discussion of the Critical
Path Initiative. I think we've heard today already, and I'll
give a unique sort of personal perspective about the rich
history of genetic research that the University of Utah enjoys.
I left a major pharmaceutical company about 10 years ago in
order to come here for the opportunity to juxtapose genetic-
based science with drug discovery. And I realize, believe it or
not, that I thought I could achieve this kind of match in my
research better in an academic setting than I could at a major
pharmaceutical company because, in many ways, of this inertia
that we talked about a little bit, being resistant to this kind
of approach in the pharmaceutical industry.
And so I have been here for 10 years at the Huntsman Cancer
Institute. And the Huntsman Cancer Institute is following in
the footsteps of the broader university community in trying to
understand what are the underlying genetic causes of the
various kinds of cancers. And if we can understand that, we can
think about better therapies to give to these patients with a
defined genetic cancer.
And one of the resources that we have--and I think that
I'll just point this out so that I can make a point that this
is already happening--is personalized medicine. It's coming
whether we want it or not. And we just need to prepare for it.
And one of the examples that I take advantage of all the
time as a scientist is that the Huntsman Cancer Institute
operates what are called ``high-risk clinics.'' And that means
we know about the people in the State of Utah who carry
specific genetic mutations that predispose them to specific
kinds of cancers.
We know about the people in Utah who have a clear genetic
inheritance of cancer, even though in some cases we don't
understand the underlying genetic basis. And these patients are
invited to come in to these high-risk clinics for screening.
And in this case we're going back and thinking about
prevention by bringing them in. In the case of colon cancer,
which is my specialty, they can undergo colonoscopy on a
regular basis, and we can think about heading off cancer prior
to its onset.
One of the things that we're able to do of course then is
that we can study these patients when they come in. We can get
their tissues. We can look at what's wrong with the tissues. We
can think about new ways of approaching it.
If you think about a specific gene that has mutated in
colon cancer right now that causes 85 percent of colon cancers,
the options for these patients who are high risk, meaning they
inherited the mutation in this gene, is to have their entire
colon removed when they're in their 30s or early 40s.
And so we are very interested now in saying, look, we have
this genetic resource. We understand who is at risk. We can now
understand the underlying biochemical problems and think about
new therapies that we can apply to them. And of course the idea
would be to go back and use these same patients that we used as
the guiding principle for developing the drug and put that drug
back into those patients.
So our overall goal is to try to improve both diagnostics
and treatment. And I think that it sort of points to what I
would say needs to happen in the drug discovery and approval
process. In that science really has moved in the last 10 years
from one investigator studying one process for his entire
career, her entire career, to using technologies that allow us
to assess globally what's wrong in disease. We know, we can
give you the molecular recipe for a colon cancer now by looking
at all genes in the genome.
And I think that my view of what needs to happen in order
to facilitate this is that the drug discovery process has to go
from being what historically is a more linear process. Meaning
that the target and the discovery of the drug is often
uncoupled from understanding toxicity of the drug and
understanding the patient population. And we need to have a
much more broad overview of the process from beginning to end.
The clinical trialist has to understand the molecular
process. The people who worry about toxicities need to think
about what are the potential toxicities up front, when the
target is going to be discovered. And I think therein we can
achieve some balance and savings by simply getting smarter
about which ones are going to go forward from the very
beginning, based on a strong genetic rationale.
And then I'll just bring up one other point that I think I
haven't heard yet, and I think this cooperation between
academia, the FDA, and industry, a coordination of that could
certainly benefit from.
And that is that when you're talking about genetic
therapies, and you're talking about therapies that are going to
go into specific populations; those populations, believe it or
not, become a commodity. Pretty soon you have a very limited
number of patients who are eligible for an EGF receptor trial,
or an APC colon cancer trial.
And I'll just give you a specific example, is that we were
interested in testing a new drug for a specific genetic form of
colon cancer several years ago, only to learn that virtually
every person diagnosed with this genetic mutation in the
country was already on another trial for a drug that was not
targeted for that specific genetic mutation in the first place.
PREPARED STATEMENT
So I would just bring up that one of the things that we
need to think about in order to achieve this is to change the
paradigm and say, look, we can't be running trials for drugs
that aren't tailored toward the genetic defect if there are
trials that could be run that are.
And so I just will conclude again and say thank you for the
opportunity. And we look forward to hearing more.
[The statement follows:]
Prepared Statement of David A. Jones, Ph.D.
Good morning. I would like to first thank Senator Bennett for
inviting me to participate in this discussion of the Critical Path
Initiative and the potential for improving the process of delivering
innovative new therapies to the American public.
The University of Utah stands on a rich history of scientific
research aimed at defining the genetic causes of human disease. In
continuing this tradition, research at the Huntsman Cancer Institute
aims to enhance our knowledge of the genetic basis underlying cancer
development. Our goal is to apply this knowledge to improve cancer
diagnosis and treatment. The broad research community has made
remarkable progress in defining the genetic causes of cancer and the
medical community is now within reach of transforming new discoveries
into new therapies. Indeed, we have heard of examples today that
exemplify the promise of this approach. The Huntsman Cancer Institute
is committed to improving patient care by tailoring therapeutics that
serve to correct or exploit the specific underlying causes of cancer.
In this regard, genetic research in a number of our laboratories has
defined promising new targets for drug development and we are currently
working to identify novel agents that will affect these specific
processes. We believe this approach will improve treatments, maximize
safety and reduce costs.
Realization of the benefits offered by personalized medicine
research is not without challenge. Success in these efforts will
require new initiatives aimed at streamlining the drug testing and
approval processes. The Huntsman Cancer Institute applauds the goals of
the Food and Drug Administration's Critical Path Initiative, which
seeks to ``stimulate and facilitate a national effort to modernize the
scientific process through which a potential human drug, biological
product, or medical device is transformed from a discovery or ``proof
of concept'' into a medical product.'' We believe that the promise of
personalized medicine can benefit from a new level of cooperation
between academia, industry and the FDA. For example, coordinated
efforts between those identifying new opportunities, those developing
innovative therapeutics and those engaged in definition of patient
populations and clinical trial design could help to ensure rigorous
scrutiny and focused application of emerging therapies. We believe this
type of coordinated effort can be facilitated by a strengthened
dialogue between the private and public sector.
The Huntsman Cancer Institute is committed to forwarding the cause
of cancer research and treatment. We are eager to engage in any
activities that will make the process of medical product approval
``faster, safer, smarter''.
Senator Bennett. Thank you very much. We've got about half
an hour now to interact with each other. Let me kick off with
one question that occurred to me in your testimony, Dr.
Woosley. You say 3 to 4 percent of the drugs are being
withdrawn. They got through the approval process. They
obviously had some significant benefit. And then they got
withdrawn.
And my question is, could the drugs still be available with
the benefit if, by virtue of what we're talking about here with
Critical Path, you say, okay, we now know not to give the drug
to X, Y, and Z, but they still should be available for A
through W?
Dr. Woosley. Absolutely. That is absolutely right, Senator.
That is the goal. The goal is not to take the drugs off the
market. Because we know they can help people. The goal would be
to know enough about the problem early enough to find out how
to deal with the problem.
And there are genetic tests today that could predict, we
believe, most of the drug toxicities that are out there, but
they haven't been validated yet. And there are a lot of
consortia biomarker groups around the country working to do
that. But we don't have the standards set yet.
So the Critical Path is all about setting the standards for
how those biomarkers, how--if we--for example, we know that
Vioxx----
Senator Bennett. Vioxx is a poster child for this.
Dr. Woosley. Exactly.
Senator Bennett. A lot of people benefitted from Vioxx.
Dr. Woosley. A lot of people still need Vioxx. And it would
be great to be able to make it available to them. About 6
percent of people don't metabolize Vioxx and most of the other
drugs like it. They don't burn it up. They've got higher blood
levels. And they're probably the ones at risk for toxicity. But
we haven't proven that.
If we could go--and we know that this is a genetic norm--
it's not an abnormality. Six percent of normal people just
don't burn up, don't metabolize Vioxx. We could today, the
genetic test is marketed and approved by the FDA today, but the
insurance companies don't pay for it because they haven't gone
to the next step to show that Vioxx patients with that genetic
abnormality should never get the drug.
So yes, the problem as I see it is we look for toxicity too
late. We need to have an active surveillance system that the
agency is working on right now. They've been having meetings
and learning how to do active surveillance, because it's not
being done anywhere else in the world right. But that's what we
need. To be able to find these problems early enough and then
deal with them.
Senator Bennett. Dr. von Eschenbach, do you have a method
in the FDA whereby you could put Vioxx back on the market?
Dr. von Eschenbach. Exactly in line with what Dr. Woosley
was alluding to, Mr. Chairman. If we can define the exact right
population for whom that drug is appropriate, we could provide
that drug on the market with those specific labelling
indications for that use and that use only.
Senator Bennett. And Dr. Prestwich, could you figure out a
test that people could go through? Or is this more easily
solved than the kind of human test you're talking about?
Dr. Prestwich. No. As with, as with what Dr. Anderson was
talking about, they're actually testing for--not so much for
the gene, but they're testing for the activity of the enzyme.
So it's the gene product, it's the phenotype.
And so both phenotypic and gene--both protein and gene
tests could be done. And I think the combination of the two is
what I would be moving towards to suggest.
Senator Bennett. Have at each other now. I've exhausted my
capacity to sound intelligent on this issue.
Dr. Woosley. Well, I was fascinated by Dr. Prestwich's
techniques that he's developing. I think that they're
absolutely what we need. We need to be able to bring together
engineers. I think that one of the real problems of the
pharmaceutical industry for many years is it's been too
isolated, and they've not brought in the other technologies
like engineering and tissue engineering.
We've been looking at rats and mice by themselves, and
being able to look at human tissue allows us to look at these
differences. And as he pointed out, it's not just human tissue,
it's the person's tissue. And that's challenging.
And, and I guess I would ask Dr. von Eschenbach, is the
agency ready to accept new methodologies that bring in
engineering and bring in tissues from an individual? I mean,
they're used to looking at mean populations. I think I know the
answer to this.
Dr. von Eschenbach. Well, the answer is no. We're not
prepared for this new future and this new reality. And part of
what I have been so appreciative of is the support that we have
received from the committee in being able to address the kind
of investment that will be required to modernize the FDA and
modernize its regulatory processes.
It is a broad, comprehensive effort that will bring these
new tools of science and technology into the regulatory
process. It is beyond just the issue of genomics. It involves
proteomics and ultimately metabolomics, or how people
metabolize these various drugs.
And we are taking a full life cycle approach. Traditionally
one might think of the FDA as a place where someone brought an
application for a drug, we made an analysis and a decision,
that drug went out into the market, and then we waited to hear
something about it.
We now are going to be engaged in the full life cycle.
Proactively engaged in the development of those drugs so we get
it right at the beginning. The best way to provide something
for a patient is to build the quality in on the front end. Use
these tools to not just determine whether the drug is going to
be effective when it gets into Mrs. Jones, but whether it's
also going to be safe when it gets into Mrs. Jones.
That needs to be done on the front end. We need to have the
processes that also enable us to stay engaged even after that
drug goes out into a large population. Because we'll never be
able to know everything that we need to know in the context of
a clinical trial. Which is just a selection or a subset that we
hope reflects the large population, but it rarely ever does.
And we now, because modern tools of science and technology,
information technologies, are available today that weren't even
available 10 years ago, we now have the ability to start
staying engaged after market, in active surveillance. To be
getting signals, not when someone actually has a heart attack
from a particular drug, but when they actually start showing
metabolic or biochemical changes in markers that would predict,
if they continue on, that will be a problem.
And that will enable the FDA to provide for the American
people a system that protects and promotes their health by
being engaged in getting them the products. And enable them to
use those products, whether it's a drug, or a vaccine, or
whatever.
Dr. Woosley. Could I ask the Commissioner to elaborate a
little bit? I've heard him talk before. And as I was listening
to Dr. Prestwich, you know, he's going to bring in your door a
tissue. And he's going to ask, Which door do I go in? Do I go
in biologics, or do I go in devices, or do I go in the drug
door?
And I know you've talked a lot about and I was really
impressed with the concept of the laptop. Do you remember that
conversation?
Dr. von Eschenbach. Well, I think what this new era is
defining for us, Senator Bennett, is that what patients need
and what they want are not drugs or biologics. What they want
is a solution to their problem. And invariably a solution will
require a combination or an integration of things.
If we look at somebody that has hair of my color, we don't
take one drug every day. We take lots of drugs every day. Some
for our cholesterol, some for our blood pressure, whatever. The
point is that solutions will involve an integration of these
drugs, biologics, and devices.
And that's going to require a transformation in terms of
how does FDA make regulatory decisions when someone brings us a
solution which is perhaps a product that is a combination of a
drug or biologic device.
And you and I have had private conversations about the
importance of addressing this, even as we see on the horizon
the benefits of progress that's being made in a field like
nanotechnology. That it's going to be bringing to us entirely
new realities that FDA has not had to address previously.
The industries and others are going to have to come
together, much like the computer industry did, in realizing
that there will always be drug companies and vaccine
development companies. Just as there are always companies that
make hard drives, and CD-ROMs, and microprocessors. But what
the patient wants is a laptop. Or what the consumer wants is a
laptop.
And how they put those parts and pieces together in a way
that shared intellectual property that allows for
interoperability is a challenge that we're going to have to
work through with the industry as they come together to share
and integrate their parts and pieces. Not only the products but
the, but the data, the knowledge about these products.
Dr. Woosley has been leading an initiative to help drive
this, where pharmaceutical companies are coming together and
they are actually sharing data that they have in their
possession about their various products as it relates to their
toxicities or their side effects.
And so that they can learn from each other, and not
inadvertently go down a road to create something that would
wind up being catastrophic and somebody else already knew that.
And we can cut that off. That's part of the leadership that I
think that FDA has to provide.
Senator Bennett. You talk about the laptop. Let me give you
an aphorism that comes out of the business school. We've got
one businessman there. But this is one of the first things you
have to learn in business. Nobody wants a quarter-inch drill.
What he wants is quarter-inch holes.
And that is exactly the basic concept here. Nobody wants a
quarter-inch drill. What they want is quarter-inch holes.
Nobody wants a television set. What they want is the Jazz game,
and the ``Super Bowl'', and ``Seinfeld'', and ``MASH'', and
whatever else.
So a lot of people spend all of their time working on
quarter-inch drills. And then somebody else comes along and
says, ``I can give you a quarter-inch hole cheaper, better, and
cleaner.''
And they say, ``Well, what's wrong with my drill?''
``Nothing is wrong your drill. I don't want a drill. I want
a quarter-inch hole.''
Okay. Any other back and forth? Yes, sir.
Dr. Anderson. Well, I don't know if this is the right group
to bring it up to, but I had a little experience in industry.
And one thing industry wants to do is give the same drug in the
same dose to everybody and have them take it every day.
Senator Bennett. Yes.
Dr. Anderson. And so at least when I was there, there was
some resistance----
Senator Bennett. There's an industry that did that, and
it's called the tobacco industry.
Dr. Anderson. How can we involve industry more fully? What
will they see in this new era of genetics? Now, I think one
answer might be that maybe they can keep their Vioxx on the
market if they can get rid of safety. But there must be a
balancing act that we can encourage them to go along with us in
this new initiative.
Dr. Woosley. One of the aspects of that, just quickly add,
is the compensation today. We pay for drugs. We pay a lot for
drugs. But we don't pay for the diagnostics yet. So I know CMS
is very much interested in personalized medicine. And we've got
to find a way to reimburse for the diagnostic. And I think
that, that will help a lot.
Dr. von Eschenbach. The other thing I would comment on that
regard is that the other lesson to be learned as far as this
new future that I've been describing is this fact that they're
going to have to rethink market share. One would consider
developing a drug for lung cancer because there are a lot of
lung cancer patients around, for example. And they're looking
for a blockbuster. A drug that's going to be the be all and end
all.
But the fact of the matter is, that one of the most
important drugs that was developed for cancer based on an
understanding of mechanisms, the fact that in order for a tumor
to grow it had to have blood supply, and so one drug was
developed to block the development of those blood vessels to
feed the tumor.
That drug, those angiogenesis inhibitors, actually are
having your greatest impact on wet macular degeneration of the
eye. Totally, completely different disease, but same mechanism.
Same molecular mechanism. So now you have a drug that actually
is going to be able to capture parts and pieces of a variety of
diseases.
We're seeing that even in some of the cancer drugs. I
alluded to the poster child for chronic myelogenous leukemia.
Turns out that that drug has dramatic effects in a tumor you
wouldn't have even imagined would be like a leukemia; a sarcoma
of the stomach.
And so we're going to see different kinds of models. And
there are going to have to be different ways of the companies
rethinking their development strategies along lines of
mechanisms, not along the lines of anatomic expression of the
disease.
Dr. Jones. So, since I am one of the people that had big
pharma experience, it is exactly this blockbuster mentality
that we needed one drug to cure all cancers that got me to
leave the industry and come here.
Because the first question that I was always asked when
proposing a new scientific project was, What is the market
share of this drug if you're able to, to do it? And if the
answer is, Well, I can treat 10 percent of the patients, the
answer--the response was, Next. Right? And who's got another
idea.
And so I think what they really are going to need is to see
some successes. What they see out there are drugs like
antihypertensives and other drugs that are prescribed widely
and generating a lot of money. This promise of these targeted
therapies really being profitable for pharmas is really just a
promise right now.
And I think that examples that come through ought to start
to change their attitude and say, look, I can live with 10
drugs that are effective in 10 different ways rather than one
that I need to treat all of them with. And so I think it's just
time in one level, but they will need some coaxing. And
hopefully we can help facilitate that.
Dr. Woosley. I think the industry people tell me now that
they have come to realize that, for example a company that
markets a drug for lung cancer where it only works in 10
percent of the people. They've gotten FDA approval, but they
can't get doctors to use it when they know that 9 out of 10
won't respond. So they're running into this. And they're now
actually ready to sit down and talk about a diagnostic.
Dr. Prestwich. So I just wanted to echo what Dr. Jones said
with the blockbuster mentality. And if we have a faster, safer
way to unplug the pipeline at the upstream end, then the
economics will not dictate that you have to go for a
blockbuster.
And the importance of that is that you can now start going
after not only lesser, smaller populations, but other targets.
There are 100--I think there are 220 or 240, I forget the
number, of compounds currently in use for treating diseases.
And they target less than 5 percent of all the potential
drugable pathways that could be used to ameliorate or cure a
given disease.
So by opening up, by unplugging the pipeline and making it,
you know, a $100 million to get a drug through the clinical
trial process and approval process, that all of a sudden gets
rid of the blockbuster mentality. You've got a lot more
targets. A lot more drugs.
And now you are able to do a personalized medicine because
you have a much bigger palette of colors. It's not, it's not
like you've got red, white, blue, and green anymore. You've
got, like they say on the computer screen, millions of colors.
That's really what we need.
Dr. Woosley. Could I put a plug in for the FDA's budget,
though? Because for that to happen the industry has to know
that there's a path at the FDA that they can follow. The FDA
put out a guidance on drug diagnostic co-development almost 2
years ago. It's still a draft guidance. They haven't had the
staff to address that.
You know, it's part of the Critical Path Initiative and I
compliment the Commissioner for all they're doing, but I think
he can't tell you how understaffed and under resourced they are
at the agency. But I talked to these people when I was at
Georgetown. I helped train most of them. And I know that they
are good people trying to do a good job under horrible
circumstances.
You know, the FDA is in Montgomery County, Maryland. The
school board budget for Montgomery County, Maryland is bigger
than the FDA's budget.
Senator Bennett. But the school board doesn't have to go
through OMB.
All right. You're not going to complain about their
request?
Dr. von Eschenbach. No, sir. But I wondered if there were
other questions that people had that related to this idea of
the Critical Path. Because one of the things that I have found
in discussing Critical Path is how easy it is for people to be
confused about what it actually means.
And I think it's been expressed here today in a variety of
ways. But at the heart of it is the fact that, as Ray has just
pointed out, there is enormous opportunity for us to bring to
health care an entirely new way of providing solutions to
patients for the diseases that plague them.
It will also help us to bring in this whole area of
diagnostics integrated with the therapeutics. And we're even
coining new terms like ``theranostics,'' and the idea that
we'll have the ability for patients to have a tool that will
enable us to understand the disease process and the person with
that disease process that's coupled with the intervention.
And that is opening up another important area that FDA has
to address. We have not embarked upon the regulatory process
around diagnostics and the integration of those diagnostics
with therapeutics. We've tended to think in terms of drugs, and
biologics, and devices. And now we're thinking in terms of
these new platforms of diagnostics. Whether they're genomic, or
proteomic, or other technologies that are going to emerge.
And it adds to Dr. Woosley's point that for FDA to be
responsive to this new reality of these new challenges and
these new opportunities it will need to be a different FDA than
in the past. And I really appreciate this opportunity to help
try to explain a small portion of that at this very important
hearing.
Senator Bennett. Let's get into science fiction for just a
minute. As I listen to this, right now when a baby is born you
can determine blood type. And that's important. And when I'm in
the Army they put a dog tag around my neck that has my blood
type on it. And there's no stigma attached to the fact that I'm
A, and you're B, and he's O, and whatever. Indeed, it's
important information.
Suppose, Dr. Prestwich, you take an 18-month old child in,
take some tissue and hand the parents, 2 weeks later, a
profile. The child will carry that profile through his or her
whole life. Becomes part of the medical history. Goes in for
checkups, whatever. We need to worry, when you're a teenager
you might have an onset of diabetes. Can we do some things to
worry about that? You have a predisposition to breast cancer.
You--so on and so forth.
Purely science fiction, purely down the road, but react to
that. How, how possible is that at some point in the future?
Dr. Prestwich. It's not really science fiction. We have, we
have essentially the capabilities of doing all of that now.
Getting information is easy. Knowing what to do with the
information and having something to do it with is the problem.
And so we're doing so many prenatal and post--and
immediately--postnatal tests already. There are some perfectly
good examples of phenylketonuria, PKU. You can diagnose that
very early during pregnancy. And still the only thing that we
can do when the kid is born is change the child's diet. There's
nothing else that we can do for a PKU kid except make sure that
the kid gets the right diet.
So it's not the information. We've got way too much
information, in fact. And way too few tools with which to act
on the information. And derth of reimbursement mechanisms to
pay for many--those that are too expensive don't get paid for.
Senator Bennett. Now, I object to your statement ``We have
way too much information.'' You don't have it properly
organized.
Dr. Prestwich. Yes. We have lots of information.
Senator Bennett. That's our fault.
Dr. Prestwich. Yes.
Senator Bennett. That's the kind of thing we need to work
on. But a child goes to school, and we have programs whereby
everybody--at least according to the law, has to have an
inoculation. We've stamped out smallpox. We've stamped out
polio.
The kinds of things that I used to experience as a child
are just medieval to my children and grandchildren. Like when I
describe the Public Health Service coming by and putting a sign
on our house that says ``Quarantined'' and nobody can go in and
out.
That's was just great, because one of my brothers or
sisters would get chickenpox and none of the rest of us had to
go to school for 2 weeks or whatever until that sign came down.
Dr. Prestwich. Yes.
Senator Bennett. Could we get to the point where as a child
goes to school, in addition to all of the inoculations and
shots, he gets this kind of profile that becomes his. And then
from that information, as further research is done later on
some physician will say, ``Let me see your profile. We can do
this''?
Dr. Prestwich. So that is science fiction. It would be very
nice well, science fiction is science fact of the future.
Senator Bennett. In other words, it is scientifically
possible----
Dr. Prestwich. Yes.
Senator Bennett [continuing]. But financially and
administratively right now?
Dr. Prestwich. Precisely. So what you are describing is
what we were able to do with infectious diseases in the past.
Now, to be able to do that with genetic disorders is a taller
order, and I think that's what we're talking about now.
Senator Bennett. Yes.
Dr. von Eschenbach. I just want to add one other dimension
to this. In ``FDA'' that first word is ``food.'' And just to
limit it to the issue of nutrition and, as you are describing,
the ability to understand an individual even from the time of
birth and through childhood and what to do during that period
of time.
One of the very important opportunities that will emerge
out of this new era of molecular medicine, if you will, is our
better understanding of the role of nutrition. Because, in
fact, the most significant biologic response modifier we put in
our mouth every day is not the drug we take, it's the food we
eat.
And over a period of time we do not understand nutrition
from a molecular perspective as well. And yet we are able to
start to do that in ways that we can begin to tailor, for
individuals, things that they should be doing even as it
relates to the role of nutrition as a way of ensuring,
preserving, and enhancing health later on in their life.
And I think even, from the point of your colon cancer, we
understand that fiber, soluble fiber, may be beneficial for
colon polyps. But in fact it does depend upon what your genetic
polymorphism is for some of those colon polyps, because in
certain circumstances soluble fiber may actually be worse
rather than better.
So personalized nutrition as well as personalized medicine
is perhaps more science fiction today than some of the things
we've been talking about, but I think will follow on very
rapidly, Mr. Chairman, as an important part of what we will do
with that child when we fully understand what that child's
potential is in the future.
Senator Bennett. Yes.
Dr. Anderson. Just to add on, from a cardiovascular point
of view one of our concerns is though we've made progress over
the last 50 years in reducing, decade by decade, the risk of
cardiovascular disease, we're now worried it's going to start
going back up again because we're getting fatter as a Nation.
And that leads to more diabetes, high cholesterol, high
blood pressure, sleep apnea, just a host of syndromes. And one
of the problems is we need to solve this thing about the
balance between nutrition and activity. And it's not just
everybody that's getting fatter, but particularly a certain
subgroup that seems to be prone to it. As you say, that's
involved with genetics.
I've noticed, interestingly enough, just recently a gene,
the FTO gene that's been identified as if you have this gene in
two--a double dose, that you weigh 8 pounds more. That doesn't
sounds like a lot, but if you add a few of those genes together
that all adds up.
And so that could well be part of this as well. Not only
the drugs we take, as you say, but what kind of diet you should
be on, and how much exercise you need, and--begin a training
program early in life.
Senator Bennett. Okay. Any last words? We're getting close
to the witching hour, but if you have some really important gem
you want to share with us, please go ahead.
All of your written statements will be included in the
record. And we will keep the record open for a week or so if
you have some absolute brain flash that you say, ``I wish I had
said that,'' you can submit it to us in writing and we will
include it in the record.
CONCLUSION OF HEARING
Senator Bennett. Dr. von Eschenbach, thank you for coming
to Utah. I think you see that we have reason for you to come
here. And thank you to the panel that has been assembled.
Again, my thanks to Senator Kohl, the chairman of the
subcommittee, who has approved this field hearing and made it
possible for us to come. The subcommittee is recessed.
[Whereupon, at 11 o'clock, Friday, June 1, the hearing was
concluded, and the subcommittee was recessed, to reconvene
subject to the call of the Chair.]
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