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[Senate Hearing 110-293]
[From the U.S. Government Publishing Office]

                                                        S. Hrg. 110-293
 
        FOOD AND DRUG ADMINISTRATION'S CRITICAL PATH INITIATIVE 

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

                                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

                               __________

         Printed for the use of the Committee on Appropriations

  Available via the World Wide Web: http://www.gpoaccess.gov/congress/
                               index.html

                               __________

                     U.S. GOVERNMENT PRINTING OFFICE

38-553 PDF                 WASHINGTON DC:  2008
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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
                                 ------                                

     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

                              ----------                              
                                                                   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

                              ----------                              

                          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\
---------------------------------------------------------------------------
    \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.
---------------------------------------------------------------------------
    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 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.
---------------------------------------------------------------------------
    \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.
---------------------------------------------------------------------------
    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.
---------------------------------------------------------------------------
    \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.
---------------------------------------------------------------------------
    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.
---------------------------------------------------------------------------
    \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.
---------------------------------------------------------------------------
    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.
---------------------------------------------------------------------------
    \14\ Roden DM, Brown NJ. Pre-prescription genotyping: not yet ready 
for prime time but getting there. Circulation 2001;103:1608-10.
---------------------------------------------------------------------------
    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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