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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 
(II) 

COMMITTEE ON APPROPRIATIONS 

ROBERT C. BYRD, West Virginia, Chairman 

DANIEL K. INOUYE, Hawaii 

PATRICK J. LEAHY, Vermont 

TOM HARKIN, Iowa 

BARBARA A. MIKULSKI, Maryland 

HERB KOHL, Wisconsin 

PATTY MURRAY, Washington 

BYRON L. DORGAN, North Dakota 

DIANNE FEINSTEIN, California 

RICHARD J. DURBIN, Illinois 

TIM JOHNSON, South Dakota 

MARY L. LANDRIEU, Louisiana 

JACK REED, Rhode Island 

FRANK R. LAUTENBERG, New Jersey 

BEN NELSON, Nebraska 

THAD COCHRAN, Mississippi 

TED STEVENS, Alaska 

ARLEN SPECTER, Pennsylvania 

PETE V. DOMENICI, New Mexico 

CHRISTOPHER S. BOND, Missouri 

MITCH MCCONNELL, Kentucky 

RICHARD C. SHELBY, Alabama 

JUDD GREGG, New Hampshire 

ROBERT F. BENNETT, Utah 

LARRY CRAIG, Idaho 

KAY BAILEY HUTCHISON, Texas 

SAM BROWNBACK, Kansas 

WAYNE ALLARD, Colorado 

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 

BYRON L. DORGAN, North Dakota 

DIANNE FEINSTEIN, California 

RICHARD J. DURBIN, Illinois 

TIM JOHNSON, South Dakota 

BEN NELSON, Nebraska 

JACK REED, Rhode Island 

ROBERT C. BYRD, West Virginia 

(ex officio) 

ROBERT F. BENNETT, Utah 

THAD COCHRAN, Mississippi 

ARLEN SPECTER, Pennsylvania 

CHRISTOPHER S. BOND, Missouri 

MITCH MCCONNELL, Kentucky 

LARRY CRAIG, Idaho 

SAM BROWNBACK, Kansas 

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
(III) 

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 

(1) 

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 cliche ́s, 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 
2 

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 
3 

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 
4 

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. 
5 

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 
6 

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 
7 

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. 
8 

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 evidencebased 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 
9 

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. 
10 

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 
11 

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 
12 

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. 
13 

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? 
14 

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. 
15 

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. 
16 

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. 
17 

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 
18 

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 
19 

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 CPath 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. 
20 

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 
21 

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. 
22 

1Lander 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. 3Guttmacher AE, Collins FS. Genomic medicine—a primer. N Engl J Med 2002;347:1512–20. 

4Thom T, Haase N, Rosamund W, et-al. Heart disease and stroke statistics—2006 update: A 

report from the American Heart Association Statistics Committee and the Stroke Statistics Subcommittee. Circulation 2006;113:85–151. 

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

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 clin-
23 

5Williams RR, Hunt SC, Heiss G, et-al. Usefulness of cardiovascular family history data for 

population-based preventive medicine and medical research (the Health Family Tree Study and 

the NHLBI Family Heart Study). Am J Cardiol 2001;87:129–35. 6 Hopkins PN, Hunt SC, Wu LL. Family history and genetic factors. In: Wong ND, Black HR, 

Gardin JM, eds. Preventive cardiology, a practical approach. New York: McGraw-Hill; 2005:92– 

148. 7 Anderson JL, Carlquist JF, Horne BD, Muhlestein JB. Cardiovascular pharmacogenomics: 

current status, future prospects. J Cardiovasc Pharmacol Therapeut 2003;8:71–83. 

ical sequel, myocardial infarction, represent the major contributors. The importance 

of family history was emphasized in a large University of Utah database study, 

which found a positive family history of CAD (onset in first degree relative at age 

<55 in men, <65 in women) in only 14 percent of the general population, but 48 percent among those with CAD and 72 percent (almost three-quarters) of those with 

premature onset of disease.5 Twin studies and other family history evidence suggest 

that heredity and environment contribute approximately equally to CAD disease etiology. The genetic contribution to CAD is believed to be multigenic and complex.6

It has been said ‘‘genetics loads the gun, and environment pulls the trigger’’. Genetics not only determine disease susceptibility but also the response to the diet, 

environmental pollutants, and medications, ever increasing in number, used to prevent and treat disease. Given the complexity and slow progress in determining genetic susceptibility to CVD, pharmacogenomics, the application of genetics to the optimal use of pharmaceuticals, can lead to the way in the application of genetics to 

prevention and treatment of CVD.7

Insights from a Personal Journey through the Healthcare System.—My personal 

journey through medicine has included many stops along the way after medical 

school, including residency training in internal medicine and speciality training in 

cardiology, bench research at the National Institutes of Health, with an appointment in the Public Health Service, many years in the practice of cardiology, volunteer service for the FDA on its Cardiorenal Advisory panel, which I also chaired, 

and even a brief adventure in industry as Executive Director of Cardiovascular Clinical Research for an international pharmaceutical company, as a Cardiology Division 

Director, and, as a practicing cardiologist seeing patients. For 28 of the past 30 

years, I have particularly enjoyed the varied experience of academic cardiology, including teaching, clinical and translational research, and, importantly, serving my 

patients as their physician and cardiologist. This varied experience has brought me 

an appreciation of the wonderful potential of modern medicine but also pointed out 

its challenges and deficiencies. 

One of these challenges is that our treatments are geared to the crowd, whereas 

I deal only with unique individuals. I am on call 24 hours a day for my own patients 

and cross-cover for my academic partner, Dr. Brent Muhlestein, and share Wednesday call with colleague, Dr. Robert Fowles, for the large Utah Heart Clinic and the 

cardiology needs of the LDS Hospital Emergency Ward. When paged to the LDS 

Hospital laboratory for a ‘‘critical value’’ when on call, I can anticipate that an ‘‘outof-range’’ value for the common blood thinner ‘‘warfarin’’ (or Coumadin®) is often 

the reason, putting that patient at high risk for a bleeding event. Rare to more common side effects of other drugs, again which occur in individuals, is a daily challenge. Individualizing selection and dosing of medications to individual patients, 

based on genetics, is a prime opportunity for better medicine for the future. 

Pharmacogenomics: Its Bright Promise for Now and the Future.—Currently, all 

patients are treated with the same drugs and doses, yet safety and efficacy vary depending on genetic background. The promise of pharmacogenomics is to customize 

therapy by determining in advance who will be responders to usual dosage (e.g., ≈60 

percent of a patient group), responders at higher dosage (e.g., ≈10 percent), responders at lower dosage (e.g., ≈15 percent), non-responders (who need alternative therapy, e.g., ≈10 percent), and those at adverse risk (idiosyncratic or toxic, e.g., ≈5 percent).7 Pharmacogenetic applications represent a very promising first major venture 

into the application of genetics to personalized medicine, and a golden opportunity 

for efficient use of resource and research efforts today. 

Pharmacogenetic-Guided Dosing of Warfarin: Applying Genomics to Medicine 

Today.—A prime target for the initial application of pharmacogenetics to broad application in CV medicine is the orally active anticoagulant warfarin. Warfarin is prescribed to over 2 million patients in the United States for prevention of clotting disorders (‘‘thromboembolic disease’’) associated with such conditions as atrial fibrillation, prosthetic heart valves, orthopedic surgery (e.g., knee or hip replacement), venous thrombosis, and pulmonary embolism. 

Unfortunately, warfarin has a narrow therapeutic index, and clinical management 

is difficult. Recurrent thromboembolism, due to inadequate anticoagulation, and se-
24 

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. 10Oden 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. 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. 12Sconce 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. 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. 

rious bleeding events, due to excessive anticoagulation, are relatively frequent. Substantial inter-patient variability in warfarin metabolism leads to variable (up to 20- 

fold) and unpredictable dosing requirements.8 Oral anticoagulation trials for nonrheumatic atrial fibrillation have determined the optimal range of the blood test, 

prothrombin international normalized ratio (INR), to be 2–3 with ratios <2 increasing thrombotic events and those >4 increasing hemorrhagic events and with a 

marked increase in intracerebral and other serious hemorrhage at INRs >5.9 10

Careful clinical follow-up and frequent blood testing for INR are required to ensure 

effective anticoagulation while avoiding over-anticoagulation and serious bleeding 

events. 

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. 

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. 

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 
25 

14 Roden DM, Brown NJ. Pre-prescription genotyping: not yet ready for prime time but getting 

there. Circulation 2001;103:1608–10. 

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. 

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-can-
26 

cer 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 industrialstrength 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. 
27 

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 
28 

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. 
29 

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. 
30 

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 
31 

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 spe-
32 

cialty, 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. 
33 

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. 
34 

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. 
35 

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? 
36 

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.’’ 
37 

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. 
38 

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. 
39 

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. 
40 

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. 
41 

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. 
42 

[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.] 

Æ