[House Hearing, 107 Congress]
[From the U.S. Government Publishing Office]
COMPASSIONATE USE OF INVESTIGATIONAL NEW DRUGS: IS THE CURRENT PROCESS
EFFECTIVE?
=======================================================================
HEARING
before the
COMMITTEE ON
GOVERNMENT REFORM
HOUSE OF REPRESENTATIVES
ONE HUNDRED SEVENTH CONGRESS
FIRST SESSION
__________
JUNE 20, 2001
__________
Serial No. 107-34
__________
Printed for the use of the Committee on Government Reform
Available via the World Wide Web: http://www.gpo.gov/congress/house
http://www.house.gov/reform
_______
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COMMITTEE ON GOVERNMENT REFORM
DAN BURTON, Indiana, Chairman
BENJAMIN A. GILMAN, New York HENRY A. WAXMAN, California
CONSTANCE A. MORELLA, Maryland TOM LANTOS, California
CHRISTOPHER SHAYS, Connecticut MAJOR R. OWENS, New York
ILEANA ROS-LEHTINEN, Florida EDOLPHUS TOWNS, New York
JOHN M. McHUGH, New York PAUL E. KANJORSKI, Pennsylvania
STEPHEN HORN, California PATSY T. MINK, Hawaii
JOHN L. MICA, Florida CAROLYN B. MALONEY, New York
THOMAS M. DAVIS, Virginia ELEANOR HOLMES NORTON, Washington,
MARK E. SOUDER, Indiana DC
JOE SCARBOROUGH, Florida ELIJAH E. CUMMINGS, Maryland
STEVEN C. LaTOURETTE, Ohio DENNIS J. KUCINICH, Ohio
BOB BARR, Georgia ROD R. BLAGOJEVICH, Illinois
DAN MILLER, Florida DANNY K. DAVIS, Illinois
DOUG OSE, California JOHN F. TIERNEY, Massachusetts
RON LEWIS, Kentucky JIM TURNER, Texas
JO ANN DAVIS, Virginia THOMAS H. ALLEN, Maine
TODD RUSSELL PLATTS, Pennsylvania JANICE D. SCHAKOWSKY, Illinois
DAVE WELDON, Florida WM. LACY CLAY, Missouri
CHRIS CANNON, Utah DIANE E. WATSON, California
ADAM H. PUTNAM, Florida ------ ------
C.L. ``BUTCH'' OTTER, Idaho ------
EDWARD L. SCHROCK, Virginia BERNARD SANDERS, Vermont
JOHN J. DUNCAN, Tennessee (Independent)
Kevin Binger, Staff Director
Daniel R. Moll, Deputy Staff Director
James C. Wilson, Chief Counsel
Robert A. Briggs, Chief Clerk
Phil Schiliro, Minority Staff Director
C O N T E N T S
----------
Page
Hearing held on June 20, 2001.................................... 1
Statement of:
Santino, Fred, Arlington, MA; Frank Burroughs, Arlington, VA;
Doug Baxter, Woodland, CA; Shannon Kellum, Ft. Myers, FL;
and David Barr, New York, NY............................... 30
Temple, Robert J., M.D., Associate Director for Medical
Policy, Center for Drug Evaluation and Research, Food and
Drug Administration, Department of Health and Human
Services; Patricia C. Delaney, Public Health Specialist,
Office of Special Health Issues, Office of International
and Constituent Relations, Office of the Commissioner, Food
and Drug Administration; and Samuel D. Waksal, Ph.D.,
president and chief executive officer, ImClone Systems,
Inc........................................................ 92
Letters, statements, etc., submitted for the record by:
Barr, David, New York, NY, prepared statement of............. 62
Baxter, Doug, Woodland, CA, prepared statement of............ 52
Burroughs, Frank, Arlington, VA, prepared statement of....... 39
Burton, Hon. Dan, a Representative in Congress from the State
of Indiana:
Article from the Boston Globe............................ 83
Information concerning David Baxter...................... 88
Letter dated June 19, 2001............................... 19
Prepared statement of.................................... 22
Prognostic disclosure article............................ 3
Kellum, Shannon, Ft. Myers, FL, prepared statement of........ 58
Santino, Fred, Arlington, MA, prepared statement of.......... 33
Temple, Robert J., M.D., Associate Director for Medical
Policy, Center for Drug Evaluation and Research, Food and
Drug Administration, Department of Health and Human
Services, prepared statement of............................ 97
Waksal, Samuel D., Ph.D., president and chief executive
officer, ImClone Systems, Inc., prepared statement of...... 116
COMPASSIONATE USE OF INVESTIGATIONAL NEW DRUGS: IS THE CURRENT PROCESS
EFFECTIVE?
----------
WEDNESDAY, JUNE 20, 2001
House of Representatives,
Committee on Government Reform,
Washington, DC.
The committee met, pursuant to notice, at 1:14 p.m., in
room 2154, Rayburn House Office Building, Hon. Dan Burton
(chairman of the committee) presiding.
Present: Representatives Burton, Morella, Horn, Ose, Lewis,
Mrs. Jo Ann Davis of Virginia, Platts, Weldon, Duncan, Waxman,
Cummings, Kucinich, and Clay.
Staff present: Daniel R. Moll, deputy staff director; James
C. Wilson, chief counsel; David A. Kass, deputy counsel and
parliamentarian; Mark Corallo, director of communications; S.
Elizabeth Clay, Michael Canty, and John Rowe, professional
staff members; Robin Butler, office manager; Toni Lightle,
legislative assistant; John Sare, deputy chief clerk; Corinne
Zaccagnini, systems administrator; Elizabeth Crane, staff
assistant; Phil Barnett, minority chief counsel; Kate Anderson
and Sarah Despres, minority counsels; Ellen Rayner, minority
chief clerk; and Earley Green, minority assistant clerk.
Mr. Burton. Good afternoon. We will have Members coming and
going throughout the hearing, but I want to go ahead and get
started because we're already a little behind schedule, so you
are going to have to look at my pretty face alone for just a
few minutes, but all of this will be on the record for all of
the Members.
A quorum being present, the Committee on Government Reform
will come to order, and I ask unanimous consent that all 11
Members' and witnesses' written and opening statements be
included in the record. And without objection, so ordered.
And I ask unanimous consent that all articles, exhibits,
and extraneous or tabular material referred to be included in
the record. And without objection, so ordered.
To be told that you or someone that you love has a life-
threatening illness, shakes you and your family to the very
core. The life that you have known is changed forever. Suddenly
you are thrown into a maze of medical tests, doctors'
appointments, and tough decisionmaking. You and your family
become experts in interpreting complex medical jargon and
searching the Internet for treatment options. At times you
think that the bureaucracy of government pales in comparison to
the medical bureaucracy.
This week, a survey published in the ``Annals of Internal
Medicine'' reports that doctors are many times not candid with
their terminally ill patients. In 23 percent of the cases in
the study, doctors would not give patients a time estimate if
asked. In 40 percent of the cases, physicians said they would
knowingly give an inaccurate estimate. Three-fourths of those
physicians said they would paint a more positive picture than
they really believed. Researchers speculated that physicians
were afraid that giving bad news would be making a patient's
condition worse.
[The information referred to follows:]
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Mr. Burton. This is a very touchy issue. Patients should be
told the truth, in a compassionate, and as much as possible, in
a positive way when asked questions about their situation. I
believe that doctors can deliver accurate information with
compassion. I also believe that your doctor should also be your
strongest advocate. He or she should offer information on all
treatment options available--standard treatments, alternative
therapies, and experimental treatments. Unfortunately, this
does not happen. Many times doctors are not aware of the latest
treatment options or do not take the time to be informed. This
is not how our health care system should function.
The decision on what course of action to take should always
be the patient's. If the standard therapies fail, they may seek
access to experimental treatments. Increasingly, individuals
will seek an integrative approach, combining conventional and
complementary therapies in an effort to treat the whole person,
not just the disease or the tumor. A patient's desire to try an
integrated approach should be respected and allowed.
I repeat--the decision on what course of action to take is
the patient's. After given the facts, if someone with a life-
threatening or terminal illness wants to seek treatments that
may offer a cure or a slowdown in the progression of disease,
then Federal agencies and red tape should not stand in their
way.
Today's hearing will focus on compassionate access to
experimental drugs. Science dictates a gradual process of
information gathering that often takes 12 to 15 years from
inception to product approval. When research moves to the point
of human subject involvement, an investigational new drug [IND]
application is submitted to the Food and Drug Administration.
There is careful review of the preliminary safety data and
protocol designed before the trials can move forward, and that
is as it should be.
Clinical trials are carefully designed to collect
information about product safety and efficacy. Access to
experimental treatments through clinical trials is the best
route. However, not all cancer and AIDS patients fit protocol
designs. Their disease may be more advanced, they may be the
wrong age, or have had too many rounds of chemotherapy or
radiation. Whenever feasible, when a patient is not able to
participate in a clinical trial, they should not be excluded
from access if there is some hope that a drug may save or
extend their life.
We are going to hear today from Dr. Robert Temple of the
FDA, that the term the public uses, ``compassionate use,'' is
actually an umbrella term for a myriad of mechanisms available
to provide patients access to drugs outside of clinical trials.
To an individual who needs access to an experimental drug,
they do not really care if it is through a special exemption
IND, a treatment IND, or a single-patient IND. They just want
access to the treatment. They want to live. They want a chance
to live.
In the past few weeks we have seen a media focus on the
plight of individuals who sought access to experimental
treatments. Frank Burroughs' 21-year-old daughter, Abigail,
lost her battle with cancer just 11 days ago. And he has our
sympathy, as does his whole family. He will share their story
of trying to access experimental drugs that Abigail's
oncologist thought would be helpful.
Fred Santino's wife, Ruth-Ann, fought a 2\1/2\ year battle
with colorectal cancer. She withstood numerous surgeries and
chemotherapy treatments, but continued to have progression of
her disease. She sought access to experimental treatments. One
option she sought was C225. This product is being developed by
ImClone Systems, had been shown in phase II studies to be
effective in treating colon cancer with metastases. She was not
able to access the treatment, and she died in May.
And one of the things that concerns me about clinical
trials, which are very, very important, is whether or not
either financial interests or statistical data being gathered
in the clinical trials is the reason that they do not give
people compassionate use of some of these drugs. And if that is
the case, one of the things that I would like to suggest today
is that the clinical trial be walled off completely, so that no
adverse information from a compassionate use be included or
have any impact on the clinical trial. And the reason I say
that is I understand the financial problems a small company
would have to be involved in if this information was put into
the clinical trials. It could destroy the company, it could
cause the clinical trial to be skewed, it could be a real
problem.
But on the other hand, if it is being effective and being
shown to be effective, and that leaks out into the public
domain, as it has in the C225 case, you have people out there
who may be without hope; their doctor may have said, ``You are
going to die'', and they want to have at least a chance to
survive. And so compassionate use of that drug should be
considered for that individual.
And if the other concerns are viable concerns, then the
clinical trial should be walled off and we should find a way to
give hope to the person who's dying and have a chance to get
that treatment.
And I will tell you that in my life, I have known people in
the medical profession, very highly regarded people, people in
our government who were the heads of major agencies that deal
with our health care, who were against using treatments outside
of conventional medicine. And yet when their loved one, their
wife, became terminally ill, they tried everything. They went
out of the country, they did everything, because it is
different when you are talking about the masses of people and
people who are suffering from a disease that is incurable, when
there is a new drug that may save their life, and when it is in
your family, when your wife or your daughter or your son is
terminally ill with a disease and there is no hope except that
long, long bomb that we are talking about, that you might throw
in a football game, with a new drug that might save their life.
And so that is why I think we ought to look at walling off
clinical trials from the compassionate use if that is what is
necessary to give every person every chance to survive.
What these two families learned, the ones I just mentioned,
is that many companies do not have clear guidelines on when
compassionate access is going to be provided. Some companies
such as AstraZeneca have clearly defined programs that are
posted on their Web site. AstraZeneca, one of the largest
pharmaceutical companies in the world, developed an expanded
access protocol for IRESSA, a lung cancer treatment they have
in development. They set this program up with a third party,
the National Organization for Rare Disorders.
ImClone, a relatively small company, had no established
program, and when researchers started talking about their
positive effects, they were overwhelmed with requests, and as a
result, have closed their compassionate access program. And we
understand the problems they are facing. And we are not here to
be judgmental today. We are here to try to find some answers
for people who are terminally ill.
Dr. Waksal, the president of ImClone, will share their
story of the challenges today.
We will also hear from one of the fortunate ones, a lady
named Shannon Kellum. Shannon, at age 28, was diagnosed with
colon cancer. She was the first colon cancer patient to try
C225, through compassionate access. She lucked out because her
physician had done some of the preclinical research on C225 and
was able to use that knowledge to convince ImClone that she
should have access to the treatment.
Doug Baxter's 16-year-old son, David, was recently
diagnosed with colon cancer. He will tell us about their
ongoing struggle to access experimental treatments and save
David's life.
David Barr is living with AIDS. He will share his
perspectives on how the AIDS community worked together to force
the FDA's hand on expanding access to experimental treatments.
How can we improve compassionate access to experimental
drugs? How can we give hope to people? And hope is a very
strong ingredient in survival. How can we give hope to people
who have been told, in effect, that they are terminally ill?
Does the FDA need to allow companies to manufacture a larger
supply of the experimental product during the developmental
process? Is money an issue? Are the reporting requirements on
efficacy data outside clinical trials a barrier? And once
again, that is why I suggested that maybe you wall off the
clinical trial.
There are many people who have had an opinion on this
topic. We received written testimony from the National Breast
Cancer Coalition, and I ask that it be included in the hearing
record. And without objection, so ordered.
[The information referred to follows:]
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Mr. Burton. We will keep the hearing record open until July
6 for those who would like to submit written testimony, and we
will continue seeking input from organizations, manufacturers
and families, about how to improve access to experimental
treatments. Whatever it takes, regulatory or legislative
changes, or better information sharing, we as the Congress
cannot ignore the needs of those with life-threatening
illnesses. And I speak with some personal knowledge of this.
[The prepared statement of Hon. Dan Burton follows:]
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Mr. Burton. I now recognize the ranking minority member,
Mr. Waxman.
Mr. Waxman. Thank you very much, Mr. Chairman, and I want
to thank you for holding this hearing. This is an important
hearing, and I think we have got a record to make and a job to
do.
Today we are going to hear about personal experiences that
no one should ever have to experience. We are going to hear
about people who have fatal cancers and no treatment options
until they hear about a promising treatment in the clinical
trial process. They appeal to the manufacturer for
compassionate use of a drug, and they are denied. They know
that other people are getting the drug on a compassionate use
basis, but they cannot. We will hear about their bravery as
they faced this situation, not giving up and continuing to
fight for access to this treatment until the end.
We will hear from the CEO of a company that makes this new
drug. He will tell us about the promise of this drug and the
progress of the clinical trials. He will tell us that when the
promise of the drug became known, 10,000 people applied to use
the drug under a compassionate use IND. However, this is a
difficult drug to make, and because it is still in the clinical
trial process, and the overwhelming bulk of the drug that was
available needed to go to the clinical trial, the company could
not meet that demand.
We will also hear from people who have had some success in
getting access to drugs that have not yet been approved, and we
will hear different perspectives about what the impediments to
access to drugs in clinical trials are.
Our job today, as Members of Congress, is to understand how
the compassionate use system works and whether there is
anything we can do to improve it. It is important to do this.
Many patients are desperately ill, and they do not have the
time to wait for a drug to make it through the clinical trials
and approval process.
As we will hear today from our witnesses, access to drugs
through compassionate use can save lives, but there are many
limits on this system. One limit is the availability of the
drug in the clinical trial stage. Often companies produce only
limited amounts of an experimental drug. Sometimes that is
because materials are in short supply, sometimes because a
process is difficult, sometimes because they do not want to
invest in a product with an uncertain future.
Then there are the limits of science. If a treatment is
approved after phase II clinical trials, this would usually
increase access to the treatment. In rare instances the data
are so dramatic and the statistics so clear, that this is
possible. For example, Gleevec, a treatment for certain types
of leukemia, was recently approved after phase II trials. And
ImClone is seeking approval of C225 for colorectal cancer after
its phase II trials as well. But in most cases, it is necessary
to conduct the larger-scale phase III trial to understand fully
whether and how well a drug works and what the possible adverse
effects are. It would be unethical to allow companies to market
a drug as a treatment unless and until it has been
appropriately tested for safety and efficacy. This is
especially true in the case of life-saving treatments against
such diseases as cancer and AIDS. So we are left with a very
difficult situation, where there are desperate patients trying
so hard to get limited amounts of potentially life-saving drugs
that are in clinical trials.
This hearing will raise important questions. How do we help
patients get access to drugs that may help them? How do we
assure that drugs are thoroughly tested for safety and
efficacy, and how can companies be encouraged to consider
treatment INDs at the early stages of the clinical trials so
that patients can have access to a treatment as quickly as
possible?
There are no easy answers here, but with the new and
exciting developments in biotechnology, and important
treatments on the horizon, these are the issues we have to
address to make sure that as many people as possible are helped
by these therapies.
I want to thank the witnesses for being here, particularly
people on this first panel who are going to tell us about their
own experiences. Mr. Chairman, I want to thank them all for
being here, and I am looking forward to their testimony.
I do want to explain however, from a personal point of
view, that there is a conflict that I have because of the
California energy crisis. Our Governor's meeting with us at
1:30, so I am going to have to leave to attend that meeting,
but I will get back here as quickly as I can.
We will have your testimony on the record. I will have a
chance to review it. By having it on the record and your being
here today, we can take what you have to say and go to our
colleagues and tell them about any potential legislation or any
other moves that we should be taking to solve the kind of
situation that you have faced and try to make this problem one
that will not be repeated over and over again.
So I want to apologize in advance for not being here for
the whole hearing. I will try to get back as quickly as I can.
But, Mr. Chairman, I want to thank you for this hearing. It is
an important one, and I look forward to working with you on
this very important issue.
Mr. Burton. Thank you, Mr. Waxman. Mrs. Davis, did you have
an opening statement you would like to make?
Mrs. Jo Ann Davis of Virginia. No, thank you, Mr. Chairman.
Mr. Burton. Mr. Kucinich.
Mr. Kucinich. I wanted to thank the Chair for calling this
hearing and welcome the witnesses. Certainly those of you who
have a personal story to tell to this committee, who have
experienced in a very profound and heartfelt way the impact of
policies which have denied loved ones the opportunity to get
help which was believed to be available, certainly have much to
communicate to this Congress. I think that as Mr. Waxman said,
your testimony will help guide the Congress in a direction
which needs to be taken. In order to make sure that the access
which has been denied people in the past can--the question of
access can be resolved. So again, I want to thank the Chair for
his sensitivity to these issues. I appreciate your ongoing
commitment to public health. Thank you.
Mr. Burton. Thank you, Mr. Kucinich. Mr. Cummings.
Mr. Cummings. Thank you very much, Mr. Chairman, for your
sensitivity to these issues. These are very, very important
issues. And we as the Congress of this great country have a
duty, I think, to address them.
The patients and their family members are frequently in
search of information about the latest drugs being researched
for effective treatment, and I represent the district in which
Johns Hopkins is located, and, of course, we just had a major
episode involving one of my constituents who died during the
process of clinical trials. I guess that is how you would
describe it. The people in the audience would know better than
I do. But it shows the problems that we run into. We have to be
very careful about the drugs and how they are used and when
they are used. But on the other hand, we have situations where
people are facing some very difficult circumstances in their
lives, and I would imagine that at times people feel that
perhaps the Federal Government goes too far in these trials.
To be very frank with you, I do not know that we will
answer that question today, exactly where do you draw the line
and where does a balance come? But the fact remains that there
is a woman, a young woman in Baltimore, who was alive not very
long ago, and now she is gone. She was healthy. And now she is
gone.
And so I think this, Mr. Chairman, is an appropriate time
for us to be looking at this issue. I am interested because I
know that there are so many people who find themselves in the
difficult circumstances that some of our witnesses do today, or
their family members have.
And to our witnesses, I want to thank you for being a part
of this hearing. In order for the Congress to do its work, we
have to put a real face on our policy. So often we look at
statistics and we hear numbers, but the real testimony comes
when we are face-to-face with people who have been places where
we have not gone. And so it makes it better for us to formulate
policy when we hear from you. And so we take this moment as a
Congress to thank you for being with us today, and I look
forward to the testimony.
Mr. Burton. Thank you, Mr. Cummings.
Mr. Santino, Mr. Burroughs, Mr. Baxter, Ms. Kellum, and Mr.
Barr, we swear our witnesses, so would you stand and raise your
right hands, please?
[Witnesses sworn.]
Mr. Burton. Be seated. Mr. Santino, would you like to
start? And I know that it is tough to say everything you want
to say in 5 minutes, but if you could get as close to that as
possible, we would appreciate it.
STATEMENTS OF FRED SANTINO, ARLINGTON, MA; FRANK BURROUGHS,
ARLINGTON, VA; DOUG BAXTER, WOODLAND, CA; SHANNON KELLUM, FT.
MYERS, FL; AND DAVID BARR, NEW YORK, NY
Mr. Santino. My name is Fred Santino. I am the husband of
Ruth-Ann Santino, who just passed away May 5th. I have it
boiled down to basically four points here: obtaining
compassionate use, the information provided, the responsibility
of drug manufacturers to communicate with patients, and
manufacturers not being penalized for providing drugs to very
sick people.
As far as the compassionate use, obtaining it, I do not
feel there is any criteria by the government, by the hospitals,
by anybody. I think there should be some criteria. When a new
product is established, part of the business plan ought to be
what criteria am I going to have once we have success? In other
words, they assume they are going to have success at some point
when they make the drug. I assume that they are thinking that
way, so let us have that as part of the business plan and let
us demand it as a government, that we do that. I work for the
government. We have policies. We have rules. We have to live by
them.
Another point is how to find out about compassionate use.
We found it is very difficult. It is not listed on any Web
sites. It is not really clear where you would find out about
it, how you would sign up for it. I happen to run four Web
sites, and I had trouble finding the information. There are so
many Web sites--I put it in my testimony, how many different
Web sites there are. They are not linked. Some of them
disagree. Some of them say trials are open. We were given a
choice of four trials. None of them were listed. I do not know
any of them as far as what manufacturers they were. I could not
find anything about them, what side effects they were, anything
like that. So I would like to see more information, and I would
like to see the information managed somehow. Have one Web site
tie them all together and have some sort of an update. If I am
in the drug business and I am having a trial, I have got to
update what is happening. Has there been serious side effects?
Has there been successes? I would like to know, because a
doctor offers me XQY322, I want to know what it is. I want to
know who makes it, I want to know whether it is successful or
not. I do not want it to be my decision.
The other thing is we were terribly ignored by a company,
ImClone. I understand they were overwhelmed with responses, but
in our case, three of my wife's letters were ignored. We wanted
to know yes or no, can I have the drug? That is all. That is
all we wanted was an answer, yes or no. I would have sent them
the 34 cents to give me a postcard back. That is all I needed,
but we were ignored. My sons wrote letters. I did not get a
letter or anything back until we got a privilege number from
the FDA and my wife was able to call the company, and she got a
call back from a doctor saying that she would not qualify
because she was too sick. Well, that took 3 months to get that
answer, and we had other options. We could have gone to another
drug at Sloane Kettering in the process, but we did not do
that.
So I feel drug companies, if they are in the drug business,
they have a responsibility to communicate with the patient. I
happen to work for the Air Force. We put out an RFP for
businesses, I do not know if 3,000 businesses are going to want
that RFP, but we have to answer every one of them. So if I am
in the drug business, I deal with patients, and those patients
ought to be answered, and it ought to be mandatory. Otherwise,
get out of the business.
My wife was sick. She said, ``I'm a dying mother, and I
want this drug. Can't you tell me yes or no?'' How can you
ignore a dying mother? How can you, Mr. Waksal? I don't
understand how you can do it. My two sons wrote letters and you
ignored them. How can you do that? Just say yes or no. I will
give you 34 cents.
We needed the information to make decisions and we were not
given it in time, so we missed out on other options, and I can
see the drug business. I have a relative in the business, and I
understand their problems, but do not go in the business if you
cannot communicate with people, and you cannot handle the
business the way everybody else does. Go out of business. Let
somebody else take you over.
I do not think you ought to be penalized for giving drugs
to sick people. If my wife is real sick, give her the drug. Do
not say my wife is too sick to have a drug. What is a drug for?
I mean, really. We were told by ImClone that my wife had seven
treatments and that would not qualify her. She was also told
that by another clinical director at a hospital in Boston, that
she could not get another drug, SU5416, she had too many
treatments. But what are the drugs for if they are not for sick
people, I mean, really?
That is pretty much all I have to say, and I think it can
be improved by getting the information together, getting the
people in a room like this. I thank Congressman Burton and the
rest of the members of the committee for having this meeting,
and I really think something ought to be done. And the reason I
am here is I hope it will help other people, and nobody else
has to suffer the way my family did. And I am really going to
stay in this business for good until something does happen, so
if anybody else needs my help, please call on me. I will be
glad to help you.
Thank you.
[The prepared statement of Mr. Santino follows:]
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Mr. Burton. I really, really appreciate you being here
today. I knew about your story beforehand, and we will have
some questions for you, but thank you very much.
Mr. Burroughs.
Mr. Burroughs. Good afternoon, Mr. Chairman and
distinguished members of the committee and guests. I am Frank
Burroughs, but for the past 21 years I have been better known
as the father of Abigail Kathleen Burroughs.
Since February of this year Abigail ran out of options in
her battle against cancer, which had spread to her neck and her
lungs. I and others began to try and find treatment with
experimental EGFR targeted cancer drugs.
We tried to get Abigail into narrowly defined clinical
trials, but she did not qualify for them. We worked very hard
to acquire the drugs on a compassionate-use basis, but got
nowhere.
The drugs that we needed, the EGFR drugs that we needed
were AstraZeneca's IRESSA and ImClone Systems C225, which
statistically, and according to her oncologist, Dr. Maura L.
Gillison at Johns Hopkins, showed a significant chance of
helping her beat her cancer.
My only child, dear, sweet, loving, talented and
compassionate Abigail died at 2:30 p.m. two Saturdays ago, June
9th. The loss of my beautiful compassionate child has left a
hole in my life. Her mother, Kathleen, who took such good care
of her, is of course, also very saddened, as is her dear
stepfather, Gene Krueger.
There was hope, but no compassionate use of AstraZeneca's
IRESSA or ImClone System's C225.
Abigail was compassionate. In her senior year in high
school she won the distinguished Harry F. Byrd, Jr. Award for
Leadership and Community Service for the Eight Virginia
Congressional District. Abigail was an Echols honor student at
the University of Virginia. Abigail cleaned toilets and changed
beds in men's homeless shelters. Abigail worked in a poor
neighborhood in Syracuse, NY, fixing up houses and running a
free day camp for inner city children. Abigail started a major
tutoring program for middle school children who were having
learning problems. And this is the short list. Abigail was
compassionate.
The world has lost a brilliant young woman who would have
done great things.
I am here today because the issue of the wider use of
compassionate use of drugs is a very important issue, because
it touches tens of thousands of lives. Compassionate Abigail
wants us to keep this issue alive, although we could not keep
Abigail alive.
I know this is a money issue. I do not have all the
answers, by the way, but I know it is a money issue, because
some large pharmaceutical companies do have wider
compassionate-use programs than others.
ImClone Systems has no compassionate use program.
Multibillion dollar AstraZeneca has a very narrowly defined
program, and it is very small. And Abigail, young Abigail, did
not qualify for AstraZeneca's compassionate use program.
A very important role of industry and government is to help
people and to save lives. We did not have a chance to get to
save compassionate Abigail.
One idea I am working on I shared with Abigail on Thursday
before she died. She fought till the end. She was a sweetheart.
She was brave. She really liked the idea. Now, it is going to
need some fine tuning. The idea is to set up a foundation or
another vehicle to raise money from private sources, from the
huge pharmaceutical industry, and from the U.S. Government, to
provide money so that we can produce more of these new
promising experimental drugs and have them available on a
compassionate use basis.
From the knowledge I have, there needs to be a clear line
drawn between clinical trials and compassionate use.
I am honored here to be with everybody on this panel, but
Doug Baxter and I have become friends. Recently his 16-year-old
son is fighting a battle with colorectal cancer. He has many
difficulties getting into trials.
Abigail was compassionate. Abigail is now in the arms of
God. Others, with the strength of Abigail's memory, beautiful
memory, and I, will keep this issue alive so others may have a
chance to live, a chance that Abigail, compassionate Abigail,
did not have.
Thank you for inviting me here today, and thank you, dear
Abigail, for giving me the strength to make it here today.
Thank you.
[The prepared statement of Mr. Burroughs follows:]
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Mr. Burton. Thank you very much, Mr. Burroughs. And I
really appreciate you being here, and I feel very sorry that
you had to give this testimony.
Mr. Baxter.
Mr. Baxter. Thank you. Honored Chairman, and committee
members, I appreciate the opportunity to testify to you
regarding our struggle with a pharmaceutical company to obtain
a drug that my son needs.
It has been a difficult journey to get to this point, a
difficult but short journey. In early March of this year, I
took my son to Phoenix for our annual week-long trip to major
league baseball training in Phoenix. We had a wonderful time.
As usual, my son got a lot of autographs. It was a time of
sunshine, joy, fun, normalcy.
The following week, David complained of some back pain, and
the world was turned upside down when he was diagnosed with
colorectal cancer. The doctors said they had never heard of
this in a kid. It only got worse the next week when we found
out that it had spread to his liver and lymph nodes.
He immediately started treatment and is now fighting the
side effects of these treatments. He has had a positive
attitude, but his smile has been few and far between lately as
he struggles through this time.
David has doctors that have been great. We were excited as
treatment began, only to cry as we saw the impact of these
treatments. At times, David sleeps almost all day on the couch,
only to get up when it is absolutely necessary, and to
frequently take the morphine to make the pain bearable. Picture
your child so sick and in such pain, wanting to help him, you
just cry.
Cancer does not kill. It first embarks on a mission of
relentless, relentless torture of hundreds of people, family
members, friends, and strangers, compassionate strangers that
step forward, wanting to help. His entire family suffers as
David struggles. Because a child is hurting, his parents are
consumed by the impacts of this process. We are consumed by
trying to find help for David. Imagine the emotional extremes
that we experienced, hearing David's doctor telling us of a
promising drug that he was treating other patients with, that
he even had that drug in his possession as part of a head and
neck cancer trial. But he could not give it to David, because
he could not give David the drug without the permission of
ImClone Systems, Inc., a permission that ImClone has not yet
allowed. ImClone has previously approved David's doctor to be a
current investigator for this very same drug for neck cancer.
ImClone has approved the facility where this doctor works, the
Sutter Cancer Center in Sacramento. His doctor has provided a
written request to the drug manufacturer requesting that he be
approved as a co-investigator so he can participate in the
colorectal cancer trial also, so my son could gain access to
this.
There has been some discussions about perhaps having my son
go East to participate in the colorectal cancer, where all of
these clinical trials are being conducted on the East Coast
only. But for a 16-year-old son, who has a prognosis of just a
few months, it would be extremely cruel to take my son away
from his family and friends to go back East and live in a hotel
to do a colorectal trial.
For this reason, we would like to have permission for this
cancer trial to be done also out West, where also people out
our way could have access to this drug. We understand that
there is a limited supply, and that this drug is important to
move forward quickly. David's doctor believes that he could
expedite the approvals through their investigational review
board and not slow up the process. I hope that this can be
looked into.
There are a number of possible things that we can consider.
Compassionate use is a very important item, especially where
there is available drug to be able to use that. But where the
drug is in short supply, I think it is also important for the
committee to look at ways of having this drug allowed in other
geographical locations so that children such as mine can have
the opportunity to participate in these clinical trials as
well.
I thank you for the opportunity to speak with you this day,
and I ask that the remainder of my testimony be entered into
the record. Thank you.
[The prepared statement of Mr. Baxter follows:]
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Mr. Burton. Thank you, Mr. Baxter, and I wish you well with
David. Tell him that we understand, and that there is a lot of
people up here thinking about him, and hopefully praying for
him.
Ms. Kellum.
Ms. Kellum. I am here today to share my testimony on how
C225 has enabled me to be here today.
I was originally diagnosed in April 1998 at the age of 28.
I was diagnosed with metastatic Stage IV colon cancer. It had
started in the colon, but had already spread to other parts of
the body. Throughout the next year, until April 1999, I
received all standard therapies, as well as trials that were
currently available that I was eligible for, none of which were
able to even stabilize this disease at all.
In April 1999, there were no other options available. I was
not eligible for surgery, and there was nothing out there that
I qualified for. At that time my doctor introduced the idea of
C225. At the same time he also mentioned that it had never been
used in colon cancer before, and that I would be the first
patient to receive it, but he would have to get approval from
ImClone and go through the necessary process.
Fortunately, that answer was yes, and I started my first
treatment of C225 in late April 1999. After four treatments, I
received over a 50 percent reduction in the tumors, which
nothing else had even phased. I continued to receive C225 over
the next several months, having a total reduction of 80
percent. At that time my tumors became stable, and so I
researched the possibility of surgery, which was necessary in
the liver. That is where the disease was. I was eligible for
liver surgery and had that in January 2000.
I am obviously very fortunate to be here today. It could
very easily be my husband up here representing me and me not
telling my story. If it was not for C225, I would not be here
right now, and there would not be the opportunity for other
people to have received it and for the knowledge that we have
gained through this, and I am here representing all of you, and
we need to get this drug approved, because no one should have
to die.
Thank you for allowing me to share this testimony.
[The prepared statement of Ms. Kellum follows:]
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Mr. Burton. Thank you, Ms. Kellum, and we are very happy
that you are here as well, and you look like you are doing
well.
Mr. Barr.
Mr. Barr. Thank you. My name is David Barr. I would like to
thank you for the opportunity to speak with you today.
Mr. Burton. Could you pull the mic just a little closer,
please? Thank you.
Mr. Barr. I am a person with AIDS, and I am also an
advocate for people with AIDS, and I have been working
specifically on issues regarding treatment access since 1987.
Access to experimental drugs is a particular concern to people
with AIDS, because the disease is so deadly and its death so
painful and humiliating. Most important, when AIDS first
appeared as a new infectious disease in 1981, there were no
standard treatments. All treatment was experimental, and early
access programs were our only way of obtaining treatment. As
research and drug development has progressed, there are now
many treatments for HIV. However, these treatments are not a
cure, they have limited effectiveness and can be too toxic for
many patients to tolerate. And therefore, access to
experimental treatments remains an important concern for people
living with AIDS.
Beginning in 1989, the FDA began to work in earnest with
patient advocates to develop standard for improved access to
experimental drugs under compassionate use mechanisms and for
accelerated approval of drugs to treat life-threatening
illnesses.
Patient advocates are often included now as members or
consultants on drug review panels, and directly involved at
FDA's request in policy-setting discussions. Determining how to
provide access to experimental treatments requires balancing
several considerations. First there is the seriousness of the
condition. In HIV we have patients who are on the verge of
death and patients who will not feel ill at all for many years.
These patients have different needs and need different
solutions.
Second, one needs to consider what standard treatment is
available and the usefulness of that treatment for the patient.
If an approved therapy is available, there is no reason to risk
taking a drug of unknown safety and efficacy.
And, finally, one must consider what is known about the
safety, efficacy and dosing of the new drug. In weighing these
considerations, one must take into account both the individual
needs of a particular patient and the effect of access on a
broader group of patients. An individual patient, faced with
terminal illness, and often living in great fear and
discomfort, may be more willing to risk taking an experimental
treatment with little safety or efficacy data. However, making
those decisions are never easy, and we usually make them with
much less information than we would like to have.
Make no mistake. Although the FDA and drug companies may
have an interest in the data from both studies in anecdotal
use, no one needs this data more than patients. We are the ones
who struggle with these life and death decisions. I would
strongly urge that such data collection be continued, and in
many cases strengthened.
Certainly, any member of the panel, when considering
whether or not to take an experimental drug, would want to know
if previously someone had toxic reactions and what success if
any the drug had offered to other people.
I believe that industry claims that they are reluctant to
participate in early access programs because of data submission
requirements by the FDA are false ones. Such requirements are
usually reasonable, not overly burdensome, and can provide
useful information about the drug.
While the FDA can set standards for approval of early
access programs and can later the proposed protocols under
which experimental drugs can be made available, the agency has
no authority to compel a company or sponsor to provide their
drug to patients. Companies are often reluctant to do so. They
are uncomfortable with any loss of control in the use of an
experimental product. However, that is not FDA's fault.
Prohibiting the FDA from collecting data in these situations
would not likely increase a company's participation in early
access programs. Companies are less concerned with data
collection than they are with control over all the data and
with drug supply. In fact, drug supply, particularly for drugs
in phase II studies, is probably the most important and
difficult obstacle. Patient advocates in HIV and other diseases
have learned the immense value of working with companies as new
drugs are developed. We have tracked the development of all HIV
drugs from a concept to a test tube, through animal studies and
into people, and we begin discussing the needs in terms of
early access programs with companies as soon as phase I studies
begin. And in this way, there is time to negotiate the real
concerns about safety, dosing, patient entry criteria and rug
supply, and it is only through those negotiations that such
programs are a success. Rarely in my discussions with industry
have concerns about the FDA and data collection been raised as
barriers to early access development.
It would be unusual for a company to develop one policy
around when or how to make experimental drugs available. Each
drug needs to be considered independently based on the needs of
patient population, what is known about safety and efficacy,
dosing, and how the drug is manufactured.
I do not want to go over.
Mr. Burton. Take your time. We just try to stay as close to
5 minutes as we can. We are not going to shoot you. [Laughter.]
Mr. Barr. Thanks. Thank you.
Patient advocates will often meet with company
representatives while phase I studies are under way to discuss
when and how an early access program can be created. The sooner
those discussions begin, the better. When companies have
refused to include early access mechanisms in their development
plans, advocates have initiated letter-writing campaigns,
demonstrations, and even boycotts to urge the company to
reconsider. At least in HIV drug development most companies
will bow to such pressure. However, the speed at which these
programs are developed and the scope of who they reach, often
leave much to be desired. Sometimes an early access program
will not begin until an NDA is filed. And this means that the
program will only run for a few months. Another situation is
the entry criteria are so strict that many patients who need
the drug are not eligible. Patient advocates to work with
companies to develop entry criteria that best meet patient
needs. And very often the entry criteria will broaden as the
program gets under way, and in this way, the company can
determine if the demand for the drug will be greater than they
are able to provide.
Again, the FDA has no authority to make these programs
broader or begin earlier. The successes of single patient
programs are more difficult to track because of the individual
nature of the program. A treatment IND will include a protocol
that will provide drug to all patients who meet the entry
criteria, and physicians will enroll patients in the program
and drug are distributed to the patients through the
physicians.
Compassionate use single-patient programs are done on a
case-by-case basis. There is no standard protocol, and that
makes advocacy more difficult. Each individual doctor and
patient must find a way for the company to provide the drug.
Information about drug development in clinical studies is often
available through patient advocacy organizations. And most
important, is the new program from the National Library of
Medicine, that has an online clinical trial directory, listing
all public and private clinical trials in the United States.
The dire needs of one patient should not be used to set
policy that can affect all patients. The difficult act of
balancing the needs of an individual and the needs of many is
fraught with problems. My impression is that the FDA, with
scarce resources, frankly, does a good job at balancing those
concerns. Most important, the idea that data collection is an
obstacle to drug provision is false and harmful to patients.
Data provides us with the only tools that we have in making
extremely difficult life and death decisions.
Thank you.
[The prepared statement of Mr. Barr follows:]
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Mr. Burton. Thank you, Mr. Barr. We will start out
questions. We will proceed under the 5-minute rule so all
Members have a chance. Let me start with you, Mr. Santino, Mr.
Burroughs, and then the others, Mr. Baxter and Ms. Kellum can
respond as well.
Did your wife and your son--your son and your daughter,
start off with traditional chemotherapy treatment?
Mr. Santino. In my case, my wife started with standard
treatment at a community hospital. And we thought everything
was fine, and then 6 months later the cancer came back. She had
to have another surgery. She had initial surgery, radiation and
chemotherapy; 6 months she was free and clear, and then the
cancer came back.
Mr. Burton. But how long after she had her chemotherapy and
radiation?
Mr. Santino. About 6 months it came back again.
Mr. Burton. So was it in her lymph nodes; had it
metastasized?
Mr. Santino. Not really. Initially it had not been, but
then it went to her lymph nodes, and then when we ran out of
options as far as standard treatment. We started looking
around, other hospitals, other cities, other cancer centers,
other whatever, to try to find something because at that point
we were desperate.
Mr. Burton. Then you started running into the wall.
Mr. Santino. Right, exactly.
Mr. Burton. Mr. Burroughs.
Mr. Burroughs. Abigail had a rare type of cancer, that
interestingly enough is starting to show up in young women at a
greater rate almost monthly. It is still not a very common
cancer. It started in her tongue, and it is the kind of cancer
old men get who have been smoking and drinking their whole
lives, very unusual in a young woman who was healthy.
We used surgery. They did not want to use chemotherapy or
radiation because they thought there was no need to, it
actually could cause more harm to her than not. Her cancer
though came back last summer. She had surgery and major
chemotherapy and radiation. It seemed to clear up for a while,
and it came back in February of this year and got progressively
worse. We ran out of other traditional drugs, chemotherapy
drugs did not work for her. So we were down to the last wire,
trying to get a EGFR targeted agent. The frustration was that
these drugs, the kind of cancer she had and the cancer cells
she had, and the high EGFR emissions that the cells gave off
showed a real promise of reacting to these new drugs. It was
very frustrating. It was like there was a lifeboat there, but
we could not get to it.
Mr. Burton. So when did you start trying to get the access
to the----
Mr. Burroughs. We actually started trying to get the access
in February, ahead of time, in case the chemotherapy she was on
failed. And it did. And we continued our efforts. She was under
another protocol, and that failed. And we continued trying to
get these EGFR-targeted agents, which interestingly enough,
showed greater promise for her than what was left on the
conventional cancer shelf that was approved.
Mr. Burton. But you ran into the wall, what, in February,
March, where you could not get any positive response?
Mr. Burroughs. That is correct. We tried to get the drug,
get her into trials. She did not qualify for the trials. The
trials are very narrowly defined both for AstraZenica and
ImClone. You know, prior treatments have an effect. For
instance, AstraZenica's IRESSA, it is only for lung cancer that
started in your lungs. Abigail's was in her lungs and her neck
and elsewhere, but it did not start in her lungs, so she could
not get into their compassionate use program, which, by the
way, is very small. A lot of ImClone's trials, there are a lot
of parameters, what kind of chemo had you had before, when had
you had the chemotherapy, whether you could get into the trial.
Mr. Burton. I understand. Mr. Baxter, is your son on
traditional treatments, chemotherapy?
Mr. Baxter. Yes, he is. David's cancer was quite advanced
when they discovered it, because it is a cancer that you just
do not look for in kids. And it had already metastasized by the
time he was diagnosed, into his liver and lymph nodes. They
started with radiation and 5-FU. That was not effective and
showed continued growth during that time. And he has gone
through some CPT-11 treatment. And what the CEA test levels are
showing is that is still increasing as well.
Mr. Burton. Have you tried to get some experimental drugs
like through ImClone or AstraZenica?
Mr. Baxter. Yes.
Mr. Burton. And what kind of response have----
Mr. Baxter. We and his doctor have requested C225.
Mr. Burton. And what happened?
Mr. Baxter. We got an e-mail message back. Also I received
a phone call from the vice president of clinical affairs. It
was courteous. He just simply explained that they believe that
they could not do it.
Mr. Burton. And, of course, you, Ms. Kellum, did get C225
after you had gone through traditional therapies?
Ms. Kellum. Correct. I had already gone through all the
standard therapies as well as any clinical trials that I was
eligible for, and researched the option of surgery, which I was
not eligible for at the time, and that is when I began C225.
Mr. Burton. Well, I see my time has expired, and I will
yield to my colleagues, but I want to find out today from you
and from the ImClone company, and others, is why is this wall
there, and whether or not the clinical trials--they may feel
the clinical trials are jeopardized by giving it to people who
would not qualify in the narrow definition of what the clinical
trial is going to be. And if that is the case--and I would like
to ask you this real quick if my colleagues let me ask one more
question--did any of you get the feeling that they were worried
about the clinical trial being jeopardized by giving you the
drug, or did they give any explanation or do you have any idea
about that? Because if that is the case, then what we want to
try to do is figure out some way to protect the clinical trial
while still giving the treatment to people for compassionate
use.
Thank you, my colleagues, for letting me ask this question.
Mr. Santino. Congressman Burton, we got the feeling from
one trial that we tried to get into, that my wife was too sick
to get into that trial. It was not C225. It was another trial
of a drug called SU-5416. I got a referral from the FDA. They
told me about it. And we did not have any idea whether it would
be successful or not. It was just another drug that we could
try, but the doctor point blank said, ``No, your wife is too
sick. She cannot get into this trial.'' But we felt behind the
scenes it was the fact that the company did not want to risk
their approval process possibly or mess up the statistics in
the trial.
C225, we never got an answer on anything. Now, maybe they
are protecting themselves by not responding, but we finally did
talk to the doctor. When my wife talked in person to the vice
president of clinical affairs, and he gave her a flat, ``No,
you could not do it.''
``There is a clinical trial coming up at Dana Farber''--
this was this spring--``but you do not qualify. You will not
get in it.'' And her doctor had been trying to get that drug
for 6 months for--three doctors had called ImClone trying to
get it.
Mr. Burton. OK. Mr. Burroughs.
Mr. Burroughs. Thank you, Chairman. Something that is
interesting is that in a ``60 Minutes'' piece that was aired on
May 6th, some--first of all, the two pharmaceutical companies,
ImClone and AstraZenica, refused to be interviewed for that
program. There was a quote--I assume it is correct--from
AstraZenica, and that was that they were worried that
compassionate use of their drug would interfere with the data
from the trials. I am not an expert on FDA issues, but that was
pretty accurate what their quote was on ``60 Minutes'',
AstraZenica's.
If you think about it, you know, the data and the trial is
data in the trial, it is empirical data, and that is what you
use to get approval of the drug. Something outside of it is
just extra data. They do not have to be tied together. Now, is
that a problem? Maybe we will learn that from the FDA
testimony. But on the surface, it looks like they should be two
separate things. Thank you.
Mr. Burton. Mr. Baxter, do you have any comment on that?
Mr. Baxter. Well, I believe that in relationship to the
C225, what I have been told is there is basically a shortage,
and they would like to provide more of the drug to more people,
but there is a shortage. They are building a large
manufacturing facility. I certainly wish that could have
started a few months earlier. Perhaps that needs to be looked
at as to how we can increase production of these type of things
earlier in the process, so that the Davids and others do not
have to go through this process, because more of the drug would
be available.
In my particular case, it goes beyond just compassionate
use. It gets into compassionate co-investigators, allowing
clinical trials not to be grouped in, you know, the Eastern
part of the country, but allow access to other very
experienced, very talented doctors such as David's doctor, who
has already been approved by them. And we would like to know
if----
Mr. Burton. Out West.
Mr. Baxter [continuing]. To know if there is a way that we
can provide greater accessibility to these clinical trials
through requiring more co-investigation locations.
Mr. Burton. Did you have a comment, Ms. Kellum?
Ms. Kellum. No, thank you.
Mr. Burton. Mr. Horn, any questions?
Mr. Horn. Thank you, Mr. Chairman. I have appreciated the
testimony that each of you have given. And I want to start with
Mr. Santino.
You showed a picture of your family the day before Ruth-Ann
passed. Your son told us that the hospice social worker
arranged for the school principal to come to your home and give
David his diploma so his mother could see him graduate. I know
that must have been very important for Ruth-Ann. We hear a lot
of reports that doctors do not make a referral to hospice soon
enough. A report this week in the medical literature mentions
that the doctors often times do not give accurate information
about life expectancy when patients ask. What was your
experience with this?
Mr. Santino. Well, right up to the end we had hoped that
she would be somehow cured of all this. The last couple of
weeks the doctor started talking hospice. He said, ``You only
have 2 weeks to live.'' And right away, you know, we went
through the roof. You know, we had to tell the kids, ``This is
it. Mom is not going to be around any longer.'' And then the
doctor changed his mind. He said, ``Maybe you can qualify for
another trial.'' And her condition got a little bit better. But
we were still ready for the hospice. The hospice was there. Her
condition did get--the doctor was wrong. The condition did get
worse. His initial diagnosis was right.
The hospice arranged for the high school principal to come
to her bedside in my house the day before she died, very
important to her. She perked right up. My son felt that she was
there at his graduation, and he got the diploma, and we had a
little ceremony, and I think she was in peace after that. I
think that was driving her to stay alive, to be at her son's
graduation.
Mr. Horn. We also hear a great deal about cancer pain being
poorly managed. What was your family's experience on the
managing of the pain?
Mr. Santino. Well, the hospice helped manage the pain. They
were experts in that part. When you go to hospice, you are
saying, ``I am not going to live any more. I just want to be
comfortable.'' And they did a very good job at that. Everything
was comfortable. Everything was counseling for the family, and
I really cannot say enough for hospice. It was really much
better than we would have had without them. I cannot say
enough.
And we did not realize it was going to happen, but the
hospice was there around us all the time, and every time I
talked to them, I said, ``Oh, no, I think you are wrong,'' but
in the end they were right, and I am glad we had them, and
managing the pain was definitely a good factor.
Mr. Horn. Mr. Santino, in the 1997 Food and Drug
Modernization Act, Congress required the Department of Health
and Human Services, through the NIH, to establish a registry of
clinical trials for both federally and privately funded trials
of experimental treatments for serious or life-threatening
diseases or conditions. The Web site available at the
clinicaltrials.gov, certainly lists about 5,200 clinical
trials. Was this a resource you consulted? And if so, did you
find it useful?
Mr. Santino. I claim to be an expert on Web sites, I guess
self-proclaimed. But I run four Web sites myself. No, they are
not helpful at all, because the information is not exactly
accurate. If you go to the Web site, you will find that there
are trials that are being offered--in our case, in Boston, Dana
Farber, that are right there, that are being offered to you
saying, ``Do you want this trial?'' You cannot find on any Web
site anywhere. We were given four trials, basically alphabet
soup to me, you know, just names. And I asked the doctor,
``What do you know about these drugs?'' ``I do not know that
much about them. They are just phase I trials.'' They are not
listed on the Web site anywhere. I could not find anything
about it. And that is when really the Web site would be helpful
to me.
On the other hand, my wife was given a drug called oxily
platin on compassionate use. That was not listed on any Web
site, so she was actually able to get compassionate use of that
drug, but it was not listed anywhere. So there are things
happening out there maybe too fast. I do not know. Maybe the
Web site is a good idea, but it is not happening in a timely
manner. Now, I think that is a Web problem, I do not think it
is a drug problem. You find probably 50 Web sites, 49 out of
them are out of date. So I do not blame the drug industry for
that.
Mr. Horn. I believe we have a vote now, do we?
Mr. Burton. Yes, we do. We have about 7\1/2\ minutes on the
clock, so Members can go ahead and vote. And if you come back--
I apologize to the panel. I hope you will bear with us. We will
be back in about 10 minutes. We have to run to the floor for a
vote, and we will be right back. And after we finish with you,
we will go to the second panel.
We stand in recess.
[Recess.]
Mr. Burton. We will call the committee to order, and would
the witnesses please come back?
Is Mr. Burroughs out for now or did he leave? OK, well, we
will wait just a moment on him then. Well, I will tell you,
while we are waiting, why don't I go ahead and ask Mr. Santino
a question.
Mr. Santino, did you and your wife look at complementary
alternative therapies as well?
Mr. Santino. You mean like health food store, that type of
thing?
Mr. Burton. Well, yeah, and----
Mr. Santino. We talked to somebody at the Marino Center in
Cambridge, MA, which is known for alternative treatments, but
nothing really caught us. And the other thing is it interferes
with chemotherapy. My wife was under chemotherapy all the time,
so there were health food store type treatments available that
are being used in Canada, but we never really--I think we
bought one of them, but we never used it because----
Mr. Burton. She was on conventional therapy.
Mr. Santino. Yes, and you have to be off chemotherapy for a
while to use it, and we were not willing to experiment on our
own. We were relying on the doctors primarily. If a doctor had
told me to use it, I would have gone for it probably. But
without the advice of a doctor, I would not do it.
Mr. Burton. Was the chemotherapy--you said it was helpful
at the beginning.
Mr. Santino. Yes. The very first treatment she had back in
1999. She had surgery April 1999 to remove the first tumor, and
she had radiation and the standard 5-FU treatment, and that was
very effective. She had no cancer for probably 6 months, and
then November 1999, she had a tumor, another tumor growing, and
she had to have a complete colostomy at that point, where she
had only had what they call a resection of her colon. She still
had use of her colon. But then she had a colostomy because of
the surgery that came up just a few months after. She ended the
treatment in August 1999, and the cancer reappeared in November
1999.
Mr. Burton. But the doctors told her that the cancer was
gone, and she----
Mr. Santino. Right, yes. We did not expect it to come back
at all. It was worse than the first time because we thought we
were out of the woods, and then, you know, summer of 1999, we
were just, you know, soon as the chemotherapy and the radiation
is over, we are back in business again as a family.
My wife actually went back to work in 1999. She was a
teacher.
Mr. Burton. I see.
Mr. Santino. She went to work for a couple of days, and
then she was very sick. We are not even sure what she had at
the time, and the tumor was probably starting, whatever was
going on at the time. And she could not work again until fall
of 1999.
Mr. Burton. I see. Mr. Burroughs, did your daughter try any
complementary or alternative therapies in addition to the
traditional therapy she was using?
Mr. Burroughs. She was on a drug late in the game at Johns
Hopkins called Herceptin, and I think that is a fairly new
drug, if I am not mistaken. But we really were not able to get
any of the new advanced experimental drugs.
Mr. Burton. I was not just talking about the experimental
drugs. I was talking about, you know, health remedies and
things.
Mr. Burroughs. Going through this, is of course, a very
difficult experience, and we just got flooded with nutritional
information. ``You should try oak bark juice.'' Sure. It has
cyanide in it. Hello. You know, just everybody was trying to
help, I guess, or maybe sell something or whatever, but there
was just so much nutritional information, you start feeling
like, am I overlooking something that could save her life? Then
you realize there is no empirical data on it, and then you even
look into some of it and find out that it is actually quite
dangerous, or that it just plain does not work. But you feel
like you have to sift through all this various piles of
nutritional information that is coming to you from friends and
wherever, because that could save her life, it could be some
secret key here. Well, if it was so amazing, why have we not
heard more about it?
Mr. Burton. If you had one recommendation to make to the
committee or the Food and Drug Administration or to the
pharmaceutical companies, and I think that is probably one of
the most important things we can ask you, what would you
suggest? Because you have all been through it. What would you
suggest?
Mr. Burroughs. That we do about the problem?
Mr. Burton. Yes, as far as getting whatever is necessary to
help your loved one or yourself in the treatment of cancer?
Mr. Burroughs. Well, you know, obviously, I have lost a
treasure, my only child, and a beautiful child that she was--
well, she is, but in a different world now. We need to have
these experimental drugs available to more people now, or as
soon as possible. If it is a money issue--I presented that in
my testimony--that there are ways that we can put together some
sort of vehicle or foundation or whatever to finance more
production of these drugs. If it is a small company, they could
even use the facilities of a larger company. There are ways I
think to solve this problem.
Mr. Burton. Production.
Mr. Burroughs. Yes.
Mr. Burton. Mr. Santino, you have any?
Mr. Santino. I second what he is saying. I also think they
have to be fair to people. You cannot be giving it out to one
person and not giving it to another, especially at the same
hospital. When my wife found out that somebody at Dana Farber
at Boston was getting C225, and we were just anticipating it
would not be available till November of that year, we went
berserk, because here we are waiting for a drug for the fall.
We got to keep my wife alive till the fall, and we find out
somebody's already got it, right in the next chair to her. I
mean, my God, how can a company be unfair like that? So, I
mean, give it out to nobody, or give it out to all, and put the
word out. Call the doctors at Dana Farber and say, ``C225 not
available.'' Then I don't have to write a letter. My wife wrote
three letters, and none of them were answered. All a doctor had
to do at the company was call Dana Farber and say that C225 is
not available. We would have got the word from the doctor,
because she went there every week.
I think the communications is lacking, I really do. I think
they are not understanding that cancer patients are people. My
wife was a wonderful person and she was a person. She was not
just a name and an address and maybe a profit center. I mean,
you are in the drug business, there are people there. So that
is all I can say, is be fair to people and understand that
there are people out there.
Mr. Burton. Mr. Baxter, do you have any recommendations to
the committee?
Mr. Baxter. Well, I think that in the case of some of these
pharmaceutical companies, that the request far, far exceeds the
demand. And to take the position if you do not give it to
everybody, do not give it--if you cannot help everybody, do not
help anybody, is not being compassionate to anybody along the
way. If they have an extra 200 pills, then put them to good
use. I think that maybe the companies need to set a priority
for compassionate use. We do not send children to war. I think
we ought to take the extra step to make sure we protect
children, that in establishing criteria, that children ought to
have, for example, priority, those who have the best prognosis
for a lengthy remission should have priority, and those who
will, in all likelihood, die before the drug is approved should
have the highest priority.
And then from that end you have to have some definition
like that of who to help, but I do not think it would be right
to say, OK, drug company, if you do not have enough drug to
help everybody, do not help anybody, because that gives the
drug company a very easy way out of just denying compassionate
use to everybody if that is done.
I think in large degree, it is a production issue. I
believe that a company will not embark on a venture of hundreds
of millions of dollars to build a facility to produce these
drugs in a high-production mode until they know it is a slam
dunk, that they have got it. And, you know, I think that
perhaps we need to look at a--we have FDA approval, which we
need to maintain that level of standard, but maybe there needs
to be some kind of initial FDA approval, such as a probable
approval level, in which a company, once they have reached that
point, they can go ahead and start building their manufacturing
facility with the blessing of the government as a backing. And
should that drug not be approved, basically the cost incurred
would be offset by a tax credit or something like that. We have
to start production earlier in order to provide the most
opportunity for the most people to participate in clinical
trials and also to be able to receive compassionate use. We got
to increase production earlier.
Mr. Burton. Ms. Kellum, you have a----
Ms. Kellum. Obviously, I am in a different situation than
these gentlemen because I am here, and that is because I did
receive C225. And I think what we all need to look at is this
disease is what is unfair. I do not know if there is a fair or
an unfair way of administering this drug, and I do not think
ImClone liked saying no. But we need--I think we need to look
at the common goal here and that is to find a cure for cancer,
because if we do not have the cure, people are going to
continue to die. And what is the answer to finding a cure. And
I do not have that answer. I wish we all had a crystal ball
that had the formula in it, but we do not. And I may be
simplifying it, but I think we need to, you know, with a drug
that has had this success, we need to get it approved as fast
as possible and get it out to everyone. But denying some people
the opportunity I do not think is the answer, because had I not
gotten it, I would not be here today, and we would not have the
knowledge or the capacity to give it to other individuals, so I
think we need to take that into consideration as well. And,
again, the common goal here is to find a cure, and whatever way
we can do that, I think is in the best interest of all of us.
Thank you.
Mr. Burton. Mr. Baxter, several years ago, a San Francisco
police officer named Rick Schiff, his young daughter was
diagnosed with a brain cancer. Her oncologist was aware of an
experimental treatment that was showing some success in her
type of cancer, but he opted not to inform the family of this
treatment, instead pushing for another treatment option. Do you
think doctors should provide families all of the options,
standard, alternative, and experimental, and let the family
decide?
Mr. Baxter. I think that is very important. I feel I am
very blessed with Dr. Rosenberg being my son's doctor. I
believe that he has kept us in the loop. We have tossed some
things off the Internet to him. He had explained why this would
or would not be beneficial to my son, and we have been very
blessed in having that type of relationship. And certainly, I
would think personally it would be unethical for a doctor not
to provide that information. It is extremely difficult though
for a family to evaluate that, and so with that information
needs to come the doctor's professional recommendations as
well.
Mr. Burton. Well, what we are talking about is making sure
that everything that is open or possible to help----
Mr. Baxter. Yes, indeed.
Mr. Burton. Ms. Kellum, what do you say to those who
haven't been able to access these experimental treatments or--I
mean, you are very fortunate.
Ms. Kellum. I am very, very fortunate, and I thank God for
every additional day that I have, and it is very difficult for
me to stand up here. And in some ways I do feel guilty because
I am still here, but I am human, and that guilt is there. But I
also feel that this is a chance for me to help get these drugs
approved quicker and to share my testimony, and to just do
whatever possible to find a cure. And again I go back to that.
We do not have a cure, and I think that is why we are all here,
is to find one.
Mr. Barr. Excuse me. Could I address the fairness issue
that you asked?
Mr. Burton. Sure.
Mr. Barr. I think that there are two issues. One is that
the FDA really needs to discuss with sponsors the need for an
expanded access program at the earliest possible stage, at the
submission of an IND.
Mr. Burton. And they did that with the AIDS epidemic.
Mr. Barr. And I think making sure that those discussions
happen--and a company might do it, a company might not do it,
but urging from the agency is really important. And the
treatment IND mechanism is probably the best way for insuring
fairness in decisionmaking across the board, because there what
the treatment IND mechanism does is it provides both the agency
and the sponsor and the patients with an infrastructure for how
decisions are made because a protocol gets created and you want
the protocol to not interfere with clinical trial enrollment,
and you want it to reach those patients who have no other
treatment options and who need this most of all. So using that
mechanism is probably the best way for providing a framework
for decisionmaking that then is not arbitrary and helps some
patients and not others.
Mr. Burton. Well, let me followup what you just said with a
couple of questions. The AIDS community has shown the world
that when life is at stake, sometimes rules do not matter quite
as much. There were peaceful protests, sit-ins, coming together
as a community to demand access to care. So what do you say to
those who would say that providing access to experimental drugs
outside clinical trials may be dangerous?
Mr. Barr. Well, I was the coordinator of a demonstration at
the FDA in 1988, and the demonstration was, I guess, my idea,
where we actually seized control of the FDA because we felt
that they were not doing what they needed to do to provide us
with the ability to make decisions about whether or not to take
risks. What we were able to show--and through the work that--
through the advocacy work that was done, the agency really
began to move and change its position. And at least if you look
at the expanded access programs, early access programs that
have been used in HIV, we have been able to show that those
programs do not interfere with clinical trial enrollment, and
they do not interfere with the running of the clinical trials.
Any efficacy data that would come out of an expanded access
program would really have no effect on a clinical study. Safety
issues might have an effect on a clinical study, if, for
example, you had an adverse event come out of a drug that was
being given on a compassionate use that was not seen in a
clinical trial. That might affect what happens in the clinical
trials, but then again you might want it to because the adverse
event could be very, very serious, and you would certainly want
to at least incorporate looking for that toxicity in the
clinical study. But those programs have not affected clinical
studies in HIV in a negative way.
Mr. Burton. Bastyr University, which trains naturopathic
doctors was the first naturopathic college to receive NIH
funding. Their research center was funded to look at
alternative medicine use in the HIV/AIDS community. Do you
integrate complementary and alternative therapies into
experimental treatment?
Do you integrate complementary and alternative therapies
into your treatment protocol, and what advice would you or do
you share with others about different approaches to health
maintenance while living with AIDS? And I think all of this is
relevant to the cancer question.
Mr. Barr. The issue of alternative therapies is I think
very complex because there is growing interest among patients
in using alternative therapies, unusually as complementary
drugs or therapies to what their doctor is prescribing. Very
often the doctor will not have very much information about
alternative therapies, sometimes just because it is not an area
of expertise for the doctor, but most often because we do not
have very much data on the use, on the effectiveness and safety
of alternative therapies, which can be just as toxic as any
pill produced by Merck or Bristol Myers Squibb, and AIDS
advocates have strongly urged that alternative therapies be
subject to the same kinds of rigorous controlled clinical
studies to determine what their safety and efficacy is as any
other kind of drug.
I think what is most important is for doctors to always ask
their patients about whether or not they are using a
complementary therapy or an alternative therapy, and then look
into the possibility of dangerous drug interactions and what
possible side effects might arise from the alternative therapy.
Very often patients feel that those kinds of therapies are
beneficial to, if not the disease that they have, in
alleviating some of the side effects from the drugs that they
are taking for their cancer or for their AIDS. And I think also
that those kinds of treatments are very important in helping
patients feel more empowered in taking more control over their
medical situation, but it is really important that they discuss
them with their doctors and that doctors ask about that stuff.
Mr. Burton. Mr. Burroughs, for our record here, did
AstraZenica and ImClone Systems communicate clearly with you?
Mr. Burroughs. That was a big problem we had. No, they did
not. We got an awful lot of run-around, ``Oh, call this 1-800
number. No, call that 1-800 number. I'm sorry. This person is
on vacation.'' ``Well, is there someone that can cover for
them?'' ``No, they will be back in a week.''
There was really poor communications. It was ridiculous.
That is the short version of the story, that it took so long to
get feedback on a question.
For instance, with AstraZenica, maybe I mentioned it
earlier, that Abigail's story, her situation, was actually
brought up at a board of directors meeting in London, and I
never heard any feedback from it, what was decided. You know,
what did they say? Why couldn't you tell me that, tell me
something? Communications was very slow. It was confused. And I
was never able to get something printed like, ``Here is our
policy on compassionate use,'' or ``Here is our definition of
our compassionate use policy,'' and ``These are a list of
trials of our drugs,'' either from ImClone or from AstraZenica.
Mr. Burton. So they really were almost nonresponsive?
Mr. Burroughs. Well, it took a long time to get answers to
a question like, ``What is AstraZenica's trial about?'' And it
took, you know, a week and a half to find out that it is only a
few people in it, it is just for people who have lung cancer
and only lung cancer, but it took me a week and a half to find
that out. I found out from ImClone, someone at ImClone, after
going through a number of different people, that there was a
clinical trial in Fairfax, VA. And I find out that, oh, great,
so I have this great hope. But that is all the information I
had. ``Well, here is the number to call in Fairfax.'' And I
call the Oncology Center of Fairfax, and find out that Abigail
does not meet the parameters of the trials. Why can't this
information be clearly communicated on a few pieces of paper or
whatever to me, or an e-mail or whatever?
Mr. Burton. So I guess the next question is irrelevant.
ImClone and AstraZenica did not provide clear enough dated
information to you on the company sponsored trials?
Mr. Burroughs. That is correct.
Mr. Burton. And they did not give you any information on
the requirements that she would need to get into the trials?
Mr. Burroughs. We had to find those out for ourselves.
Mr. Burton. OK. Anything else? Mrs. Morella. OK, Mrs.
Morella, go ahead.
Mrs. Morella. Thank you, Mr. Chairman. Thank you for
arranging this hearing. I want to thank all of you who have
testified on this first panel, for sharing your stories with
us. Indeed, you bring a real human dimension to the issue, and
that helps focus attention on it through the stories that you
have told.
Mr. Santino and Mr. Burroughs, I offer my sympathy to you
on the loss of your daughter and your wife. And reading about
and hearing about your son, Mr. Baxter. And the fact that you
are doing well, because of C225. And, Mr. Barr, I hope that you
will continue to do well. It is an area I have been very much
involved with, that area of HIV and AIDS, and what we can do.
Mr. Santino, I grew up in Somerville, MA. Matter of fact, I
know St. Clement School. I read the article that your son wrote
about it, so I can identify very much with----
Mr. Santino. What a coincidence.
Mrs. Morella. I am sorry?
Mr. Santino. What a coincidence.
Mrs. Morella. It is indeed. That brings us even closer
together. I also have the National Institutes of Health in my
district and FDA, Food and Drug Administration.
And I was listening to your response to the questions that
the chairman has asked, and they are pretty much some of the
concerns I had, trying to figure out before we go to our
administrators, FDA and ImClone on the next panel, but what you
see needs to be done. And I guess I can deduct from what you
have said--and you can tell me whether I am right or whether
something should be added--but first of all, there is, I think
as you have said, Mr. Barr, no standard protocol for
compassionate use of new drugs. If you are not in a clinical
trial, then it is helter skelter whether your doctor knows
about it, whether you find a Web site that happens to be
accurate at that moment, whether there is someone else who
links you up with a possibility of being looked at on a case-
by-case basis for being eligible, whether there is an adequate
supply that is available.
And so it seems to me that maybe one of the questions we
will want to ask the second panel is, ``Are you working on
establishing some process that people would know about and
making sure that there is information available?''
I also discern that not all doctors know about the various
clinical trials in those areas, so it seems as though maybe the
professional reaccreditation or what doctors do to get the
professional training, should make sure they are including how
to be up to date in those particular areas.
So I want to give you an opportunity to comment. Is there
anything I am missing in that dimension when I look to what we
would ask the next panel to help to clarify this situation, Mr.
Burroughs?
Mr. Burroughs. Thank you. Something I tried to bring out in
my testimony was that I do think that part of this issue is
money. Isn't that something that affects so many things? I
think that, for instance, what I also brought out in my
testimony is that some companies do wider compassionate use of
drugs than others. Some do not do any. It is an issue of money.
The companies do not want to spend the money to make more of
this drug, because they are not going to make any money off of
it. But there is a way to solve that problem. And not to make
anybody the bad guy here, why do we not all work together? Why
do we not have the pharmaceutical industry, the government,
other private sources or whatever, solve the money problem,
because it is expensive to make these drugs. I do not have the
exact answer, but I brought that out in my testimony that some
sort of foundation or other vehicle to provide the funding to
make more of these experimental drugs.
In the case of Abigail, statistically, there was a 54
percent that AstraZenica's IRESSA could have saved her life,
and we could not get the drug. On the other hand, there are
companies like Pfizer and Bristol Myers Squibb and Burroughs-
Wellcome, do quite a bit of compassionate use of drugs. I think
it is a money issue.
Mrs. Morella. Maybe it would be appropriate to have a
conference or some kind of a meeting where you get these
partnerships, the Federal Government for its role, the private
sector, individuals, who could come together and----
Mr. Burroughs. Pharmaceutical industry. Yes, I think that
we do not want to make anybody here the enemy. That never does
anybody any good, but we want to take the resources we have in
the pharmaceutical industry and government and elsewhere, and
come up with a funding to help make more of these drugs. If
there are FDA rules that affect the application or the
availability of compassionate use, let us solve that problem. I
think it is a solvable problem. Thank you.
Mrs. Morella. Would anyone else like to comment? Mr.
Santino.
Mr. Santino. Mrs. Morella, I question the process. Why does
somebody like myself or Mr. Burroughs have to go off on their
own and do the research, when it should be a medical person? I
do not even know what I am talking about when I look at a
medical Web site, like make a call to a company. I did not know
what carcinoma was, for example. How would I know what that is?
Because I am an engineer. Why should I--I mean, if I have an
aspirin, I ask the doctor, and he says, ``Take the aspirin,
OK?'' I do not have to call the company and say, ``Is it all
right for me to take the aspirin?'' You know, I deal through an
intermediary who is a medical person. I mean this is such an
awful disease we are talking about, in my case, my wife's colon
cancer. Why should I be on the phone calling companies or
writing letters or, you know, making ImClone the bad guy, when
maybe the medical community should have solved that way before.
So when ImClone is offering the drug under compassionate use,
let them tell Dana Farber Cancer Center or whatever cancer
center, about that, and take me out of the loop. I mean, now, I
do not have a wife. I do not have an advocate. If I get cancer,
I have to do it myself while I am sick. I did it for my wife
because I was well and she was sick. I could do it. I could do
all the research and the digging and whatnot, but I question
why does the family have to do that in the first place? Is this
the same for every disease? I mean, I do not even know.
Mrs. Morella. Dissemination of the correct information to
the parties involved has definitely got to be one of the major
points that will come from your testimony.
I just want to--I'm sorry. Mr. Baxter.
Mr. Baxter. I believe that FDA is endeavoring to do a very
good job within the framework that they now exist, and the
approval process is obviously important for society at large,
but I think that also it is important to look at the risk
factors versus approval. As a drug goes toward approval,
progressively they know more and more about it. Progressively
they know the risk and stuff like that. And so you get up to a
point where, OK, this is FDA approved. But at the same time, it
is like my son having a scratch on his arm, and the other arm
being chopped off and bleeding to death. I mean, while we want
to make sure you are not going to get any infection in this
scratch while he is bleeding.
I think it is important also to realize that progressively
my son's prognosis is becoming progressively more skeptical,
and so the risk of him dying becomes greater and greater all
the time. So at some point, especially--I do not know if there
is another step or another classification of approval, say, for
terminally ill patients that FDA approval could be authorized
for those patients that have been classified, and which by far
the risk of death from the actual cancer far exceeds any
potential side effects and stuff like that. But I think that
for the terminally ill, that type of hope, because if a patient
does not have hope, they are lost, you know? They need to have
a level of approval perhaps that is a little bit different for
those who are terminally ill, and maybe that is something that
needs to be looked at as well.
Mrs. Morella. That is a very good point, and I think it is
one that should be posed to the second panel. Thank you, Mr.
Chairman.
Mr. Burton. Mrs. Davis.
Mrs. Jo Ann Davis of Virginia. Thank you, Mr. Chairman, and
thank you all for coming and testifying today. I know it has to
be difficult for some of you. And, Ms. Kellum, I would just
encourage you to not feel guilty because you were able to be
helped, because I think it is good that you have the testimony
that the drug did help, so that now it can hopefully help
others.
And Mrs. Morella touched a little bit on what I wanted to
ask, was until--actually, until I read the article about your
daughter, Mr. Burroughs, I was not familiar with compassionate
use drugs. And I guess my curiosity, my question is, how did
you--how did any of you know about compassionate use drugs? I
mean, how did you know who to contact? How did you know who had
them and whatever, because if I remember correctly, in the
article, the first two, ImClone and----
Mr. Burroughs. AstraZenica.
Mrs. Jo Ann Davis of Virginia [continuing]. You could not
get, but then I think the week before she passed away, another
pharmaceutical company heard about her case and came up with a
drug, but it was too late.
Mr. Burroughs. About 2 weeks before Abigail died, she got
into a trial of OSI Pharmaceuticals, OSI-774 in San Antonio,
TX. They are a very, very small company, but I will tell you,
they really kept in touch with us, and as soon as they had the
drug manufactured, as soon as they had a trial open, they
called us. Now, I know they are small, but I think a big
company can have good communications too. These people were
absolutely wonderful. The problem we had was it was too little
too late. Abigail was not strong enough to make it to San
Antonio to be--she could not even do the traveling let alone be
in the trial. She died 2 weeks after we got that news. But that
was OSI Pharmaceutical, very small, little company.
Mrs. Jo Ann Davis of Virginia. And I guess that brings to
the question of how did you know? How would you have known to
have contacted OSI? I mean, how did any of you know to
contact----
Mr. Burroughs. What is interesting, what you do is you
learn a lot from working and talking to people. You keep
gaining more and more knowledge. Initially we knew about
ImClone's C225 and AstraZenica's IRESSA from her oncologist,
Dr. Maura L. Gillison at Johns Hopkins. And she says, ``It is
going to be hard getting these if you can get them at all. You
better get working ahead of time before Abigail is off of the
current chemotherapy as a backup in case it does not work.''
We got to work right away, believe me. And we started
learning how difficult it was to get into narrowly defined
trials, how compassionate use is almost nonexistent in both
companies--well, it is nonexistent in ImClone. It is almost
nonexistent in AstraZenica. OSI Pharmaceutical is a very tiny
little company. They were, like I said, wonderful, but the way
we found out about them was I made a phone call from a
suggestion from a friend of mine to call the Dana Farber Cancer
Center up in Boston at Harvard University, and I got hold of
some nice people there that said, ``Have you heard of OSI
Pharmaceutical?'' I said, ``I have done a lot of Web site
searches on EGFR-targeted agents, believe me, and I have had
people--and they just did not show up on the radar screen.''
And they were a late player in the game, but they came through
for us once they had the drug manufactured and helped us--kept
in touch with us. They were wonderful people, very good
communications.
Mrs. Jo Ann Davis of Virginia. Mr. Chairman, I guess that
is my point I wanted to have made, was that when I was speaking
to a young lady in my office who had cancer, and she, by the
luck of the draw, someone she knew had heard that she had
cancer, and she happened to have been on a Web site and saw a
drug, and then told her about it, and then she was able to go
and get into an experimental program and had success like Ms.
Kellum did. Not the same type of cancer, but that is the point,
and I think Mrs. Morella touched on it, is that as, you know,
the people who have cancer in their families, why are they
having to search the Web site to find out if there is anything
that can help them?
And, Mr. Baxter, I will tell you, I have a 19-year-old son,
and I cannot imagine what you are going through, and my prayers
will certainly be with you.
Mr. Baxter. Thank you.
Mr. Burton. Thank you very much. I appreciate your
patience.
Mrs. Jo Ann Davis of Virginia. I think we have another
comment, Mr. Chairman.
Mr. Burton. Oh, I am sorry.
Mrs. Jo Ann Davis of Virginia. Not me. Mr. Santino.
Mr. Santino. On the compassionate use, we had both the good
and the bad. And the way it should work is the way it worked
for us the first time. My wife had been at Beth Israel Hospital
in Boston. That was her second hospital she had been to when
she was taking CPT-11, which is one of the standard treatments
that was not working. And the doctor there had a friend at Dana
Farber, and he said, ``I think there is a drug, oxily platin
that they are giving out in compassionate use. We do not have
it here at Beth Israel, but I think you should go to my friend,
Dr. whatever, at Dana Farber and take it.'' And the minute we
got over to Dana Farber, they put her right on the oxily
platin, and it was a compassionate use drug. We had never heard
of compassionate use. We had never heard of oxily platin, but
the doctors arranged it for her.
Then we got into the C225 and the other drugs, which we had
to do all the work. I feel that it should be doctor to doctor,
not me and a Web site or Mr. Burroughs or whoever, because we
do not know what we are doing. We are wasting time. We are
wasting money for the insurance company. The insurance company
paid for my wife to go to Sloane Kettering to get all her
information sent there and whatever. We never even used it. She
died before. We did it on our own. We arranged to go to Sloane
Kettering. I arranged other types of things on my own because I
thought they were worth a try. But I guess I am questioning,
why am I in the loop, why not a management person who is a
medical doctor, just the way oxily platin worked? You know, I
never heard of compassionate use. It did not matter. It was a
treatment she needed, and the two doctors worked it out
together, and that was--I think that is the moral for what I
would propose. Everybody should know about it, and the doctors
should have access to the information somehow, and take us out
of the look, really, because who knows if we are doing the
right thing? And we are wasting money. We are wasting insurance
companies' money. We are wasting time, and maybe we are not
going to go down the right path.
So oxily platin was not even on a Web site anywhere when we
got it, so it was the right thing. It worked for a while, but
it did not work a long enough time for her, but she was able to
get about 6 months of relief with the oxily platin, and that is
my statement on it.
Mr. Burton. Thank you, Mrs. Davis.
I really appreciate your testimony. Before you leave, I
want to put some things in the record. I would like to submit
into the record an article published in the ``Boston Globe'' by
David Santino about his mother, and we will put that into the
congressional record.
[The information referred to follows:]
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Mr. Burton. I would also like to submit to the record a
series of articles from the ``Washington Post'' on cancer
issues, including one today about pediatric cancer patients not
being given adequate end-of-life care.
And this comes in conjunction with one of my colleagues,
Debra Price's daughter, who was treated for cancer, and had a
terrible time with it.
And I have copies of statistics by State of cancer
incidence and cancer mortality that I want to submit to the
record.
And for anybody's information, in Indiana, it was estimated
last year that 27,000 new cases of cancer were diagnosed, and
12,600 people died from it. And just you wonder how many could
have been saved had they had a chance to have some
compassionate use from these clinical trials.
In any event, God bless all of you. Thank you very much for
being here. We really appreciate it. And hopefully because of
your testimony and the testimony of others, we will come to
some conclusion on how to deal with this problem. Thank you
very much. Glad you made it. Thank you.
[The information referred to follows:]
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Mr. Baxter. Thank you.
Mr. Burton. Our next panel will be Dr. Waksal, Dr. Temple,
and Ms. Delaney. Would you please come forward?
If you could, would you please stand, so I can have you
sworn?
[Witnesses sworn.]
Mr. Burton. Dr. Temple, do you have an opening statement?
Dr. Temple. Yes, I do.
STATEMENTS OF ROBERT J. TEMPLE, M.D., ASSOCIATE DIRECTOR FOR
MEDICAL POLICY, CENTER FOR DRUG EVALUATION AND RESEARCH, FOOD
AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN
SERVICES; AND PATRICIA C. DELANEY, PUBLIC HEALTH SPECIALIST,
OFFICE OF SPECIAL HEALTH ISSUES, OFFICE OF INTERNATIONAL AND
CONSTITUENT RELATIONS, OFFICE OF THE COMMISSIONER, FOOD AND
DRUG ADMINISTRATION; AND SAMUEL D. WAKSAL, Ph.D., PRESIDENT AND
CHIEF EXECUTIVE OFFICER, ImCLONE SYSTEMS, INC.
Dr. Temple. Mr. Chairman, members of the committee, I am
Dr. Robert Temple. I am Associate Director for Medical Policy
at the Center for Drug Evaluation and Research of FDA. I am
also Director of the Office of Drug Evaluation I, which is
where the Division of Oncology Drug Products resides.
With me today is Ms. Patricia Delaney from FDA's Office of
Special Health Issues, the cancer liaison program, and I have
submitted my full statement for the record.
I would like to highlight three main aspects of the use of
investigational drugs to treat seriously ill patients, who have
no satisfactory alternative, an arrangement sometimes called
compassionate use, but that we call treatment use.
The first point I want to make is that FDA has, for many
years, supported access to potentially useful drugs that are
still under study. Since the 1970's, in fact, we have allowed,
and even encouraged, treatment use of investigational--that is,
drugs that are not approved yet--drugs.
Many believe this kind of availability began with AIDS, but
in fact, we had allowed manufacturers of a number of kinds of
drugs to make them very widely available before that, notably a
kind of beta blocker for angina called cardio-selective, a wide
range of new anti-arrhythmic drugs, and probably the largest of
all, the calcium channel blocker, nifedipine, which was used to
treat coronary artery spasm. Well over 20,000 people were
treated with nifedipine before it was approved.
In all of these cases there was reasonably mature evidence
of benefit and an acceptable safety record, and vigorous drug
development efforts were going on.
In 1983 we proposed, and in 1987 formally promulgated, the
treatment IND regulation, which was an effort to formalize
premarketing availability of certain drugs that seemed
particularly promising, and I want to mention several features
of that rule.
It was explicitly intended to make promising new drugs
available for treatment use as early in the drug development
process as possible. It was expected, though, that availability
would usually be relatively late in that process, in phase 3,
except that it might be earlier, during phase 2, for
immediately life-threatening diseases, which cancer generally
is. The rule requires the drug to be under active investigation
by a sponsor who is actively pursuing marketing, and a
treatment IND for a life-threatening illness must be based on a
showing that the drug may be effective. That is the standard.
The rule also requires that availability of the drug would not
expose patients to unreasonable and significant additional
risk. Thus, a certain amount of data is needed even to support
early use under a treatment protocol.
FDA can stop an expanded access study if it is interfering
with the conduct of the controlled trials of the drug. Sponsors
who make drugs available under a treatment IND can recover
costs once there is adequate enrollment in the controlled
trials. Whether to offer a drug for use in a treatment protocol
is solely within the discretion of its sponsor, although we
sometimes suggest this pathway to the sponsor.
It was expected from the beginning that sponsors would make
information about a treatment IND, about its existence, widely
available to people, although we did not specify the ways that
they would do that. In a treatment protocol access is usually
open to any physician/patient combination that meets the
protocol requirements, not just to selected patients or
physicians identified by the company.
When we proposed the regulation in 1983, we were concerned
that access to promising drugs had been available only to
certain people who were ``in the know,'' and we thought that if
a drug was ready for this kind of use, any appropriate patient
should have access and any appropriately qualified physician
should be able to give the drug. We are aware that in some
cases when supplies of drugs were limited, sponsors have used
lotteries to choose among the people who had sought to get the
drugs.
When we first began the process, we thought that all
treatment use would be under treatment INDs, but that was
probably unrealistic and has not proved to be true. Rather, a
wide range of other kinds of requests for treatment use,
especially treatment uses in specific individuals, which is
sometimes called compassionate use, have emerged. Commercial
sponsors are not required to agree to supply drug in those
cases, but if they do, what is called a single-patient IND may
come to us. In some cases a single-patient exception to the
sponsor's ordinary protocol may be submitted to an existing
IND. That is how many of these so-called compassionate uses
occur.
Although we thought drugs would be available for treatment
use only if there was a reasonable amount of data on safety and
effectiveness, in oncology particularly, but in other cases
too, critically ill patients and families sometimes seek
treatments that have very little evidence supporting their
value or safety, perhaps on the basis of animal studies or
persuasive theories. As a general rule, unless there is a
clearly better therapy for the patient, or clearly inadequate
evidence of safety, our practice has been, and is, to allow
these uses, at least in a modest number of a patients. But this
is a matter that deserves careful scrutiny.
And that leads me to my second point, which is that
allowing very early access to drugs, that is, access before
there is really any evidence at all that they work, is a very
complicated matter and does not necessarily represent a benefit
to patients. As patients run out of treatment options, some
will search out a new treatment, every one not yet well tested.
But we have experience with this. Typical early studies of new
cancer drugs, are carved out in patients who have exhausted
available therapy. It turns out that when the new agents are
given to those patients, they are usually not very helpful, and
significant responses are extremely unusual. Moreover, in most
cancer chemotherapy trials, toxicity can be considerable,
especially early, before approaches to managing toxicity are
well established and before an appropriate dose is chosen.
It should also be appreciated that reasonable hypotheses do
not always work out, as the current controversy over high-dose
chemotherapy with bone marrow or stem cell research
illustrates.
That said, I want to mention something that arose in the
previous discussions. One of the things companies are sometimes
asked to do is try a drug that is already being developed for
one disease in treatment of a different tumor, perhaps in one
or a small number of patients. Doing that is not unusual and
actually resembles ordinary drug development. The proposed new
use is like what is called a phase 2 study in cancer
development parlance. And if a patient with a novel, a
different tumor, such as a head and neck tumor, were to be
incorporated into a study as a single patient for a drug that
is being predominantly worked up for, say, lung cancer, that
would not be a very unusual thing to do, and it would rarely
give us any difficulty, even if there was not yet much
information about the new use.
Because early access to drugs has both potential value and
potentially serious risks, in December of last year and June of
this year, FDA asked its Oncology Drugs Advisory Committee to
consider when it is appropriate for FDA to allow
investigational drugs to be used to treat individual cancer
patients. The issue is obviously a complex one, but several
speakers were surprisingly skeptical about individual patient
use at very early stages. The statement of the National Breast
Cancer Coalition [NBCC], for example, which I understand you
have talked to, urged that access to investigational
interventions outside of clinical trials be very limited, and
expressed concern about unreasonable expectations created for
women who have exhausted standard treatment. They feared that
too-ready access would undermine clinical trials and the
principle of evidence-based medicine, and might actually be
harmful to patients.
The NBCC also thought that making access fair was very
difficult, given practical and economic constraints. On the
other hand, they strongly endorsed wide availability for
patients not eligible for existing trials through a formal
expanded access program when the therapy showed some
effectiveness and low risk in phase 2 trials. They were very
enthusiastic about the treatment IND.
They also urged that off-trial access, even at early
stages, when it occurs, be in the form of an expanded access
protocol, not through single-patient INDs. Many of the FDA's
Oncology Drug Advisory Committee members expressed similar
views.
Now, these are obviously complex and difficult issues that
require balancing competing values and interests. We plan to
hold a broadly based workshop involving regulators, NCI
academics, patient groups and individual patients to discuss
these issues further. I believe, based on what I've heard
today, we will also try to address formally the question of how
to make information available about expanded access programs
once they do exist.
The last point I want to emphasize, as others have today,
is that fairness is extremely important. Any suggestion of
unfairness in the way access to last-resort drugs is provided
is extremely troublesome to everyone involved. It is becoming
clear that any manufacturer with a drug that is arousing
interest among patients and physicians should consider an
organized program for providing whatever level of access it
considers appropriate at a given stage of development. Access
may have to be limited because of lack of data, insufficient
drug supplies, or concern about use by physicians not
experienced in how to use the drug. Or access may be more
extensive, if that is supported by sufficient efficacy and
safety data. But in any case, there ought to be a plan and
people can find out what the plan is.
We have begun to urge companies developing cancer drugs to
pay far more attention to this aspect of expanded access, and
Ms. Delaney can tell you more about that later. For patients in
search of treatment, a clear statement from sponsors as to what
access is available is critical. Patients and family members
have told us, time and time again, as they just told you, that
they want clear answers. Even if the answer is no, knowing that
answer sooner rather than later can allow patients to pursue
other options.
That is the end of what I had prepared. I have a couple of
comments in response to what I heard a little earlier, which I
will do now if you like, or later.
One of the concerns people had was that companies might
fear that data from access programs would contaminate their
data and in some way impede approval of their application. I do
not think, and I note Mr. Barr said this too, there is any real
chance that would happen. We completely recognize that the
efficacy data from an expanded access program is not the same
as, or is to be mixed with, the efficacy data from an organized
clinical trial. The expanded access patients have many reasons
for being less responsive, and I do not believe anybody should
have anxiety that we would confuse the two populations. It is
true that if, in a wider access program, adverse effects were
seen that had not been seen previously, we would want to know
about those. But I think everybody would want to know about
those. So I do not believe there should be a ``fire wall''
between those two kinds of studies. But I cannot think of a
drug whose fate has been damaged by an adverse effect in an
expanded access program. It could happen. Wider access, as we
know, after drugs are marketed sometimes reveal things that we
did not know from the smaller data base of drug development.
I guess the third point is that we do not just tolerate
wider use of drugs prior to approval. I've already mentioned
the treatment IND; in addition, we also actively support wider
use prior to approval more generally. I used to call this phase
3\1/2\, and we used to try to get companies to, as they are
getting their marketing application ready to submit to us, make
the drug more widely available so that in fact there would be
more safety and conceivably efficacy data available. So this is
in no sense grudging. We think it is a good idea.
Finally, just briefly, the standards for approval of
oncologic drugs are shaped unequivocally by the nature of the
disease. The amount of data, the level of evidence that is
required is usually far less than it would be for drugs for
comparatively trivial illnesses. So we share the view that
greater risks are acceptable for people who are facing the
rigors of cancer.
Anyway, thank you, Mr. Chairman, and we will be glad to
answer any questions.
[The prepared statement of Dr. Temple follows:]
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Mr. Burton. Thank you, Dr. Temple.
Ms. Delaney, do you have an opening statement?
Ms. Delaney. I do not have formal remarks, but I am
available for questions.
Mr. Burton. OK. Dr. Waksal.
Dr. Waksal. Good afternoon. Thank you.
Mr. Chairman, my name is Dr. Samuel Waksal, and I am the
president and chief executive officer of ImClone Systems. I
appreciate the opportunity to testify before the committee this
afternoon.
Before I go on with the rest of my testimony, I just want
to briefly interrupt and say that is a very difficult situation
to ever deal with with patients, with family members of
patients who have cancer and our sincere--and our hearts go out
to these patients. There is no answer to give to husbands and
fathers and other family members of patients who have died of
cancer. And this is not meant as a rebuttal to anyone. We are
here to talk about what we are trying to do in the same way
that this committee interests allies, in looking forward to
figuring out how to best deal with this very difficult disease,
and we share this committee's goal and a commitment to all of
that. In fact, ImClone scientists have spent the greater part
of their careers moving forward and trying to discover these
new approaches to the treatment of cancer that we hope will
change the way cancer is treated in this next millennium.
I want to discuss today our experience with the treatment
IND or compassionate use IND that we have been talking about,
and our experience is with the development of our first
therapeutic agent, IMC-C225, and I hope that what we tell you
here today will help this committee look at the very difficult
issues that we are talking about.
We are currently going through the FDA approval process to
get IMC-C225 approved and out into the market, and we have been
testing this drug in patients now since January 1995. We have
been looking at a variety of cancers. We have been using IMC-
C225 in the area of head and neck cancer, in colorectal cancer,
in pancreatic cancer and lung cancer. And in May 2000 we had
data that was presented at the American Society for Clinical
Oncology that showed great promise for this drug in colorectal
cancer and head and neck cancer in patients who had failed
conventional chemotherapy, and there was a lot of media
attention at that time on our drug because of the results that
were presented.
Because of all of that we had really an onslaught of
requests for compassionate use protocols for IMC-C225, and we
have been moving forward and completed, in effect, this last
year, our phase II studies for the use of our drug in
colorectal cancer in patients who had failed conventional
therapies. The FDA has given us fast-track designation to move
this forward, and we expect to move it forward with a biologics
license application very soon.
For us the critical issue has not been money. For us the
critical issue is not that we are afraid of contaminating our
clinical trials, and in fact are moving forward with our
clinical trials, and believe that our first obligation,
obviously, is to prove that this drug is safe and is effective
in standard clinical protocols that we put together in
conjunction with the FDA.
For us the critical issue has been manufacturing. This is a
biologic. It is a protein-based drug. Unlike small molecules
that most pharmaceutical companies developed and are developing
of the kind that AstraZenica or OSI Pharmaceuticals make, this
is a protein-based drug that has very stringent biologic
manufacturing standards. And in effect, we are so committed,
that early on, before we really knew that this drug was going
to have any activity, when it was still in preclinical studies,
we built a pilot manufacturing facility that would allow us to
move forward in clinical trials, and we did that back in 1994.
Moreover, at the present time, we only have enough clinical
supply to give us about 10 weeks of additional therapy for each
of the patients on our clinical protocols.
Also we have a contract manufacturer that we have gone out
to find because we are living in a world right now where there
is not enough manufacturing capacity for these types of
protein-based drugs, and there has been a lot of news about
that over the past several months. So, in effect, we do have a
contract with a third-party manufacturer, and again, money has
not been an issue. We have requested every single run that they
might have in their facility to make our product and are doing
that as we move forward. However, this supply is limited and
our obligation and the obligation to the future of--to future
cancer patients is to move forward through clinical trials,
prove that the drug is safe and effective, and get it on the
market.
Prior to May 2000, when very few people who knew about this
drug, the only compassionate use requests that we got were from
clinicians that were in our clinical trials and had experience
with our drug. Between January 1995 and May 2000, we had very
few compassionate use requests, and we put 15 patients on
compassionate use protocols up until May 2000. After May 2000
and until January of this year, when we ended our compassionate
use program, we treated an additional 15 people. But the
requests were very different. Instead of physicians that really
knew how to use this drug and knew about the drug, it was more
the media and a lot of word-of-mouth because of clinical data
that was being presented at conferences that really drove a
huge amount of these types of requests, and as we put into our
testimony, we have had almost 10,000 requests for this drug,
about 8,000 different patients that have requested IMC-C225 for
various types of cancers, and this has been a very difficult
thing for us because as compassionate as we are, we are a small
biotech company, not a big pharmaceutical company, and it is
very difficult to process that kind of request, those kinds of
requests by this many patients.
Initially what we did was really try to set up a hotline
right after May 2000 to deal with some of these requests, and
we really feel badly. We probably should have put a form letter
together. We were unexperienced at the time, and the data that
we had generated was really new to us at that point, and in
effect, perhaps we should have put a form letter together to
get back to these patients to tell them that there were limited
amounts of slots available for these compassionate use
programs. Indeed, what we initially put together was a list of
first come-first serve, and when that got too big and we were
afraid that we were going to give false hope to anybody that
even got on the list, we finally ended our program and decided
to concentrate on getting the drug approved because we felt
that was the best way to get this drug out to as many people as
possible in an approved fashion.
So after having to turn away all these people, we are now
concentrating on a couple of things. One, is we have, even
before we had the further data that our drug was working in
colorectal cancer in the refractory setting in patients who had
failed conventional therapies, and in the setting of head and
neck cancer, in January 2000 we broke ground on a very large
manufacturing facility. So we took that huge risk ourselves. No
one helped us. We were not partnering this drug with a big
pharmaceutical company at the time, and we took the risk to
make sure that a major facility could be built that would make
this drug available to cancer patients in the future. We just
completed the physical completion of that facility in record
time, I might say, and now we are beginning to get ready to
make it in that facility, under very strict FDA guidelines, so
that facility can later be approved and we can have material
available for patients after the drug is approved, and also to
revisit how we would put together an expanded access program
for even more patients.
So would we do things differently in the future or would we
have done things differently in the past? The answer is yes. We
were a very young and inexperienced company, concentrating on
putting together and discovering new novel therapeutics for the
future treatment of cancer that were different than the kinds
of therapies that had been discovered in the past, and we are
happy to say that we, as pioneers in that area, have pioneered
a new approach of targeted oncology to get these new kinds of
drugs out there. We are in the last stages of dealing with the
FDA and moving forward in conjunction with the FDA to try to
get this product approved, and at the same time, expending our
meager resources--and they are far less than big pharmaceutical
companies--but expending all the moneys that we can to make
sure that we have the manufacturing capability available, to
have drug availability for these individuals, and to do
everything we can to treat disease that are heart wrenching in
every individual aspect. And what we are trying to do is get
out there and serve the thousands of patients in the future
that need our drug.
Thank you, Mr. Chairman.
[The prepared statement of Dr. Waksal follows:]
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Mr. Burton. Thank you, doctor.
Dr. Temple, Ms. Delaney, given the information that Dr.
Waksal just gave us, how long would it take from this point on
to have the C225 approved and ready for dissemination to the
populace? They started the clinical trials, I guess, in 1995;
is that what you said?
Dr. Waksal. Yes. We started clinical trials in 1995, but--
--
Mr. Burton. So in 1995. Now we are 6 years into it, and it
is showing some promise, and, you know, having 130,000 cases of
colorectal cancer this year, and every one of those people,
knowing that it has some positive results, would probably like
to have this product. So how long does it take the FDA to get
that done?
Dr. Temple. Well, I cannot speak about that biologic for a
number of reasons. For one thing it is reviewed in a different
center.
Mr. Burton. Wait a minute. Excuse me. It is in a different
center? I thought when--we wanted FDA to send some people up
here that were familiar with this particular product.
Dr. Temple. Well, this may be a terrible error on our part,
and if so, I am sorry, but the request to us----
Mr. Burton. You mean there is nobody here from FDA that can
tell us anything about----
Dr. Temple. About this drug? That is, I am sorry to say,
correct. The request for information was quite a generic one
about general policies, so we assumed that the specific request
for me was deliberate, and I did not know that you wanted
someone who could talk about C225, and I really cannot. But I
can tell you some things about the approval rates for cancer
drugs and how long things take. As you undoubtedly know, we
approved Gleevec in 2.4 months. The data was very good and very
powerful. for any drug that is a fast-track drug, as this one
apparently is, we have a response time of 6 months. We
essentially always meet that goal, so that once C225 is before
us, I am quite sure there will be an answer in that time or
less.
Mr. Burton. So the timeframe you are talking about in a
generic way is about 6 months?
Dr. Temple. Well, that is the time for response. The answer
could be yes or no.
Mr. Burton. So the data will be reviewed within 6 months?
Dr. Temple. Yes. That is our goal date for any drug that
receives priority----
Mr. Burton. And then after 6 months, if there is a problem
with the drug, then there is a continued reevaluation?
Dr. Temple. Well, our initial response is one of three
things at the present time. It is, ``you're approved,'' and
here is the label that is approved; you are ``approvable'' with
modest amounts of additional information--the amount of
information can be changes in labeling or something more
important. If it is just changes in labeling, we respond to the
resubmission in 2 months. If it is more, we respond within 6
months. Or it could be nonapproval because people do not
believe the data are persuasive. I have no idea what the
outcome on C225 will be. From what everyone says, they seem
optimistic, but I cannot tell you any more than that.
Mr. Burton. Can we make a formal request that we get that
information from FDA, whoever is in charge of that, so we can
take a look at that?
Dr. Temple. OK. I will ask them to provide what they can.
It may have to be provided to you in confidence, because those
are commercial considerations, but we will certainly get you
what we can.
Mr. Burton. Well, I can understand the ramifications.
Dr. Temple. Let me mention one other thing. I do not know
that they are ready to do this and I do not know what we would
say in response to it, but if the company wanted a treatment
protocol approved, we respond to those requests within 30 days,
and that has been in the rule since 1987.
Mr. Burton. Dr. Waksal, have you requested that treatment
protocol?
Dr. Waksal. What we are doing right now, and we have
consulted with advocacy groups and talked to the FDA, we do not
have yet the manufacturing capability, according to FDA
guidelines, that will make enough of this drug available in a
treatment protocol.
Mr. Burton. I am not familiar with how all of this works,
so I am kind of a neophyte in this area. But let us say that
you had not necessarily your drug, but some drug that showed
promise, and you knew that there were 130,000 people a year
that were suffering from this and it had been shown to be
pretty successful. Can you subcontract with a major
manufacturer of pharmaceuticals to get that to the market while
at the same time you are working on getting approval for your
new facility?
Dr. Waksal. Yes, one could, and that is exactly what we
have done with IMC-C225. What we did, because we knew that we
had to build a larger facility and we did not want to wait,
there is--now, it is a little different than from the--in the
Bureau of Biologics, where we are dealing with our protein-
based drug, than the group that Dr. Temple normally deals with.
So each of the facilities that make our particular drug have to
be licensed by the FDA for our particular drug. So we went to a
group that does contract manufacturing, Lanza Biologics, to put
together an agreement, where they would make our product for us
under contract, and we have put together--for our approval
process, we used their facility as the site that made our drug
for our FDA application which we are going to put in very soon.
Our own facility being completed right now will have to go
through the same type of approval process, that is, that we, as
we scale up and begin to make our drug in our own facility
later this summer, we will go through and make three
consistency lots, and then apply for that facility to be
approved, and then have more drug available for these kinds of
programs.
Mr. Burton. But the contractor that you are using right now
to produce the product is limited in the amount that they can
produce.
Dr. Waksal. That is correct.
Mr. Burton. And that is why you stopped compassionate use?
Dr. Waksal. That is correct. Right now, even the contract
manufacturer that we are working with, has one 5,000-liter--
just to give you size dimensions--one 5,000-liter fermenter
committed for about 25 runs, you know, this year. Our facility
that we are building has three 12,500-liter fermenters with
10,000 liters of capacity each. So we have invested a good deal
of moneys to try to get enough of this drug available later so
that we can make this available for all the people that need
it. And even with that, that is not going to be enough for the
future, we do not think, and we will be breaking ground in the
future for an even larger facility.
Mr. Burton. How many people are in your clinical trials
right now; do you know?
Dr. Waksal. We have treated thus far, between January 1995
and now, over 700 patients.
Mr. Burton. 700, and you have treated 30 approximately for
compassionate use.
Dr. Waksal. Yes, about 4 percent.
Mr. Burton. And the capacity of the production facility is
taxed with just that number?
Dr. Waksal. That is right. Sadly enough, we are looking at
opening up new clinical trials, and I must say that the really
sad thing is, for every patient that gets the drug in a
compassionate fashion, patients on the clinical trials do not
get the drug when we are limited by the type of drug, a
protein-based drug that we are making, we are so constrained
right now, that we are limiting the amount of clinical trials
that we would otherwise be able to do simply because of the
lack of drug.
Mr. Burton. Is there anything that could be done--and this
is a generic question--the FDA has to approve these things. And
I mean, obviously, that is something that I think we all agree
needs to be done. You do not want a contaminated product put in
the market that is going to kill people rather than help them.
But is there anything we could do to speed up the process from
your producer now, and whatever company, and I do not want you
to get in trouble with the FDA and have them give you a hard
time because of what you are going to say. But I would like to
know if there is anything that can be done to speed up the
process for these new promising drugs like this one?
Dr. Waksal. Look, actually, we have had a very good working
relationship with the FDA.
Mr. Burton. Do not be diplomatic.
Dr. Waksal. No, I am not being diplomatic. I am telling
that we have gotten fast-track designation. They have worked
with us to try to help direct us what we need to do in our new
manufacturing facility. I am sure there is lots of things that
the FDA could do to speed up the process in terms of what we
believe is going on, but I am sure that they are as constrained
as we are in timing.
Nevertheless, we are moving forward. We believe that this
product is moving forward very rapidly through the FDA approval
process, and could very well be on the market sometime in the
first half of next year.
Mr. Burton. First half of next year.
Dr. Waksal. Yes.
Mr. Burton. But it still will be limited because of your
production facility.
Dr. Waksal. Well, the new facility, we hope will be up and
will be going through the approval process, so that we can make
enough drug available for the approval process after launch.
Mr. Burton. I have some more questions. Mrs. Davis, do you
have some questions?
Mrs. Jo Ann Davis of Virginia. Thank you, Mr. Chairman. I
guess I have one, and it relates to Mr. Baxter's son. As I
heard in his testimony, his son's doctor has the drug out in, I
believe, California, and I guess I am curious as--and I
understand that he is 16, and that you are not allowed to give
it to--I guess you could not give it to anyone under 18, but,
you know, granted this is a disease that you do not expect to
find in a 16-year-old. And I guess my question is, if the
doctor has the drug, could you not then ask the FDA to make an
exception and let you give it to this 16-year-old, whose
prognosis is just a couple months? He cannot wait till the
first half of next year.
Dr. Waksal. No. That is absolutely true. That is not the
issue here. One, we will go to--we would go to the FDA, and we
made it clear that we would go to the FDA to lower the age
requirement, and I am sure the FDA would comply in that
particular case. I do not think that is the issue here. And the
issue of clinical trial sites is one, where we do these
clinical trials all over the country. We have clinical trials
going on in California out West, obviously. Dr. Rosenberg is
one of our investigators in our head and neck trial.
Unfortunately, in the colorectal study, the closest state to
the Baxter family is Indiana. We have one of the clinical
trials going on in Indianapolis right now. But it is very
difficult to open up a new site, not knowing still whether
David is a candidate yet for C225. We have no idea yet. He has
not failed his conventional therapy yet, and we do not know
whether he is positive for the molecule that our particular
antibody attacks, the EGF receptor. So we cannot open up a site
prior to knowing whether or not a patient is a candidate. So it
is still unclear right now, and we do try to be as
accommodating as possible in this particular situation, but
again, it is a very difficult situation. You cannot open up a
site for a single patient prior to knowing whether or not the
patient is going to be eligible for one of those trials, and it
takes a good deal of time to do just that, to open up one of
these sites and to go through the approval process for those
institutions.
Mrs. Jo Ann Davis of Virginia. And I guess that brings me
to the question, back to, I guess, Mr. Santino. I believe his
wife was denied because she was, from his testimony, too sick
or had too many treatments. And could you explain that to me so
I could understand it a little better?
Dr. Waksal. Well, first of all at the time, unfortunately,
and I feel terrible about Mrs. Santino, but we had no
compassionate use protocol in place after January. We ended it
because of number of patients that we had. We could not
successfully deal with the list any longer. We did not really
have enough drug to make it available after that. The list had
gotten too long. And I am very sorry that, unfortunately, from
the point of view of the Santino family, that we did not
communicate that properly, and probably should have had letters
sent out. Unfortunately, our medical affairs director tried to
answer all of these phone calls personally, and it was not
something that was acceptable to the Santino family.
But at the point in time that we design these trials, these
trials have very fixed criteria, and we cannot deviate from
those criteria. Those criteria are negotiated with the FDA, and
once they are set, they are set, and the people that enter
those trials have to fit the age, the disease stage, and etc.
All of the criteria that we negotiate with the FDA to move
these drugs forward in a proper fashion so that the clinical
community and the FDA can assess whether or not these drugs are
going to be useful to the population at large, to the clinical
population that we are talking about.
So, in effect, sometimes patients are too sick to get on
one of these trials, because their health does play a role in
all of these things, and obviously, that is who we are dealing
with, sick patients, but the clinical trial protocols are so
defined, that there are patients that cannot enter them.
Mrs. Jo Ann Davis of Virginia. Thank you. And I agree with
what Ms. Kellum said in her testimony. I think we all would
like to find a cure to this terrible disease. It has affected
my family and my husband's family. And it is just something
that I wish you the best, and if there is anything you can do
to help David, I would appreciate that.
Dr. Waksal. We are trying.
Mrs. Jo Ann Davis of Virginia. Thank you, Mr. Chairman.
Mr. Burton. Thank you, Mrs. Davis.
How do you determine if someone is positive for the EGF?
Dr. Waksal. There is a test that is done that is a
pathological test, where we utilize a marker that sort of
lights up the molecule if it is there, and then the pathologist
can say that the patient's tumor is either positive for this
receptor or not.
Mr. Burton. OK. We have had a number of cases in my family,
one that is current. And I have been in a lot of facilities
where they administer chemotherapy on a regular basis. And a
lot of people who get chemotherapy, their immune systems are
depressed while the tumors are being killed hopefully. And I
just wondered, if people go through a complete series of
chemotherapy treatments, does it make them more likely to be
able to take C225 or less likely?
Dr. Waksal. Well, our drug----
Mr. Burton. Does it depress their immune system to such a
degree that they would not qualify?
Dr. Waksal. No. And if----
Mr. Burton. Or can you give me a comparison, those who--and
I do not know if you have this kind of information--those who
have taken C225 without chemotherapy being first administered,
and those who have had it administered?
Dr. Waksal. Well, some of the first studies that we have
done are obviously in patients that have become refractory to
chemotherapy, that no longer respond to their chemotherapy. And
then they get to IMC-C225 in combination with the therapeutic
agent that they failed. So the earliest responses we have seen
have been in patient populations that have already failed all
the existing and approved chemotherapeutic agents. We have
data, earlier data that suggests that in patients that have not
necessarily failed but are more stable disease patients, that
we may even have a better response. And the whole purpose of--
--
Mr. Burton. Do I interpret that to mean that those who may
not have had chemotherapy?
Dr. Waksal. Well, those who are not failing chemotherapy,
but are taking the chemo and the chemo is having some effect.
In those patients there may even be a better response, and in
fact, that is our approach to this whole process of getting
approval. We are first applying for approval on the phase II
data using the fast-track designation that Dr. Temple talked
about for cancer drugs, but it is provisional, sort of
conditional approval. And the next thing that we are going to
be doing and that we are opening up right away is an earlier
stage study, a very large clinical trial in patients who have
never received chemotherapy and who have just been newly
diagnosed with these types of tumors with colorectal cancer.
Mr. Burton. So you are starting a new study right now on
people who have not taken chemotherapy, but----
Dr. Waksal. Who are chemo-naive, that is correct.
Mr. Burton. To see if C225 is more effective or less
effective. I see, OK.
Let me ask Dr. Temple or Ms. Delaney. Ms. Delaney, we have
not been able to get you to answer any questions. But one of
the things that I think that Mrs. Davis, Representative Davis
talked about and the people of the first panel talked about,
was the lack of answers, the lack of communication. What can
FDA do in conjunction with these manufacturers of new drugs to
get this information on the Internet so that people can find
it? And if they do not have--if they are not Internet literate
or computer literate, as many people are not in this country,
how they can get a hold of this information by contacting the
FDA. I know that you have a lot to do over there, but it seems
to me that one of the most hopeless things people go through is
seeing a loved one or themselves being in this situation, and
they say, ``What is available? What can we try? What can we do
to save their life?'' And they cannot find the answers. I mean,
that has got to just drive them up a wall, especially if after
the fact, after somebody dies, or they are so depressed and
their immune system is so depressed that they cannot survive,
they find out there was something out there and they could not
find it. And we had a couple of people on the panel before you
that mentioned that.
So what can FDA do in conjunction with the private sector
to make sure all that knowledge is accessible?
Ms. Delaney. Well, actually, the scenario that you just
presented, Mr. Chairman, is pretty much the standard phone call
that we get to our office every day. And it is people who are
pretty much out of options, or many people believe once they
are diagnosed they are out of options. They are very confused
and upset by what has happened.
In cases like that, when it is a first diagnosis, we
recommend that people first of all talk to their doctor. Second
of all, that there are many, many cancer patient advocacy
groups that are out there to help them, and we have a huge
resource list. But the National Cancer Institute is really--
there is a huge educational arm to the Cancer Institute, and
the best place for people to find out information about new
drugs in development in their cancer is the Clinical Trial
Registry. It is known by its acronym of PDQ, but it is
available through clinicaltrials.gov, and----
Mr. Burton. Excuse me. I cannot remember which gentleman it
was. I believe you said that you had four Internet sites
yourself?
Mr. Santino. Well, the----
Mr. Burton. I know, but you are obviously Internet
literate.
Mr. Santino. I do. I have four myself.
Mr. Burton. You have four yourself. And you went through
everything time and again, and you could not find information
that should have been readily available. I think that is what
your testimony was.
Mr. Santino. What is available it is not on the Web site
anyway.
Mr. Burton. It is not on the Web site.
Ms. Delaney. But that is just for people that are first
diagnosed, and clearly, Ruth-Ann Santino had been through all
the standard treatment.
And so when we get a call or people want to know about a
drug, and they have exercised all of their options with the
standard treatments, we then try to assist them in finding the
different places where they might look for drugs. There are Web
sites, that--actually, when I talked to Ruth-Ann, the Web site
we told her about, which she did not know about prior to that
phone call, was pharma.org, and that is the Pharmaceutical
Research and Manufacturer's Association Web site. They do a
publication every other year in cancer called ``New Drugs in
Development in Cancer.'' There are 402 drugs listed by tumor
type, and it is available on the Internet, and you can search
it in a PDF file very easily.
Mr. Burton. Let me ask you this question. You indicated
that after they have gone through their conventional treatment,
what if they do not want to go through what is called
conventional treatment? What if they have an aversion to, say,
chemotherapy?
We have a young man, the Thomas Navarros case. I am sure
you are familiar with that. It has been all over the media. And
he was denied access to experimental treatment because he had
not first failed what the FDA said was a standard form of care,
chemotherapy and radiation. Why is that and can people get
information if they do not want to take chemotherapy and
radiation because they think there is a----
Ms. Delaney. I am going to let Dr. Temple answer that
question, but I wanted to--can I tell you about what we do with
companies to make sure on this compassionate use, before he
answers that question? Would that be OK?
Mr. Burton. Sure, sure, sure.
Ms. Delaney. When it is clear that there is a number of
phone calls that are coming in on a new drug--for example, this
happened with C225 and a number of others in the last 2 years--
we then place a call to the company, and we say, Look, I am
sure you are getting many more calls than we are getting. The
National Cancer Institute is also. We need to sit down and talk
about what is your policy? Do you have one? If you do not have
one, please develop one, and we will help you sit down with the
patient advocacy community and make that policy clear to them,
so that a phone call to the Colon Cancer Alliance is the same
thing as a phone call to the National Cancer Institute or a
phone call to ImClone. So that a patient or family member is
not having to call all these different places, that everybody
knows that, for example C225 will not be available. I think
Fred Santino said it eloquently. It wastes to much time.
And so what we have done, not only with ImClone, but we
also have done it with a number of other companies, is to bring
everybody together. So we are sort of the convener. We do not
have a lot of authority in this area. It is an initiative if
you will. But we convene the groups, and I think Dr. Waksal
could talk about what we did specifically with their company.
Now, I will let you speak to Dr. Temple on the Navarro
case.
Mr. Burton. It sounds like, from the first panel and from
other people I have talked to, that they have difficulty in
finding all this information, and if the FDA and HHS could look
into that to see if there is some way to streamline the process
so that on the Internet and through mail if necessary or faxes,
that people can get as much information as quickly as possible
might help a lot.
Dr. Temple.
Dr. Temple. It may be those very sites ought to link to
each other somewhat better than they do, for example. We can
look into that.
The cases we have been talking about are all ones in which
someone wants to use a treatment that is under investigation
outside of a clinical trial. I would say, as I said before, our
usual answer to those requests is yes. Sometimes these are
individual cases that come to us, and sometimes investigators
have a program of making drugs available for such uses.
The one case where we are inclined to say no is when there
is an existing therapy that is surely lifesaving and possibly
even if it is clearly life-prolonging. And in the cases that
you are talking about, we thought that people were going to be
denied therapy that had significant cure potential. Those are
the only two cases, where, to my best knowledge, we have denied
them.
Mr. Burton. Well, I do not want get into a debate about
that.
Dr. Temple. I realize there was a debate about that.
Mr. Burton. Yes, a big debate. But anyhow, go ahead.
Dr. Temple. Right. But I understand there can be
differences of view about whether the toxicity is worth it and
a variety of other questions. But that is the one case where we
have trouble.
If one--I am not going to talk about C225, but if we were
looking at someone who wanted to use a drug for colorectal
cancer that had not been well studied but looked promising, we
would certainly ask whether the person had already received
fluorouracil-leucovorin and CPT-11, two treatments that are
known to improve survival. So we would think, at least
initially, that it would not be sensible not to use those
first. Now that could be----
Mr. Burton. Would you deny them access then to the new
experimental drug? Because Dr. Waksal said a while ago they are
going to start a new clinical trial on people that did not take
chemotherapy.
Dr. Temple. Yes. We are enthusiastic about the trial. And
he also did not say that it was being combined with
chemotherapy in that case, which it is.
Mr. Burton. It is going to be combined with chemotherapy?
Dr. Waksal. Yes, it is.
Dr. Temple. Yes, that would be the usual thing to do. You
do not----
Mr. Burton. What if the patient does not want chemotherapy,
they cannot get into the clinical trial, they cannot take that
C225?
Dr. Temple. I think that our first responsibility is to get
the drug approved, they patients then and physicians can make
available the drug to those patients who do not want
chemotherapy. But this drug works best, like other anticancer
agents, in combination therapies, and when we see it being used
in combination with radiation or in combination with other
antineoplastic agents, we really get the most dramatic types of
responses.
Mr. Burton. I see Dr. Weldon has joined us. Did you have
any more comment before we yield to Dr. Weldon? Dr. Weldon, do
you have any questions?
Dr. Weldon. Yes, I do, and I want to thank you, Mr.
Chairman, for calling this hearing. I was unfortunately tied up
in another committee on some space policy issues, which as you
know, is very important for the District that I am in.
But this--I have been--it is kind of been there and done
that. I have seen these cases where you have patients with a
problem that could possibly benefit from a clinical trial drug
and does not meet the qualifications for the clinical trial for
a variety of reasons and is denied. And do we need to seriously
look at--maybe I will ask you, Dr. Temple. You are with FDA, I
understand.
Dr. Temple. Right.
Dr. Weldon. I would imagine FDA is coming under increasing
pressure, and NIH, on this issue, as the proliferation of the
Internet and the health care consumers, cancer patients getting
much more knowledgeable of what trials are out there and what
drugs are available. Now today, that Internet is so amazing,
anybody could sit down in their living room, particularly if
you have a high-speed access, and you can just get incredibly
well educated. Literally, what you used to have to hire staff
or professionals to research for you, poring through libraries,
you can access in minutes. And do we need to consider changing
policies either at the administrative level or the law, to
allow more compassionate use of these compounds?
Dr. Temple. Well, far be it from me to comment on whether
you need a new law without direction from the Department, but
our current policies are very permissive on those matters, as
my testimony says. Once a drug looks interesting and promising,
there are many ways to make it widely available if a sponsor
wants to. But as Dr. Waksal has pointed out, there may be
impediments to that, availability of the drug, dilution of
their own resources.
And also you could ask about doing it fairly. Any
individual case of a person who has failed other therapy is
obviously evocative, as we have all heard, and quite terrible
in many ways.
The question though that comes further is, if you took all
people who had failed the available therapy for colorectal
cancer, which unfortunately is most people with metastatic
colorectal cancer, do we have enough information to make the
drug available to all of them even before the studies are well
along? That is a difficult question. I am not trying to tell
you what the answer is, but we have a system that says that
there is supposed to be a certain amount of evidence before you
essentially make the drug available to the whole population.
That is a difficult question.
I actually think that is less of a problem than one might
wonder whether it would be, because the number of drugs that
sort of look exciting like that at any given time is modest.
That is unfortunate in some sense, because you would like to
have more of them. But for the few drugs that are getting
people very excited at the oncology meetings, I believe the
system can cope with them, but people have to be willing and
able, and as Dr. Waksal just said, they were not able. They did
not have the drug.
Again, I cannot speak for the particular case, but this is
a drug where an application is imminent or with us? An
application is imminent. They finished phase 3 studies, and
there appear to be responses. The definition of what is
acceptable for a treatment protocol or a treatment IND it has
finished all its trials and looks promising in the trials, and
treats something that has no other treatment. Well, people who
have exhausted standard therapy for colorectal cancer have no
other treatment, so it could very well meet the requirements
for treatment IND. Again, I am not trying to speak for the
Center for Biologics.
But those mechanisms are available to be used. It is not
that the criteria are onerous or anything like that. In fact,
you are even allowed to sell the drug.
Dr. Weldon. So these stories that get in the press, they
are the exception?
Dr. Temple. Well, again, I am not going to say that because
I cannot say I know the entire experience. I am sure there are
people who are frustrated by the fact that they have exhausted
available therapy and have nothing to seek. Well, sometimes
that is because there is not anything reasonably well developed
to seek. But where there is, where, as I said, it is sort of
exciting people at ASCO, whether it is Gleevec, it is C225,
there are mechanisms to make those drugs widely available, and
we encourage them to be widely available. There is no reticence
on FDA's part; there really never has been.
And such arrangements do exist, but, you know, distributing
the drug to 10,000 people one-by-one, investigator-by-
investigator, is a lot of work for a drug company. They may or
may not want to do it, and they want to devote their resources
to gaining approval and making the drug available to everybody.
It is a complex judgment. I would not want to have to make it
for them.
Ms. Delaney. May I add to that? From the cancer patient
advocacy community perspective, this whole issue--and I think
in other disease areas as well--there is unanimity of
agreement, that a much broader public discussion needs to be
had because there are so many questions that are--some are
beyond our agency's authority. The ethical issues that are
involved here, disease by disease differences. I mean, it is
interesting to see. In the advocacy community, the positions
are more rigid in opposition to compassionate use in the
disease areas where there are a lot of treatment options. But
in the disease areas where there are fewer treatment options,
they have much more liberal views about this. And so it is
something that, you know, that a lot of the advocates feel
needs a much, much larger discussion that would involve the
government, the industry, and the patient advocacy community in
many disease.
Dr. Weldon. Thank you, Mr. Chairman.
Mr. Burton. Thank you.
Mrs. Davis, you have any more questions right now?
I have a few more questions. It is going to take a little
bit of time. In other countries, there is different therapies
and treatments that are being utilized today that have not yet
been approved by the Food and Drug Administration in this
country. Many patients are going to other countries because
they want to try these other therapies which have not been
approved by our health agencies.
Do you share any information or talk to these other
countries like Germany or other countries where they are
providing treatments which have--some of them have some pretty
good track records because we checked into those? Do you talk
to them? Do your health experts at FDA and HHS communicate with
them at all?
Dr. Temple. We do not necessarily talk to them about a
specific drug that is available. What triggers our interest
generally is an application from a company to market a drug or
to study it. If there are drugs that are very promising that
are not even under study in the United States, I am not aware
of any. We are aware of some drugs that are marketed elsewhere
that have for one reason or another not been approved. And we
are committed, actually, to encouraging a manufacturer of any
drug that looks promising abroad and that is not here, to come
in. We have only a limited capacity to be encouraging. Nobody
has to come to us if they do not want to, but in the cancer
program we outlined some years ago, we made a commitment to do
that. And we have not found very many that we are not aware of
or that are not at least under study here. But, you know, you
may have found some we do not know about.
Mr. Burton. You serve as adviser to the National Center for
Complementary and Alternative Medicine, do you not?
Dr. Temple. I am one of our representatives, right.
Mr. Burton. How much involvement have you had with offering
advice on research to them?
Dr. Temple. Well, when people want to study an alternative
therapy and submit an IND to us, which we encourage them to do,
we definitely give advice on how to do the trials and how to
make them optimal. I can give one example. It is outside the
oncology area. When the NIMH, in conjunction with NCCAM, wanted
to study St. John's Wort for depression, they came to us with a
trial, and they were going to do a direct comparison of St.
John's Wort and placebo. We advised them that they ought to
include an active control standard agent as a treatment also
because we knew that many trials of good design cannot tell
active drugs from placebo. So they are doing a three-arm trial
that will give a much more definitive answer than the recent
trial that compared St. John's Wort with only placebo. So we
try to give the best advice we can.
Mr. Burton. Do you think patients should have the right to
go completely alternative in their treatment of cancer, or
should they go with a conventional treatment, chemotherapy,
radiation?
Dr. Temple. Well, they have the right. I mean, these things
are available.
Mr. Burton. I was asking your opinion.
Dr. Temple. Oh, I think they should have the right as a
sort of freedom issue, and in any event, the law allows them
that right. So do I think it is wise, is a different question?
But I think I will not offer a comment.
Mr. Burton. Do you remember the young man we were talking
about a little bit earlier, Thomas Navarro? His parents and he
wanted to have that right, and they were denied that right and
had to go through the other processes.
Dr. Temple. Well, I probably misspoke. This is a drug,
although it is alternative in some sense. It is a drug that is
being studied for its ability to treat cancer. And it has
been--its use has been allowed in hundreds of people despite
not a great deal of evidence of effectiveness, and we have not
tried to discourage that at all.
Mr. Burton. Only after the traditional therapies were used.
Dr. Temple. Or if there are not good therapies. There are
many tumors where there are not good therapies. The cases where
we have objected were where curative therapy was being denied.
Again, I accept the idea that people can disagree on that, but
I think our principles were fairly clear.
Mr. Burton. There may be disagreement, but when you are the
person that has the cancer of the pharynx or the husband or the
wife of the person that has the cancer, it takes on a little
different dimension. The former head of HHS had one view of a
cancer therapy treatment when he was Governor. Then when his
wife became ill with cancer, he tried all these other
treatments that were not approved because he wanted to save her
life. So, you know, when your ox is gored, it is a little bit
different.
For instance, let us take you for instance. Are you
married?
Dr. Temple. Yeah.
Mr. Burton. If you are married and conventional treatment
is not helping your wife and she is going to die, would you try
other things?
Dr. Temple. Well, that is not the question we are talking
about here. We have not hesitated to allow the treatment you
are talking about in people who have exhausted other therapy.
Mr. Burton. After they have exhausted other therapies.
Dr. Temple. Well, that is what you asked me about. If my
wife had something and had not responded to available therapy,
would I try something else? My answer is I probably would not,
but I am mulish that way, and besides, she would be the one to
decide. That is how it works in my house anyway.
Mr. Burton. Do you think an individual ought to be allowed
to opt out of chemotherapy and radiation, and then go straight
to treatments while they are experimental, that might be less
toxic?
Dr. Temple. Well, again, when that issue has arisen, where
the therapy is importantly effective--this is what I am talking
about--there are many cancer therapies where the effect is
modest or uncertain, and we have not insisted that people try
those. It is only where the available treatment was curable. In
the two cases we are talking about, the cancers were curable by
available therapy. That is not a very common situation in
widespread cancer, unfortunately.
One was Hodgkin's disease and one was a malignant glio. So,
you know, we just could not, as physicians and as regulators,
think that was reasonable.
Mr. Burton. Have you heard of the National Foundation for
Alternative Therapies?
Dr. Temple. I am not sure.
Mr. Burton. A former colleague of ours is the head of that,
and I think they have examined, I think, 73 different clinics
and facilities around the world that provide alternative
therapies, and they found some that have some fairly great
results, one in particular in Germany that has been very
successful. And I guess the question I asked a while ago I
would like to ask again, how do you communicate with these
other clinics and other facilities around the world that may
have had some success by using a different approach to dealing
with things like cancer?
Dr. Temple. Well, again, what triggers our interest in
something is that someone wants to use it here, wants to use it
under an investigational program or market it. When they do
that, they bring forth the data that they think supports this
use. We strongly encourage investigation of alternative methods
or bringing the data and seeing whether it needs to be
investigated further. We are, perhaps surprisingly, non-
dogmatic about theories of cure. We are skeptical about all of
them. So we like to see people bring forth the data, and
alternative treatments can be studied just as regular ones can.
Mr. Burton. But there is no outreach program. I mean, you
wait till they come to you with alternative or complementary or
new therapies or new--there is no program by FDA to reach out
to other facilities and other governments around the world that
may have tried a different approach that has been successful.
And I guess my question is: why is that? It seems to me that
that might be a resource that our health agencies haven't been
tapping. Why would you not talk to the people over in Germany,
or England, or France or other countries, Spain, where they
have had some very positive results with other therapies? Why
do you wait until they come to the United States and have to go
through the bureaucracy of the FDA?
Dr. Temple. Well, our bureaucracy with respect to studying
things is de minimis. It is very easy to get into clinical
trials, and someone has to want to do that.
Mr. Burton. I understand, but they have been in this
clinical trial mode since 1995. We are 6 years later. Hundreds
of thousands of people have died from colon cancer probably
during that time period. If there is a facility in Germany or
someplace else that has had some success with that, why isn't
there an outreach program that would eliminate a six or 7-year
delay while clinical trials are going on? Why would we not at
least try to find out about it?
Dr. Temple. I am not following that. This is how long it
has taken to develop C225.
Mr. Burton. He said that they started the clinical trials,
did you not say, in 1995?
Dr. Waksal. That is correct.
Mr. Burton. OK. 1995. It is 6 years. It takes a long time
for a drug to be improved even if the efficacy of it is proven.
It takes a while. It takes about 5 or 6 years. And so what I
am----
Dr. Temple. Wait, wait, wait. We have got to be sure we are
talking about the same thing.
Mr. Burton. Well, it takes that long----
Dr. Temple. No. They have been developing the data. They
have only treated 700 people in those 6 years. That is how long
it has taken them to get data on 700 people. The approval
process, once they submit the data to us, nowadays for a drug
that is so-called fast-tracked or priority review, is something
like 6 or 7 months. I know that for people who are impatient
and waiting, even that is long, but it is not 5 years. The time
it takes is to develop the data, and nobody knows how to do
that much faster than it gets done now. You have to accumulate
patients, and you have to start small and get larger and so on,
so that is what we do.
I have to say, if there are curative treatments for
colorectal cancer out there, and somebody is hiding them in a
clinic, that would be a really strange thing. I mean, it is a
dreadful disease----
Mr. Burton. No. I am not saying they are hiding in a
clinic, but they have had some success----
Dr. Temple. Well, how would we not know that? I mean, there
must be publications or something. Where is this drug? What
could it be that is curing colorectal cancer and nobody knows
about it? I am skeptical of the existence of those things.
Mr. Burton. But there is no communication outreach program
from FDA to other governments and other facilities around the
world.
Dr. Temple. We are trying to encourage study of any drug
that is marketed in other countries for cancer. We are
interested in them and have explored how to get it studied. And
there are a few drugs that are approved abroad that are under
study.
Mr. Burton. I am not necessarily just talking about drugs.
I am talking about alternative approaches to--in a yes or no
answer, there really is no outreach or communication program
with other countries and other health--and their health
agencies?
Dr. Temple. Well, the answer is no on that question. The
other health agencies do not approve alternative medicines in
the same way as they approve drugs. It is a different system.
They do make botanicals available in Germany in a fairly well
characterized way, but it is not the drug regulatory authority
that does that. It is a different group.
Mr. Burton. I know. I guess we are splitting hairs here.
The question is if they have a success rate, it seems to me it
would be something that our health agencies would at least take
a look at to see if it could be applicable to people here in
the United States.
Let me just ask a couple more questions, then I should be--
do you have any questions? I do not want to monopolize this.
We have been told that companies are owned--sir?
Dr. Weldon. Sorry to interrupt. I did have a sort of a
followup to what you were getting into before.
Mr. Burton. Sure, go ahead.
Dr. Weldon. I have a little bit of experience in this
arena, but just for the record--and maybe Dr. Waksal can talk
about this--and you alluded to it, Dr. Temple. The time it
takes to accumulate the data. You know, I worked on a drug for
ovarian cancer when I was in medical school, and maybe you can
just elaborate on this a little bit. It is not like you can
just go to Wal-Mart and accumulate patients.
Dr. Waksal. No, you are absolutely correct. We started our
clinical trials in January 1995, and first had to show, both
for ourselves and the FDA, that the drug was safe by itself,
and we had a small cohort of patients that we treated to show
safety and see if there was any hint of biologic efficacy,
whether the drug was working at all. And as we went forward, we
saw that the drug was safe eventually, and we began to use it
in a number of different situations, in combination with almost
every chemotherapeutic agent out there and in combination with
radiation. And over----
Dr. Weldon. If I can interrupt you, you could not use the
drug unless somebody failed other treatments, correct? You
could not just----
Dr. Waksal. That was not the case, actually. First we went
into patients that had failed prior therapies. But then we put
together trials, for example, in patients that had local,
regional--that were receiving radiation for local, regional
disease with head and neck cancer, that were not surgical
candidates, but had not had metastatic spread of that disease.
And we used it in combination with radiation in that patient
population before we went off into phase III studies, to prove
statistically that our drug worked in combination better than
radiation alone. And we are doing that. And that trial is
moving along.
Dr. Weldon. So you have to accumulate a large enough
statistic sample and you have to have controls and it just
takes time for those patients to come into the system.
Dr. Waksal. Absolutely. I mean, one of the things that we
have done, and it is because of the FDA guidelines on unmet
medical needs, is in the colorectal study, we really were not
using our drug in colorectal cancer initially, and it was
actually because of the compassionate use situation with
Shannon Kellum and her physician that we learned that our drug
had activity, significant activity in colorectal cancer. We
then began a clinical study to see whether or not in a patient
population that ended up being about 139 patients, whether or
not in that patient population, where we could ascertain in
statistically significant fashion that this drug was working.
We began that trial last February. We completed enrollment in
that trial at the end of last July. We closed the sort of
statistical timeframe at the end of January, and we are going
to be imminently filing for approval for that particular
indication. So that is the period of time that it has taken for
this particular indication to go through the process from
enrollment to completion of the clinical package. We presented
that data at the cancer meetings in May. We are about to file
and begin the biologics application process with the FDA, and
hope that it will be one that will be rather expeditious.
Ms. Delaney. May I just say something about--you are
talking about recruitment, at least alluding to it. And while
it was not particularly an issue with C225, the cancer patient
advocacy community is deeply concerned about the issue of adult
recruitment to cancer clinical trials. The statistics that is
used most often is between 3 and 5 percent of adult cancer
patients end up in a trial. In pediatric cancer, that number is
roughly 70 percent. It is at least 70 percent. And many believe
that is the reason that we have the breakthroughs that we have
had in the childhood cancers. This is a subject that has been
studied a lot, about why recruitment is so difficult. And a lot
of studies have been done on it, and there are a list of
reasons, but it is a very difficult problem.
Dr. Weldon. You wanted to add something?
Dr. Temple. Yes. There is a quirk in the system that tends
to get people late in disease studied sooner than people early
in disease. Some years ago, actually, Dr. Waksal referred to
this, we made it clear that we were prepared to approve drugs
for refractory patients, people who have exhausted other
options, on the basis of tumor response alone, that is,
shrinking the tumor. Now, tumor response is a surrogate end
point that suggests a reasonable likelihood of patient benefit,
but it really does not demonstrate it. It is, however, much
easier to demonstrate an effect on tumor size than it is to
show that you have actually improved survival.
Dr. Weldon. So you are talking about you doing a scan or an
ultrasound, some measure----
Dr. Temple. Yeah, right. Shrink the tumor by 50 percent.
Dr. Weldon. Shrinkage, no demonstration of, per se,
improved survival or clinical improvement.
Dr. Temple. Right.
Dr. Weldon. Just purely in imaging.
Dr. Temple. Right. In contrast for approval as initial
therapy for, say, colorectal cancer, we would ask that people
show that there is improved survival or improved symptomatic
benefit or something like that. It is much harder to do those
studies. They take longer, so they are generally left for
later. It is not that people ignore that population, and it is
not that if the drug were available, someone could not use the
drug in that population also, but the quickest route to
approval is through treatment of refractory patients. You could
also say they are the most needy in some sense too. So I am not
arguing that is irrational or unreasonable, what we do, but
that is partly why it happens.
Dr. Waksal. And that is exactly the approach we have taken,
first to look at that population of unmet medical need, and now
moving forward into first line of therapy, and going to be
initiating a much larger clinical study sowing survival
benefit.
Dr. Temple. But if they had wanted to make their first
trial standard therapy plus--not their first trial, but their
first clinical trial--standard therapy plus or minus C225, in
the control trial, I do not want to speak for biologics, but in
a drug setting, we would not object to that. It is OK. But that
is a much harder trial to do.
Dr. Weldon. Ms. Delaney, I just want to get back to the
issue you were talking about, the pediatric cases. Could it be
that the vast majority of pediatric oncology cases end up at
pediatric teaching hospitals?
Ms. Delaney. Yes.
Dr. Weldon. Versus adult cancers treated at the community
hospital level?
Ms. Delaney. Well, the pediatric oncology community was
real smart back in the 1960's. They all got together. They
said, ``Look, you know, we only represent a small percentage of
the cases, like there are 10,000 cases of pediatric cancer in
this country out of 1.2 million this year.'' So if you have got
that many, you know, at St. Luke's you have got four kids with
leukemia and then you have three with Hodgkin's disease out
here, you know how are we going to get--so that pediatric
oncology community got together and they formed a cooperative
group, and they started----
Dr. Weldon. Nationwide?
Ms. Delaney. Yes. And they started pretty much every kid on
a trial, which has resulted in huge breakthroughs in Hodgkin's
disease, in leukemias. You know, not necessarily cures, but way
up in the high percentages of survival with metastatic disease.
What the adult cancer advocacy community wants to do is
achieve those same kinds of cooperations to improve
recruitment. I remember reading--I wish I could get the
citation. I cannot find it again, but after animal studies, the
most time consuming aspect of cancer drug development is the
recruitment to the phase 3 trial. I mean, a drug like C225 is
very unusual in the amount of publicity that it has gotten and
the attention. So, no, it is not hard to recruit to a trial
like that. But there are some other promising drugs out there
that nobody knows about, that are struggling to try to get
patients to the trial, and also National Cancer Institute
trials, which are new combinations of already approved
treatments that deserve attention. So it is something that the
advocacy community is very focused on, that we spend a lot of
time in our office with them on, and with the pharmaceutical
industry.
Dr. Weldon. Thank you, Mr. Chairman.
Mr. Burton. Did you have any more questions, Mrs. Davis?
Mrs. Jo Ann Davis of Virginia. I guess something Ms.
Delaney just said struck a chord. You said there is a lot of
drugs out there that would love to have recruitment. But wasn't
that the very thing that we were asking the question, how do
these people know that there are drugs out there? I mean, we
are going back to the same thing. You know if you had cancer
and knew that there was an experimental drug out there, you
would certainly want to be recruited I would think.
Ms. Delaney. Well, one of the ways is for the
pharmaceutical industry to place their drug trials in a public
access data base and that is one of the FDAMA laws or rules,
section 113, is that once a drug reaches the point of looking
into efficacy, that drug, in life threatening diseases, needs
to be added to a public access data base. And right now in the
National Cancer Institute's data base there are about 1,835
clinical trials. Only--well, really, the number right now is
exactly 184, are from the pharmaceutical industry. We know that
here--you know, just abstractly, that there are many, many more
drug trials out there in cancer than that. So we need to have
better cooperation. We are working with them. There is a draft
guidance out for the pharmaceutical industry to use, but we
need to have more of their input--that is how people will learn
about what those drugs are, what trials are out there, is if
there is better cooperation with making the information
available at least at phase 3.
Mr. Burton. Would you yield to me just a minute? FDA has
all kinds of regulatory authority. Why cannot you just tell or
pass a regulation over there, which you do quite frequently,
and say that the pharmaceutical companies have to do that so
that the information is available through FDA to be able to be
put on the Internet? I mean, why say, well, they are out there
and they are not telling us all that stuff. Why don't you just
say that they have to do that.
Ms. Delaney. Well, there is a draft guidance and it is
process that is----
Mr. Burton. Wait a minute. It is a draft guidance and it is
in what process?
Ms. Delaney. There is a process, and a draft guidance has
been developed, and you know, we have received responses from
industry, and it is incorporated. But in the meantime, the
advocacy community--and I am not speaking for FDA right now--
the advocacy community has been asking them to cooperate, and
it has been difficult.
Mr. Burton. Who has been asking--you have been asking the
pharmaceutical companies to cooperate?
Ms. Delaney. Yes.
Dr. Temple. Well, why doesn't FDA tell them to cooperate?
Well, actually, you told them to. FDAMA has a clear obligation
for them to do it.
Mr. Burton. Well, if they were told to do it, why are they
not? Are they violating the law?
Dr. Temple. I do not fully know the answer to that. We will
find out what the difficulties are. I cannot tell you off the
top of my head.
Mr. Burton. Well, the information is extremely important,
and I think the gentlelady asks a very important question. If
that is out there, and there is new therapies and new processes
that can be utilized to help people fight cancer, it is almost
criminal not to let all that information be put on the
Internet, or in some way to communicate.
Do you have any other questions?
Mrs. Jo Ann Davis of Virginia. Well, I just wonder, are we
not letting the oncology doctors know about it, so that they
can give the information to their patients?
Dr. Temple. My experience is most oncologists, especially
at good centers, are very aware of the latest drugs that look
exciting, but if something is below that level, they may not. I
think we have to find out why not as many things are getting on
that site as we think should, and I do not know the answer. We
will look into it.
Mrs. Jo Ann Davis of Virginia. Thank you.
Mr. Burton. We will be following up on this, I promise you.
We will followup on it, we will make sure, and I want to thank
you gentlemen for being here to tell us your stories.
I have two more questions quickly, and then what I would
like to do is submit to you questions for the record because I
do not want to keep you here past midnight, so if you would
accede to our wish to answer some questions we submit to you in
writing, we will not ask you all those questions now.
And, Dr. Waksal, I appreciate very much your candidness
with us today, your candor. You have been very helpful. And I
just wish that there was more ability for you to produce more
of your product so that people could use it for compassionate
use. I just--it seems like to me if it is that effective, it is
just a shame that you are not in that mode yet. But we
appreciate your candor.
Dr. Waksal. We are working as hard as we can to take care
of that situation.
Mr. Burton. Well, good. Two questions. We have received a
number of complaints from families, who when reviewing cancer
research papers, are dismayed that researchers report patients
as successes from the treatment even when the patient dies. How
can families be secure that a treatment offers hope when
reducing a tumor is more important than keeping a patient alive
in research? I mean if the patient dies, how can it be a
positive in the research?
Dr. Temple. Well, there is a difficult and unpleasant
reality in the treatment of solid tumors that are metastatic,
and that is that cures are extremely rare, even for drugs we
consider promising. The standard therapy, initial therapy for
colorectal cancer is fluorouracil-leucovorin. Now you add a
drug called CPT-11.
Mr. Burton. Chemotherapy.
Dr. Temple. Chemotherapy. Surgery, if you can get the tumor
out, those are sometimes cures, and that is fine. But if the
tumor metastatic, and if it is not removed by the surgery,
mortality is almost universal.
Mr. Burton. In what timeframe?
Dr. Temple. Oh, that varies very much depending on the
tumor. It could be 12 months for some as an average, and it
could be 3 years for others. Breast cancer is famous for being
much longer. Success is--it depends on how the study defined
it. Success may mean they shrank the tumor by 50 percent for a
period of a certain number of months. Now, you might not think
that is very important if the person then goes on to die at 6
months, and I would not disagree with you, but it is a proper
measure of tumor activity. One of the things we have learned in
other parts of oncology in the treatment of leukemias and
things like that is sometimes you can find one drug that does a
little something, another drug that does a little more, and put
them together and you start to see responses that are better
than you would have predicted from the others, and that is what
everybody is dreaming about.
But so far the treatment of metastatic solid cancers,
except for some odd things like testicular, is grim.
Mr. Burton. You know, it seems to me that there ought to be
a way to clarify that when you do your statistical analysis. I
mean if a person is judged to be cured for a cancer and they
die in 6 months----
Dr. Temple. They are not judged as cured.
Mr. Burton. Well, whatever the----
Dr. Temple. Well, the usual endpoint in a cancer trial that
is looking at mortality is whether you have delayed death. That
is the endpoint.
Mr. Burton. Well, then should it not be more clearly
defined and clarified?
Dr. Temple. I would have to see the things that people are
upset about, but----
Mr. Burton. The reason I say that is because people base
their decisionmaking process on what kind of treatment to get
for themselves and their families based upon the statistical
data that you give them, and that is given by FDA to the
doctors. You know, because doctors all the time quote, well, 50
percent of these people live 5 years and 60 percent live this
long, and that statistical data is very, very important and it
should be very clear and accurate.
Dr. Temple. Well, I completely agree. The usual measure in
a clinical trial is--well, there is a complicated statistical
analysis to determine whether there was an improvement, but the
convenient number one gives is median survival. That is how
long the average patient lived. You look at how long the
average patient who did get the drug lived, and you look at how
long the patient who did not get the drug lived. And if you see
a difference, that is an improved survival.
To the extent anybody believes that is cure, they are not
understanding the data.
Mr. Burton. Well, is that explained in the data, that the
survival rate is increased by 3 months or 6 months because this
drug was used?
Dr. Temple. All of our labeling would have a figure of
something like that, yes.
Mr. Burton. One more question, then I will let you go, and
I do appreciate your patience.
I think, Dr. Temple, you stated that doctors are generally
aware of investigational drugs that might benefit their
patients. But various reports suggest that fewer than 5 percent
of primary care physicians have ever referred a patient to a
clinical trial, and far fewer than half of the physicians
associated with teaching hospitals have referred a patient to a
clinical trial. In fact, a member of my staff, who wrote this
question, who was in a clinical trial for a leukemia drug, did
not learn about the drug he is testing, which is called
Gleevec, previously called STI571. He did not learn about that
from his doctor or from a government sanctioned Web site. He
learned about it by an informal Web site that was established
by a patient who was successfully treated in an earlier phase
of the drug trials. His primary care physician knew nothing
about it. His oncologist was somewhat aware of the drug, but
vigorously discouraged him from applying for a clinical trial,
stating, ``That drug is in short supply, and they are not going
to waste it on someone of your age.''
In view of that, do you not agree, Dr. Temple, that a lot
of work remains the help doctors become generally aware of the
investigational drugs that might benefit their patients, and
thus the Web site information?
Dr. Temple. Yes. We are very enthusiastic about that. I
think the points that have been made earlier about making sure
Web sites contain these things is important. I actually do not
have any belief that the average doctor necessarily knows about
the latest cancer chemotherapy. I do think most oncologists do
know about the more prominent and promising things. But I think
for the family practitioners who may be serving a lot of
people, at least initially, more information does need to be
available.
Mr. Burton. Well, let me thank you all. Any more questions?
Well, first of all, thank you very much for being here. Thank
you for your patience. I know it has been a long day. And Dr.
Waksal, thank you very much. Thank you for being here. And we
will be in touch with you for further hearings down the road.
Thank you very much.
We stand adjourned.
[Whereupon, at 5:05 p.m. the committee was adjourned.]
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