[Senate Hearing 108-110]
[From the U.S. Government Publishing Office]
S. Hrg. 108-110
TISSUE BANKS: THE DANGERS OF TAINTED
TISSUES AND THE NEED FOR FEDERAL
REGULATION
=======================================================================
HEARING
before the
COMMITTEE ON
GOVERNMENTAL AFFAIRS
UNITED STATES SENATE
ONE HUNDRED EIGHTH CONGRESS
FIRST SESSION
__________
MAY 14, 2003
__________
Printed for the use of the Committee on Governmental Affairs
88-247 U.S. GOVERNMENT PRINTING OFFICE
WASHINGTON : 2003
____________________________________________________________________________
For Sale by the Superintendent of Documents, U.S. Government Printing Office
Internet: bookstore.gpr.gov Phone: toll free (866) 512-1800; (202) 512�091800
Fax: (202) 512�092250 Mail: Stop SSOP, Washington, DC 20402�090001
COMMITTEE ON GOVERNMENTAL AFFAIRS
SUSAN M. COLLINS, Maine, Chairman
TED STEVENS, Alaska JOSEPH I. LIEBERMAN, Connecticut
GEORGE V. VOINOVICH, Ohio CARL LEVIN, Michigan
NORM COLEMAN, Minnesota DANIEL K. AKAKA, Hawaii
ARLEN SPECTER, Pennsylvania RICHARD J. DURBIN, Illinois
ROBERT F. BENNETT, Utah THOMAS R. CARPER, Delaware
PETER G. FITZGERALD, Illinois MARK DAYTON, Minnesota
JOHN E. SUNUNU, New Hampshire FRANK LAUTENBERG, New Jersey
RICHARD C. SHELBY, Alabama MARK PRYOR, Arkansas
Michael D. Bopp, Staff Director and Chief Counsel
Claire M. Barnard, Professional Staff Member
Joyce Rechtschaffen, Minority Staff Director and Chief Counsel
Kathryn J. Seddon, Minority Professional Staff Member
Darla D. Cassell, Chief Clerk
C O N T E N T S
------
Opening statement:
Page
Senator Collins.............................................. 1
Senator Coleman.............................................. 4
Senator Pryor................................................ 6
Senator Carper............................................... 24
WITNESSES
Steve and Leslie Lykins, parents of Brian Lykins, accompanied by
daughter Tammy................................................. 6
Steven L. Solomon, M.D., Acting Director, Division of Healthcare
Quality Promotion, National Center for Infectious Diseases,
Centers for Disease Control and Prevention, U.S. Department of
Health and Human Services...................................... 15
Jeanne V. Linden, M.D., Director, Blood and Tissue Resources,
Wadsworth Center, New York State Department of Health.......... 17
Jesse L. Goodman, M.D., Director, Center for Biologics Evaluation
and Research, Food and Drug Administration, U.S. Department of
Health and Human Services...................................... 26
Alphabetical List of Witnesses
Goodman, Jesse L., M.D.:
Testimony.................................................... 26
Prepared Statement with an attachment........................ 61
Linden, Jeanne V., M.D.:
Testimony.................................................... 17
Prepared Statement with an attachment........................ 55
Lykins, Leslie and Steve:
Testimony.................................................... 6
Prepared Statement........................................... 39
Solomon, Steven L., M.D.:
Testimony.................................................... 15
Prepared Statement........................................... 44
Exhibits
1. GDeposition of James C. Vander Wyk, Ph.D., taken on January
21, 2003, on behalf of the plaintiff in the case of Steve
Lykins v. CryoLife, Inc.; Civil Action File Number 02105613-24;
Superior Court of Cobb County, State of Georgia; pages 1-4, 25-
32, 69-80, and 189-192......................................... 84
2. G``Update: Allograft-Associated Bacterial Infections--United
States, 2002,'' Mortality and Morbidity Weekly Report; Centers
for Disease Control and Prevention; March 15, 2003, at http://
www.cdc.gov/mmwr/preview/mmwrhtml/mm5110a2.htm................. 91
3. G``Hepatitis C Virus Transmission from an Antibody-Negative
Organ and Tissue Donor--United States, 2000-2002,'' Mortality
and Morbidity Weekly Report; Centers for Disease Control and
Prevention; April 4, 2003, at http://www.cdc.gov/mmwr/preview/
mmwrhtml/mm5213a2.htm.......................................... 96
4. GLetter from Senator Susan M. Collins, Ranking Minority
Member, Permanent Subcommittee on Investigations, to Bernard A.
Schwetz, D.V.M., Ph.D., Acting Principal Deputy Commissioner,
Food and Drug Administration (FDA), December 21, 2001,
concerning the death of Brian Lykins and the status of the
FDA's tissue action plan....................................... 100
5. GLetter from Senator Susan M. Collins, Ranking Minority
Member, Permanent Subcommittee on Investigations, to Bernard A.
Schwetz, D.V.M., Ph.D., Acting Principal Deputy Commissioner,
Food and Drug Administration (FDA), February 11, 2002,
concerning the status of the FDA's tissue action plan.......... 101
6. GLetter from Melinda K. Plaisier, Associate Commissioner for
Legislation, Food and Drug Administration (FDA), to Senator
Susan M. Collins, Ranking Minority Member, Permanent
Subcommittee on Investigations, April 3, 2002, concerning the
status of the FDA's tissue action plan......................... 103
7. GLetter from Senator Susan M. Collins, Ranking Minority
Member, Permanent Subcommittee on Investigations, to The
Honorable Tommy G. Thompson, Secretary of Health and Human
Services, April 12, 2002, concerning the status of the FDA's
tissue action plan............................................. 106
8. GLetter from The Honorable Tommy G. Thompson, Secretary of
Health and Human Services, to Senator Susan M. Collins, Ranking
Minority Member, Permanent Subcommittee on Investigations,
August 28, 2002, concerning the status of the FDA's tissue
action plan.................................................... 109
9. GResponses to questions for the record, transcript of hearing
on the nomination of Mark B. McClellan, to be Commissioner of
the Food and Drug Administration, Department of Health and
Human Services; U.S. Senate Committee on Health, Education,
Labor, and Pensions, October 2002.............................. 110
10. GFDA Notice of Inspectional Observations (Form FDA-483) from
Inspection 3/25/2002-4/12/2002 (FEI #3001451326), issued to
James C. Vander Wyk, Vice-President of Quality Assurance/
Regulatory Affairs, CryoLife Inc., dated April 12, 2002........ 111
11. GLetter from James C. Vander Wyk, Ph.D., Vice-President,
Regulatory Affairs and Quality Assurance, CryoLife, Inc., to
Mr. Ballard H. Graham, District Director, HFE-SE100, Food and
Drug Administration, regarding ``Initial reply to Notice of
Inspectional Observations (483) from Inspection of 3/25/2002-4/
12/2002 (FEI #3001451326), dated May 15, 2002.................. 119
12. GSample of Complaint Record, CryoLife, Inc................... 121
TISSUE BANKS: THE DANGERS OF TAINTED TISSUES AND THE NEED FOR FEDERAL
REGULATION
----------
WEDNESDAY, MAY 14, 2003
U.S. Senate,
Committee on Governmental Affairs,
Washington, DC.
The Committee met, pursuant to notice, at 9:37 a.m., in
room SD-342, Dirksen Senate Office Building, Hon. Susan M.
Collins, Chairman of the Committee, presiding.
Present: Senators Collins, Coleman, Carper, and Pryor.
OPENING STATEMENT OF CHAIRMAN COLLINS
Chairman Collins. The Committee will come to order.
Good morning. Today, the Committee on Governmental Affairs
is holding a hearing on the dangers of tainted human tissue and
the need for Federal regulation of the tissue bank industry.
Tissue banks procure, process, store, and distribute human
tissue for transplantation. Tissue transplants have soared in
recent years due to advances in technology that have greatly
reduced the risk of rejection. The American Association of
Tissue Banks estimates that more than 800,000 tissue products
were made available for transplantation last year in the United
States. Yet despite the ever increasing number of transplants,
there are serious questions about the safety of our Nation's
tissue supply.
Some of these concerns stem from the Food and Drug
Administration's failure to finalize much-needed regulations
governing the tissue bank industry. This is not a new problem.
In fact 2 years ago this month I chaired a hearing of the
Permanent Subcommittee on Investigations exposing the safety
issues concerning the practices of some tissue banks. Yet in
the intervening 2 years, the FDA has made virtually no progress
in strengthening the regulatory requirements for an industry
whose products are in wide use and affect human health.
While many people are familiar with the concept of organ
donation, tissue donation is not as well understood. Human
tissue, including tendons, bone, and skin is unlike an organ
transplant because it is not usually transplanted as-is from
the donor's body into that of the recipient.
Rather, donated tissue generally undergoes considerable
processing before it is transplanted into a patient. Bone from
a donor's femur, for example, may be completely reshaped into a
component designed to give support to a recipient's spine. The
reconfigured tissues are also known as allografts.
Once processed, donated tissue can be stored for a period
of time before it is used to enhance, improve, and even save
lives. If, however, human tissue is not properly processed, it
can pose dangerous risks to the recipient.
Therefore, it is critical that the tissue come from
carefully screened donors, and that it be properly processed
and stored. Otherwise, communicable diseases such as HIV and
hepatitis, among others, can be transmitted through the tissue
to the recipient.
The FDA has been aware of these public health risks for
years. In 1997, the agency examined the health issues involving
tissue transplantation and concluded that the existing
regulatory framework was insufficient. The agency undertook the
review in response to incidents in which imported foreign
tissue had tested positive for serious diseases.
The FDA then notified the tissue bank industry that it
intended to make regulatory changes to strengthen the oversight
of tissue banks. The changes were threefold. First, all tissue
banks would be required to register with the FDA. Second,
screening of potential donors would be expanded to require
testing for the human variant of mad cow disease, syphilis, and
other viruses. And third, and perhaps most important, a rule
would be issued on the methods and controls used during the
processing of human tissue.
This third proposal, known as the good tissue practices
rule is intended to help ensure that tissues are not
contaminated as they move from recovery to distribution.
The hearing that I held 2 years ago exposed dangerous
practices by some tissue banks as well as the inadequacy of the
regulatory framework. The testimony that we heard at that time
was deeply troubling. First of all, we learned that the Federal
Government had no idea how many tissue banks were operating in
the country. The Department had estimated that there were about
150, but approximately 350 tissue banks registered with the FDA
when the registration requirement went into effect. But that
indicated that many tissue banks were operating without any
Federal oversight whatsoever.
Second, there was also considerable testimony about the
unacceptable practices of some tissue banks. For example, a
deputy inspector general from the Department of Health and
Human Services testified about unscrupulous tissue banks that
engaged in a practice in which tissues that initially tested
positive for contamination were simply tested over and over
again until the technicians achieved the negative result they
wanted.
Another witness testified that a Lion's eye bank, which
also participated in tissue recovery, accepted a donor who was
82-years-old and had a history of cancer. That is a frightening
example of inadequate donor screening by a tissue bank.
Based on our findings, it was evident to the Subcommittee
that Federal oversight of tissue banks was woefully inadequate.
Until the necessary changes were made, gaping holes would
remain in the safety net that protects patients who receive
transplanted tissue. Now the FDA assured us at this hearing 2
years ago that it would act expeditiously to remedy this
problem by implementing the long-overdue regulations.
Since that time, I have repeatedly pressed the FDA to
finalize its regulations. I have offered help to the agency to
overcome any obstacles that it might face along the way.
Senator Durbin and I asked the FDA to provide a breakdown of
the costs for implementation of the proposed regulations. We
never received a response. I wrote additional letters to the
FDA. I then wrote to the Department of Health and Human
Services about the very troubling delays and seeking assurance
that the implementation of the regulations was a priority. In
its response, the Department agreed that the FDA needed to move
as quickly as possible to finally put the regulations in
effect.
Unfortunately, the FDA still has not kept its commitment to
addressing this public health risk through effective
regulation. And, as I predicted 2 years ago, the result of this
bureaucratic inertia has been tragedy.
My greatest fears were realized when Brian Lykins, a
healthy 23-year-old man from Minnesota, died in November 2001
after receiving a tissue transplant in his knee during routine
surgery. The tissue was infected with a deadly bacterium, and
yet it made its way from Georgia to St. Cloud Hospital in
Minnesota.
Good tissue practices appear to have been totally absent in
this case. CryoLife, the company that processed the tissue used
in Brian's transplant, accepted a tissue donation from an
individual who had been deceased for 19 hours and his body had
not been refrigerated during that time. I dare say that if
Brian had been aware of that fact alone, he would have refused
to have a transplant of that donor.
Brian's parents will testify before the Committee today
about the devastating loss that their family have suffered. It
is a tribute to them and to their daughter Tammy that they have
agreed to come forward and testify publicly about this most
painful and private event. They have done so in the hope that
others will not have to endure the tragic loss that they have
suffered.
I just want to thank them publicly for their willingness to
speak out and for their commitment to seeing that no other
family suffers the tragedy that they have. So I want to thank
you for being with us today. My hope is that their
participation in today's hearing will finally be the catalyst
that prompts the FDA to act.
In the wake of the tragedy of Brian's death, 6 months later
in May 2002, an FDA official stated on national television that
the agency intended to make the regulations final within 1
year. Yet here we are a full year after that, without any
discernible progress having been made toward issuing the
regulations. I just do not understand that. That is why I am
holding this hearing today.
Moreover, there is now evidence to suggest that the absence
of regulations is being used as a legal defense for
questionable practices. After Brian Lykins died, his family
filed suit against the tissue processor, CryoLife.
In a deposition, a CryoLife executive stated that the FDA
had not imposed final regulations regarding what industry
practices should be, but instead had issued only non-binding
guidance. That CryoLife representative is correct on that
point. Under the current regulations, a tissue bank is not even
required to report situations to the FDA in which an adverse
event--that is bureaucratic language for what happened to Brian
Lykins--has occurred. Reporting is completely voluntary. As
outrageous as that may seem, perhaps the industry's defense
strategy will provoke the FDA into action.
Recent evidence confirms that Brian Lykins' case was not an
isolated event. Last year after his death, an investigation was
undertaken by the Centers for Disease Control and Prevention
along with the New York and Minnesota State Departments of
Health, to determine what killed him. That inquiry led the CDC
to examine other cases of allograft-related infections.
In its March 2002 report, the CDC identified 26 cases of
infection in donated human tissue that had been linked to
allografts used in transplants. The CDC now reports that more
than 60 cases of transplanted tissue infections are now being
investigated. We will hear more about that from the CDC today.
It is also surely significant that New York State, which
has the most stringent tissue oversight regulations in the
country, had not experienced the same problems. Today we will
hear testimony from that State's top tissue oversight official
regarding the authority that has allowed New York State
residents to have greater confidence that the tissue
transplants they received are free from infection.
It is well past time for the FDA to finish what it started
more than 6 years ago when the agency correctly identified a
serious threat to public health and the need to improve
regulatory oversight of the tissue industry. The remaining
safety regulations must be completed without delay, and tissue
banks that do not comply with the regulations must be suspended
from doing business and punished for jeopardizing public
health.
Last year, Senator Durbin and I introduced a bill, the
Tissue Transplant Safety Act of 2002. It would have required
the FDA to impose tougher safety standards. Later today,
Senator Durbin, Senator Coleman, and I will reintroduce that
legislation which we, with the family's permission, are naming
in honor of Brian Lykins. This time we will require the FDA to
issue the final regulations within 90 days. It is obvious to me
that without a statutory deadline, FDA will continue to delay
and delay.
I look forward to hearing the testimony of our witnesses
today and at this time I would like to yield to my colleague
from Minnesota, who has a special interest in this case, for
his opening statement as well as to introduce our first panel
of witnesses.
OPENING STATEMENT OF SENATOR COLEMAN
Senator Coleman. Thank you, Madam Chairman. It will be an
honor to introduce today, Steve and Leslie Lykins, and their
daughter Tammy. I want to thank you for calling this hearing.
Twelve years ago, the FDA first studied this issue. Two
years ago almost to this day you held hearings on this issue.
During those hearings the FDA promised to issue regulations
soon. A year and-a-half ago Brian Lykins died, he did not die
of complications stemming from the procedure. He was a healthy
young man and his death should have been prevented.
His death was followed by national press and CDC studies
that once again pointed to the need for national standards. The
FDA still has not acted. So today we are revisiting the issue.
I suspect we will hear roughly the same testimony we heard 2
years ago. But this time we will also hear from the Lykins
family about the death of their son. I can only hope that 2
years from now we do not have to revisit the issue and listen
to the same testimony again perhaps with yet another victim
whose friends and family had to watch their son or daughter
die.
I suspect the problem here is a bureaucratic desire to
draft the perfect rule, regardless of the cost in time or
lives. I believe in the old 80/20 rule, about 80 percent of the
problem can be dealt with with only 20 percent of the effort.
It is the last few bits that require the most time. We all
agree on certain things like the ability to trace tissue from
recipient to donor and back to other recipients, and the need
for testing for additional diseases. We could at least get some
components in place. No doubt there are more difficult issues
that do take a long time to resolve, but why are we still
waiting to do the easy stuff, the stuff we know can make a
difference?
New York, as the Chairman has noted, has put a law into
place which can serve as a model. New York did not wait, nor
should we. If nothing else, we can move forward with
legislation modeled on the New York law setting up a simple
system for testing and tracking. The system could be later
augmented by further rules that would allow us to avoid having
to return here in 2 years to hear from another family.
Although I will reserve final judgment until I hear from
the FDA, it appears to me that this hearing should not have had
to be held to deal with this issue. We dealt with it 2 years
ago.
Madam Chairman, it is my great but sad honor to introduce
today's first witnesses, Steven and Leslie Lykins from Willmar,
Minnesota, and their daughter and Brian's sister, Tammy. I wish
they did not have to be here today. Brian's death was
especially tragic because it occurred after an elective surgery
not from medical complications stemming from the procedure
itself but rather from a cause that could have been presented
if proper regulation had been in effect.
I do not think most people can possibly understand how
painful it would be to discuss the death of your children
before a roomful of strangers. I want to thank the Lykins for
their courage and their commitment for being here today. I want
to commend the Chairman for having hearings on this issue. But
I also want to remind ourselves that hearings are not always
enough.
Madam Chairman, under your leadership, the Permanent
Subcommittee on Investigations held a hearing on tissue banks
on May 24, 2001, 6 months before Brian's death. But again, as I
noted before, the FDA did not take the required actions. It
seems to me that the Lykins are doing something we should all
admire. Faced with a personal tragedy, their first instinct was
to use the painful lessons learned to try and make the world a
little bit better.
For our part, we should pledge to them that we will not
need to relearn this issue at the cost of someone else's life.
Hopefully, and more than hopefully, the FDA will promulgate
final regulations that address the problem. If they do not then
we need to, and we will move quickly forward on legislation
that the Chairman is bringing forth. One way or another we must
honor the Lykins' experience not just by listening to their
story but by acting on it.
Madam Chairman, it is, as I said, a great but sad pleasure
to introduce Steven and Leslie and Tammy Lykins from Minnesota.
Chairman Collins. Thank you very much, Senator. Before I
call on Mr. and Mrs. Lykins for their testimony I want to see
if my colleague Senator Pryor has any opening comments.
OPENING STATEMENT OF SENATOR PRYOR
Senator Pryor. Thank you, Madam Chairman.
Thank you all for being here today. Madam Chairman, I am a
recipient of an Achilles tendon from a donor bank. I must tell
you that was about 7 years ago. I had a very rare and deadly
form of cancer in my Achilles tendon. I had great results, but
one thing that I took for granted was that the tendon I was
receiving out of a donor bank, which happened to be in New
Jersey was going to not be tainted and healthy. And it was.
But I must tell you that what I have been reading in
preparation for this hearing, I am bordering on outrage at some
of the lack of control out there and the lack of supervision.
It really is troubling to me. So I really do appreciate you all
coming. It takes a lot of courage to be here. I know it is a
sad story that you are going to tell. But we are going to do
everything we can to listen and try to make the situation
better.
Thank you, Madam Chair, for allowing me to speak.
Chairman Collins. Thank you, Senator Pryor. I think your
experience shows exactly the way most people would react. You
would never dream of getting a tissue transplant that you might
be putting your life at risk.
Senator Pryor. That is right.
Chairman Collins. Yet properly done and safely done, a
tissue transplant can save lives.
Senator Pryor. Absolutely. It definitely saved my leg.
Otherwise I probably would have had to have an amputation. You
have so many other considerations at that point. Depending on
why you are having the transplant--it could be cancer, it could
be any number of ailments, any number of reasons why you are
doing it. But you are so preoccupied with that. You always know
there is a chance of some sort of tissue rejection. We all know
the medical risks there, and the medical community has gotten
that risk down to a very low level, a very manageable level.
The last thing the patient needs to be concerned about is that
he may receive some tainted tissue. Thank you.
Chairman Collins. Thank you. Mr. Lykins, I would ask you to
proceed with your testimony. Again, thank you so much for being
here today with your family.
TESTIMONY OF STEVEN AND LESLIE LYKINS,\1\ PARENTS OF BRIAN
LYKINS, ACCOMPANIED BY DAUGHTER TAMMY
Mr. Lykins. You are welcome.
---------------------------------------------------------------------------
\1\ The prepared statement of Steve and Leslie Lykins appears in
the Appendix on page 39.
---------------------------------------------------------------------------
In September 2001, our son Brian had arthroscopic surgery
to remove a bone chip in his knee. It went very well.
Afterwards, Dr. Mulawka, the surgeon, showed us pictures of
Brian's knee which revealed a quarter-size divot in the bone.
He told us that Brian should have follow-up surgery in order to
prevent future arthritis in his knee. He also explained that a
piece of bone from a cadaver would be used in the procedure and
told us about the effort and testing that went into ensuring
the donated bone tissue would be clean and safe. It was
supposed to be a routine surgery, one that Brian could have
lived a completely normal life without. In other words, it was
strictly a preventative and elective procedure. The recovery
from the procedure was expected to take a little longer than
the previous one, but no one expected any significant
complications.
On Wednesday, November 7, Brian had the follow-up surgery
which went well. Dr. Mulawka told us that Brian would become a
little sick from the medications and possibly experience more
pain than the previous arthroscopic surgery, but otherwise the
recovery should go well.
After the operation, Brian was experiencing a lot of pain.
He had a horrible headache, upset stomach, and felt like he was
burning up. The nurses, however, said his temperature was
normal. The doctor decided to keep him overnight for
observation. Leslie and I drove home to Willmar for the night.
We did not expect any complications so I left for work the next
morning and was scheduled to work in Minneapolis for the 5
days.
Ms. Lykins. After Steve left, I drove to St. Cloud Hospital
to pick Brian up. When I got there I found out that he was sick
to his stomach and in excruciating pain. The pain pack the
doctor had inserted into his knee during the operation
apparently was not working. The purpose of the pain pack was to
administer medication directly to the knee to help control the
pain.
After Brian was released from the hospital I drove him to
the St. Cloud Orthopedic Clinic where they removed the pain
pack. Brian was originally scheduled to go to the doctor on
Friday, the following day, but the doctor thought that he could
wait to see Brian until Monday morning. So instead we drove to
my home in Willmar where Brian stayed with me overnight.
Throughout the evening, Brian began to feel better. His knee
was still sore and he felt warm at times, but otherwise he felt
fine.
On Friday morning, Brian woke up feeling much better. Of
course his knee was still sore, which was to be expected. That
afternoon he said he felt well enough to go home. At his home
he rested, ate and drank a bit, used the exercise machine they
had sent along, and occasionally iced his knee. His recovery
was going exactly as we thought that it would. That evening we
watched a movie together and he told me that he felt fine and
if I wanted to go home I should, which I did.
On Saturday, I had previous plans to be out of the house
for most of the day so I was up early. Brian called me, told me
that he felt fine, and asked some questions about when he was
supposed to take his medication. He said his leg was still
sore, but otherwise he felt fine. Then I went out, returned
home at about 5 p.m. that night and called Brian. He told me he
had been sick to his stomach for a while, which we had
expected. I told him, I would come on over to his house after I
took care of a few things and he said that was fine. I got to
his house about 6 p.m. As soon as I arrived I realized that he
was in worse shape than he had let on. He was throwing up, and
told me he almost passed out twice walking to the sink. He
complained about feeling warm but he did not feel warm to the
touch.
I called Dr. Mulawka's office right away and I got the
answering service. They told me that they would call the doctor
and have him call me back soon. Shortly after that someone else
called from the clinic. When I explained how Brian was feeling,
he told me to change the dosage on one of the medications which
was likely the culprit of the stomach problems. Brian told me
he would like to spend the night at our house so we packed up
some of his things and we started to drive to my house which is
only two and-a-half miles away.
On the way Brian said he would like to stop at the hospital
and have them check him out. We got to the emergency room about
8 p.m. When the nurse and the doctor on duty examined Brian
they suspected that he was simply dehydrated and they put him
on IV. I think they also gave him something in the IV to help
settle his stomach. He still complained about burning up, and
he stripped off his shirt and his blankets but he still did not
register a fever. Brian also complained about his knee hurting,
but the nurse could not find any unusual swelling, redness, or
hot spots. A couple of times he doubled over with an upset
stomach before the medications seemed to kick in and help him.
The nurse and the doctor thought he would feel better once
he was more hydrated from the IV. His vital signs seemed to be
OK. The doctor also ordered chest x-rays and had blood drawn.
After that was done, Brian was back in his room and he was
resting better. No one seemed alarmed about anything at that
time and they told us that he would be going home soon. Brian
finally appeared to be dozing off to sleep. I was tired and
told the nurse that I would go out into the emergency room to
get some rest. At that point it was about 1 a.m. in the
morning.
I was in the waiting room for about 15 maybe 20 minutes
when someone came in and told me to come right away. Brian had
suddenly taken a turn for the worse. He had been moved to a
larger room in the ER where several people were anxiously
working around him. He was awake at that time. After a few
minutes, the doctor told me that Brian's vital signs had
changed all of a sudden and that they were trying to find out
what was wrong. Then the doctor asked me if there was anyone in
town who I wanted to call to be with me. I began to worry.
He told me that I should call my husband who, thankfully,
was in Minneapolis and not on a trip as he is a pilot. I called
Steve and the doctor explained to him that he should come to
the hospital immediately, that things did not look good for
Brian. I had not expected any of this when I brought Brian to
the hospital. We thought he was just dehydrated and nauseous
from the strong medicine. The doctors were now planning to move
him to the intensive care unit.
I made my way to the ICU when Brian was being wheeled into
a room. The doctor was trying to ask Brian questions and he
answered them in short little statements. He had not been in
the room long when Brian had a convulsion. He sat straight up,
gave a loud, long groan. I think that was the point that he
went into a coma. The doctors and nurses got me out of the
room, attended to Brian, and some time passed. A nurse came and
got me and brought me back to Brian's room. I was not in there
for long before he had another convulsion. It appeared as
though he stopped breathing until the doctor put some sort of
respirator on him. I was then led back into the waiting room.
Steven got to the hospital about 4 a.m. The doctor filled
him in on Brian's condition and told him they were not exactly
sure what was happening but that it was life-threatening.
Mr. Lykins. Brian was in a coma when I got to the hospital.
His blood pressure had been at zero for several hours. All the
organs in Brian's body were failing. His heart was the last
organ to fail and at 6:21 a.m. our son died.
Shortly after Brian's death we learned that the tissue put
into his knee was infected with a deadly bacteria. This
infected tissue was allowed to be implanted in Brian's knee due
to several industry and government failures.
First, there were no Federal guidelines for the automatic
rejection of high-risk cadavers. The cadaver that supplied the
tissue for Brian's operation should have been rejected for at
least two reasons. First, he died due to suicide so the time of
death was uncertain. Second, the body was allowed to remain
unrefrigerated for at least 19 hours before tissue harvesting
began.
Second, CryoLife procedures for testing and preparing the
tissue to make it clean and safe were flawed.
The Centers for Disease Control began an investigation into
the cause of Brian's death because two other men from the same
area died within about 1 week of each other after having
routine knee surgery. One of the men had his surgery in the
same hospital as Brian. The CDC found that the other two men
died from blood clots. They did not have cadaver tissue put
into their bodies. Their knee operations were completely
different from Brian's.
However, due to the presence of the deadly bacteria found
in Brian's body, the CDC continued with a lengthy investigation
into the cause of our son's death. Over the next 6 months I
talked on a regular basis with Dr. Kainer from the CDC who was
running the investigation. I could not believe the things that
I was hearing about the tissue industry as a whole and CryoLife
in particular. How could a medical industry in the United
States of America be allowed to operate like this? A medical
industry allowed to operate with little or no State and/or
Federal regulation, how could this be?
The FDA had known about the problems in this industry for
years and for some reason was dragging its feet in bringing
about the necessary regulations. The CDC had clearly defined
the problems in this industry and the FDA would do nothing
about it.
It became very clear at that point that the CDC had no
power to bring about change in this industry and the FDA was
not going to do its job. CryoLife was going to continue to
operate in the unsafe manner that caused the death of our son.
So at that time we decided to bring a lawsuit against CryoLife.
The purpose of our suit was to bring about change in this
company and this industry. Money was never the motivation for
the suit. It was only the vehicle that would get people to pay
attention.
We did not sue Dr. Mulawka and we did not sue the hospital.
We only sued the people responsible for Brian's death because
they would not fix the problems on their own. All we ever
wanted was for the people involved in Brian's death to learn
from what happened and fix the problems. It became clear that
CryoLife and the FDA would not fix the problem without the
lawsuit. Less than 30 days after we filed the suit, the FDA
shut CryoLife down due to their unsafe practices.
Unfortunately, there are still no Federal regulations to
prevent companies like CryoLife from operating in unsafe ways.
One and a half years after Brian's death, the FDA is still
only proposing regulations for the tissue industry. Nothing has
changed. The tissue industry can still operate any way they
want with little or no Federal regulations. What is taking the
FDA so long? In our lawsuit, we listed seven areas of
meaningful reforms that are needed in this industry. First is
rejection of high-risk cadavers such as diseased cadavers that
have cancer, meningitis; cadavers that are over 70-years-old;
cadavers unrefrigerated for over 10 hours; suicide cadavers.
Second, testing of tissue when cadaver is received.
Third, sterilize tissue before distribution.
Fourth, discard cadaver if any contamination is found.
Fifth, mandatory reporting of contamination to Federal
agencies and the end-user doctor.
Sixth, certification of cadaver harvesting personnel,
uniform basic qualifications and uniform training.
And seventh, mandatory annual procedure and inventory
audit.
Had these reforms been in place at the time of Brian's
operation, our son would not be dead and many other people
would not be dealing with some very serious medical conditions.
How much longer is it going to take the FDA to do its job and
bring the tissue industry into the 21st Century? This industry
has been allowed to operate like something out of the Wild West
for too long. Too many people have had their lives ruined and
too many people have died. We need reforms and regulations in
this industry now, not some day. There is no question that the
tissue industry is necessary and important for the advancement
of quality of life. However, there is no need for it to operate
in such a dangerous manner.
Chairman Collins. I want to thank you both for your very
eloquent testimony. I know I speak for everyone in this room
when I say that I am so sorry for your loss. My hope is that by
your coming forward that we have put a human face on this
problem, and that it will prompt the FDA to act. I just want to
pledge to you that I am going to ensure that they act. We have
given them too long already and I believe that your experience
and your moving testimony will help convince our colleagues
that far too long an amount of time has passed already and that
we do need prompt action.
You mentioned that prior to Brian's surgery that there was
a discussion with his physician about the transplanted tissue.
Now I know that anyone undergoing any kind of surgery signs a
standard informed consent form, but was there any discussion of
possible risks of the tissue itself, Mr. Lykins?
Mr. Lykins. Dr. Mulawka sat with my wife and I and Brian
and we talked about that and he explained over--it was quite a
lengthy explanation of all of the safety standards that went
into ensuring that the tissue was safe. After he finished
explaining that to us, we were very confident that the tissue
was going to be clean, that there would be no problems. It was
never even a consideration that the tissue may not be safe to
be put in Brian's body.
Chairman Collins. Did you assume at that time that as with
organ transplants, as with medical devices, that there was
Federal regulation of the tissue industry so that you really
did not need to worry about the safety, Mrs. Lykins?
Ms. Lykins. Yes, we did, at that time. We just assumed,
which now from hindsight we know better, but that just like
any--like the organs and such, that these things were already
handled through the medical field and knew them to be safe.
Chairman Collins. I think that is a very logical assumption
for you to have made. It is one that I think most health care
professionals made, including the physician. The surgeon who
treated your son obviously assumed that there was a process in
place to ensure the safety of the transplanted tissue.
How did you learn of the cause of Brian's death, Mr.
Lykins?
Mr. Lykins. When Brian died, the doctor in the ICU, even
when he died they said, we do not know what happened. So we
talked with him and we ordered that they do an autopsy on Brian
to find out the cause of what killed him. That is where we
started the learning process was from that autopsy.
Chairman Collins. When did you learn that the cadaver from
which the tissue had been taken had been left unrefrigerated
for at least 19 hours, clearly raising the risk of infection
and other problems?
Mr. Lykins. During that next 6 months after Brian's death
when we were in contact with--first it started with the
Minnesota Department of Health and then it went to the CDC,
that is when we started learning things like that. It was
sometime during that investigation that the fact that it had
been unrefrigerated for 19 hours came up.
Chairman Collins. During the course of your lawsuit against
the tissue bank that procured and processed the tissue for
Brian, which is CryoLife, did you learn of any previous
complaints against the company or other problems that CryoLife
had experienced?
Mr. Lykins. Yes, there were at least two of them that we
were familiar with. One, and I cannot remember the gentleman's
name but he is out in the San Francisco area that a couple of
years before Brian's death he had a knee operation where he
received tainted tissue which caused him some real severe
medical problems.
Chairman Collins. Is there anything that you have learned
from this experience that particularly concerned you?
Ms. Lykins. I think it probably would be in the medical
field in dealing with this is that we did not have the
information and that our doctors did not have this vital
information that was so needed.
Mr. Lykins. Of course we have done a lot of talking with
friends and family and even acquaintance at work about it and
the thing that I really struggle with is if they had given us a
document when we went in for this operation that said that the
tissue that your son will be receiving is not regulated, in
fact we do not know where it is coming from, we have no
standards for how it is produced, we cannot guarantee it is
going to be safe, and there is a risk of death or serious
infection from this we would, of course, have said, no, we were
not going to do that operation. We were not given that option
because nobody knew that at the time.
So the fact that we were not given that option, but we
assumed, like every other part of the medical industry, that it
is regulated, when it is a public safety thing--that companies
just cannot operate like that where they can pose a serious
health risk. I cannot think of any industry--I am a pilot and
you look at the high regulation in the airline industry and you
look at all the other areas where we have such good safety
standards in place and then to see this one with none, I think
that is the part that has bothered us the most.
Chairman Collins. I am going to yield to Senator Coleman at
this point because I know he is on a very tight schedule.
Senator Coleman. Thank you, Madam Chairman. I am not going
to ask any questions. I hope to have an opportunity to visit
with the family a little later. My daughter and her class are
in my office and I am going to go down there and see them in a
couple of minutes.
But I do want to note, in their testimony the Lykins said
their purpose here was not to sue people for money. It is to
fix the problem. I will say to them publicly what I said
privately, that the Chairman is very serious about this issue,
and that something will come from this testimony today. So your
purposes will be achieved and I just want to again thank you
for your courage and your commitment.
Thank you, Madam Chairman.
Chairman Collins. Thank you, Senator. I just have one more
question before I yield to my colleague and one comment. When
we met yesterday, just to expand on your last response, you
told us that if there were a sign up in the operating room or a
form given to a patient saying, warning, the transplant you are
about to receive has no safety guarantee it all. The Federal
Government does not really regulate it. Unless you are living
in one of three States there is no State regulation. Proceed at
your own risk. That your son would not have proceeded with this
operation. Indeed, it would be the end of the tissue bank
industry, which is unfortunate because there is a lot of good
that comes from tissue transplants.
But I think that you are absolutely right and that only
makes the case for effective regulation even stronger, because
we want to make sure that transplanted tissue which literally
can save lives, does not take lives. That is what this is all
about.
My final question for you is, we will have a representative
from the FDA testifying before us today. In his defense, he has
only been on the job for a few months. He is new to his
position. But this is an indictment of the agency for failure
to act. I just want to ask you if there is any question that
you want me to pose to the FDA representative today? Mrs.
Lykins.
Mrs. Lykins. I think what we have put in here is, how can
the American public, the people, the patients that are needing
this help, how can they turn their back and oppose some safety
that these people can rely on and know that they will indeed be
getting tissue that will be helping them in their life?
Chairman Collins. Thank you. Mr. Lykins, do you have
anything to add?
Mr. Lykins. I guess I really do not. In our statement we
have said it. We just do not understand why this is taking so
long. We have heard at least two or three times since Brian
died, and statements before that, just one more year, just one
more year and we will have it done. We just heard that again
recently, just one more year. It does not seem like it is that
hard to get some kind of, like Senator Coleman was saying, let
us get the basic framework in place. New York has it right now.
If nothing else, let us adopt New York's and get it started.
But there are people that are at serious risk today having
these operations that do not even know about it. We have got to
get something going here.
Chairman Collins. Thank you. Senator Pryor.
Senator Pryor. Thank you. Again thank you all for being
here. I have a factual question about your case and that is,
CryoLife, is that a private company? Is that an association? Is
that a for-profit company? Is that a lab? What is that or what
was that?
Mr. Lykins. It is a for-profit corporation and they do a
lot of different things and part of the things that they do is
they supply this tissue.
Senator Pryor. Did I understand what you said a few moments
ago that they are no longer in business?
Mr. Lykins. No. Just shortly after we filed this suit the
FDA went in and stopped, shut down their tissue processing part
of their business. They were stopped from doing that except in
life-threatening circumstances until they got their house in
order. I forget exactly how long but they eventually did comply
with the FDA's request so they are back operating now.
Senator Pryor. Tell me about your contacts with the FDA. It
sounds like you had some litigation going and you have also had
some contacts with the Food and Drug Administration. I would
like to zero in on your contacts with the FDA. Give me a feel
for how you have communicated with them. Is it by letter, by
phone call, by personal visit? How have you communicated with
FDA?
Mr. Lykins. We have not personally communicated with the
FDA at all. Our attorneys, during the lawsuit there was
communication there, but we have never personally communicated
with them.
Senator Pryor. Has the FDA taken steps to keep either you
or your attorneys advised about the status of the process
within the agency?
Mr. Lykins. Not that I am aware of.
Senator Pryor. Have they ever been proactive in any way
with you to try to give you any kind of assurance that they are
working on this problem as quickly as they can? Are they going
to try to move things out as quickly as they can to prevent
this from happening in the future?
Mr. Lykins. No.
Senator Pryor. This incident occurred in 2001?
Mr. Lykins. Yes.
Senator Pryor. How old was your son?
Mr. Lykins. He was 23.
Senator Pryor. You made a statement about this industry,
that it is analogous to the Wild West. When you say that, do
you mean that your concern is it is totally unregulated and
there is no government supervision about what is going on out
there, or at least it is very limited?
Mr. Lykins. The symbolism behind that statement was, I see
this industry as operating like a bunch of Wild West
gunslingers that are just shooting from the hip, doing it any
way they want to do it, and with no laws or regulations they
are just making it up as they go. That was the thinking behind
that statement.
Senator Pryor. Have you been in contact with other families
who have had similar experiences?
Mr. Lykins. We have had several families that have called
us and talked to us, yes. Yes, we have.
Senator Pryor. One last question on the nature of the
bacterial infection. What was the origin of that bacterial
infection? Was it because the tissue was not handled properly?
Or was it pre-existing in the cadaver? Do you know?
Mr. Lykins. The bacteria is called Clostridium sordellii.
My understanding of it is it is a spore-based bacteria, which
to me means it is in a little, kind of like an egg shell. It is
a normal part of a decomposing body. It starts in the
intestines and then moves out into the body over time. That is
where the time issue is such a big deal. So it was not a pre-
existing. It was allowed to----
Senator Pryor. It is naturally occurring if proper steps
are not taken to prevent it?
Mr. Lykins. That is right.
Senator Pryor. Madam Chair, that is all I have.
Chairman Collins. Thank you very much, Senator Pryor.
I want to thank you so much for your very courageous and
moving testimony. I want to thank Tammy for being here as well.
If you have anything that you feel that your parents forgot to
say today or that you would like to add I just wanted to give
you the opportunity. If you feel it has been covered, that is
fine too.
Ms. Tammy Lykins. I think they covered it.
Chairman Collins. Thank you. Again, thank you so much for
sharing your story with us. All of us simply cannot imagine the
pain and anger you must have endured. But I want to tell you
that we are committed to working with you to make sure that no
other family goes through what you have gone through. That is
our goal and I know it is yours as well. So thank you so much
for being with us today.
Mr. Lykins. Thank you.
Chairman Collins. I would now like to call forward our
second panel. Our first witness on the second panel will be Dr.
Steven Solomon. Dr. Solomon is the acting director of the
Division of Health Care Quality Promotion at the National
Center for Infectious Diseases which is part of the Centers for
Disease Control and Prevention. We also will be hearing from
Dr. Jeanne Linden, the director of Blood and Tissue Resources
for the New York State Department of Health. We want to thank
both of you for your willingness to participate today and, Dr.
Solomon, I would ask that you go first.
TESTIMONY OF STEVEN L. SOLOMON, M.D.,\1\ ACTING DIRECTOR,
DIVISION OF HEALTHCARE QUALITY PROMOTION, NATIONAL CENTER FOR
INFECTIOUS DISEASES, CENTERS FOR DISEASE CONTROL AND
PREVENTION, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Dr. Solomon. Thank you. Good morning. I am Dr. Steven L.
Solomon, acting director of the Division of Healthcare Quality
Promotion in the Centers for Disease Control and Prevention's
National Center for Infectious Diseases. Thank you for the
opportunity to report to you on CDC's activities with regard to
the problem of infections occurring in association with the
surgical implantation of human tissue. As a physician and as a
parent, I want to express my sympathies to the Lykins family
for their tragic loss.
---------------------------------------------------------------------------
\1\ The prepared statement of Dr. Solomon appears in the Appendix
on page 44.
---------------------------------------------------------------------------
An allograft is human tissue which is recovered from
cadavers and processed before being transplanted into another
person. The most common type of allograft is bone. Tendons,
skin, heart valves, and corneas are other common types of human
tissue allografts. Allografts may be lifesaving and can
substantially improve the quality of life for many patients,
reducing disability and restoring mobility or sight. The use of
allografts has increased dramatically in recent years.
As with any surgical procedure, the implantation of human
tissue allografts may be associated with complications,
including infections at the surgical site. Although rare, some
of these infections are associated with bacterial contamination
of the implanted allografts, a complication that can result in
serious morbidity and death. In collaboration with the Food and
Drug Administration, the Health Resources and Services
Administration, and other partners, CDC continues to
investigate reports of infections and assess the need for
possible changes in the processing and quality control methods
for allografts as a means of preventing allograft associated
infections.
As indicated, transplanted tissue is commonly obtained from
cadaveric material. After recovery from the cadaver, allografts
may be either sterilized or undergo aseptic processing without
sterilization. In aseptic processing, careful handling ensures
that no new organisms are introduced during the recovery of
tissues from the cadavers. Tissues may be treated with
chemicals or antibiotics to minimize intrinsic contamination,
that is, bacteria that contaminate these tissues following
death and prior to, or during recovery of, the tissues. Thus,
the tissue is not sterilized. The processing is intended only
to reduce intrinsic contamination and prevent further
contamination of the tissue.
In November 2001, CDC began an investigation after
receiving a report from the Minnesota Department of Health of a
fatal case of infection with Clostridium sordellii bacteria in
a young man who had recently received a bone cartilage
allograft. Clostridium sordellii bacteria were identified in
cultures of this young man's blood obtained prior to his death.
Investigators at CDC contacted the tissue bank from which the
transplanted allograft had been obtained and the tissue bank
provided CDC with samples of non-implanted tissues from the
same cadaveric donor. CDC laboratories identified C. sordellii
bacteria in some of these tissues. As a result of this
investigation, CDC concluded that this young man's infection
had resulted from intrinsic bacterial contamination of the
transplanted cartilage tissue.
CDC subsequently contacted the health care providers of all
patients who had already received transplanted allografts from
this same donor to determine if other infections had occurred.
CDC found that tissues had been transplanted into nine patients
located in eight States. One of these patients developed an
infection following the surgical procedure. This patient's
infection was successfully treated with antibiotic therapy and
the patient recovered.
To follow up this investigation, CDC, in collaboration with
FDA, requested that cases of allograft-associated infections be
reported to CDC through State and local health departments in
addition to the reporting of such cases to FDA. Cases reported
to FDA were shared with investigators at CDC and State health
departments. As of March 2003, 62 reports of allograft-
associated infections had been reported to CDC. Ninety-three
percent of these infections were associated with
musculoskeletal tissues. Cases of infection were reported from
20 States and involved tissues that had been treated at 12
different tissue processors. These surveillance findings have
been shared with FDA, the American Association of Tissue Banks
and others.
In addition to investigating infections associated with
bacterial contamination of allografts, CDC has investigated
reports of infections caused by fungi, parasites, and viruses
following transplantation of organs and tissues. Examples
include the transmission of hepatitis C from a bone allograft,
and transmissions of West Nile virus and Chagas disease, a
parasitic infection, following solid organ transplantation.
CDC believes that the best way to reduce the risk of
infectious agents associated with tissue transplants is to
develop new methods of sterilizing tissue that do not adversely
affect the functioning of the tissue when transplanted into
patients. Every effort should be made to use suitable
sterilization methods. However, if that is not possible, every
effort should be made to minimize the risk of intrinsic
bacterial infection. Recovered tissue should be cultured before
suspension in anti-microbial solutions, and if bacteria
commonly found in the human bowel are isolated, all tissue from
that donor that cannot be sterilized should be discarded.
Other public health interventions that will greatly
facilitate the prevention and control of infections associated
with tissue and organ transplantation are enhanced surveillance
and enhanced communication with clinicians. Addressing the
problem of infections associated with tissue and organ
transplantation is part of the larger problem of patient safety
requiring significant changes through all parts of the health
care industry.
Organizations involved in organ and tissue procurement, and
suppliers and processors of tissues must put in place
assiduously-followed procedures to assure that any risks
associated with tissue transplantation are greatly minimized,
if not completely eliminated. State and Federal public health
authorities must continue to enhance their ability to collect,
analyze, interpret, and disseminate information about potential
patient safety hazards due to biological products, medical
devices, and medical procedures
Clinicians and medical professionals must, with our help,
increase their awareness of specific patient safety problems
and fulfill their role in reporting such problems promptly to
the appropriate authorities so that necessary public health
action can be taken. CDC, FDA and other partners, as noted
earlier, are actively engaged in ensuring that biological
products, including tissue allografts are as safe as possible.
Thank you so much for the opportunity to present this
information to you today. I am happy to answer any questions
that you may have.
Chairman Collins. Thank you, Dr. Solomon. Dr. Linden,
welcome.
TESTIMONY OF JEANNE V. LINDEN, M.D.,\1\ DIRECTOR, BLOOD AND
TISSUE RESOURCES, WADSWORTH CENTER, NEW YORK STATE DEPARTMENT
OF HEALTH
Dr. Linden. Thank you. Good morning Members of the
Committee. My name is Jeanne Linden. I direct the New York
State Department of Health's Blood and Tissue Resources
Program. New York State has spearheaded development of many
innovative programs and maintains an active regulatory
oversight in many important areas of public health. Since
infected tissue poses the risk of pathogen transmission to
recipients, oversight of tissue banking activities is an
essential component, we feel, of any comprehensive public
health regulatory program.
---------------------------------------------------------------------------
\1\ The prepared statement of Dr. Linden with an attachment appears
in the Appendix on page 55.
---------------------------------------------------------------------------
In addition to the well-known risks associated with viral
and prion-associated diseases, bacterial infections in
recipients of aseptically processed cadaveric tissues, and
infections with emerging agents such as West Nile virus,
possibly SARS, are also of grave concern.
In New York State regulation of tissue banks began with
adoption of standards for hematopoietic stem cell banks in
1988, for semen banks in 1989, and for human milk banks in
1990. In 1991, a successful comprehensive tissue bank oversight
program was developed and instituted in New York. Comprehensive
rules set standards for donor medical history assessment, and
evaluation of risk factors for disease transmission, laboratory
testing, and recordkeeping to ensure the ability to track
disposition of donated tissue from donor to recipient and vice
versa. These standards were formulated based on the medical
literature, consensus of experts in the field, and existing
standards of professional organizations such as the American
Association of Tissue Banks, the Eye Banks Association of
America, and the American Society for Reproductive Medicine,
which at that time was known as the American Fertility Society.
Technical requirements are in place for all human tissues
intended for transplantation, also for research or education,
including cardiovascular tissue, musculoskeletal tissue, skin
tissue and eye tissue. Licensure requirements for tissue banks
apply to all facilities that collect, process, store, or
distribute, or transplant tissue in New York State. At present,
736 tissue banks are licensed to operate in the State,
including more than 130 facilities located outside the State.
The table included with my written statement enumerates the
various types of tissue banks that are licensed to operate in
New York.
Comprehensive tissue banks include cardiovascular,
musculoskeletal tissue banks, skin banks, eye banks, semen
banks, oocyte donation programs, bone marrow collection
centers, umbilical cord blood banks, human milk banks, and non-
transplant tissue banks, which is what we call tissue for
education and research purposes.
In New York State, facilities that use tissues clinically,
including hospitals, ambulatory surgery centers, and even
physician's offices are subject to tissue bank licensure as
well as the specific administrative recordkeeping and quality
assurance requirements. Errors and accidents detected after
distribution of tissue as well as adverse events must be
reported to the Wadsworth Center of the State Health Department
within 7 days of discovery, affording another mechanism for
effective oversight. Licensed tissue transplantation facilities
must report any adverse events and patients that might be
linked to the tissue.
From the very inception of the New York licensure program
staff identified unacceptable practices going on in tissue
banks. In one case, two semen bank operators were using only
themselves as donors but through the use of fictitious names
led physicians and recipients to believe that more than a dozen
donors were available through the program. Testing and
recordkeeping at this bank were virtually non-existent. We
actually needed to wind up following the money and subpoena
bank records to track that case.
Another reported incident concerned a hematopoietic stem
cell bank that transmitted the wrong component, that is the ABO
incompatible red cells that had been removed from the bone
marrow rather than the marrow itself. Had the marrow not been
retrievable, the patient, who had already undergone ablative
therapy, could have died as a result of a severely impaired
immune system. One surgical bone bank lost the skull flap of an
autologous donor. These cases demonstrate the crucial
importance of thoroughly identifying tissues used for
transplantation.
The death of Brian Lykins in November 2001 brought the
inherent risk of using aseptically processed allografts to
national attention. This tragic event spurred an immediate
investigation that has been described by my colleague. In
cooperation with State health departments, the CDC was able to
locate non-transplanted tissues from the same donor and
identify the bacterium. A second recipient from the implicated
donor also developed an infection but cultures had not been
done. I apologize, my written statement is incorrect in that
regard. They were not done. They were not negative. This
patient, fortunately, responded to antibiotic treatment.
The CDC investigation determined that CryoLife, the tissue
bank involved, at that time routinely cultured allograft
tissues following suspension in an anti-microbial solution,
which was not acceptable. Such a culturing protocol can lead to
false negative results because of the bacteriostatic nature of
certain bacteria, particularly spore-forming anaerobes like
Clostridium.
In February 2002, absent its own jurisdiction or assistance
from any other Federal agencies, CDC asked the New York State
Department of Health's assistance in obtaining records and
seeking additional tissue samples from the donor implicated in
the Lykins case that remained in CryoLife's inventory, as well
as records and tissues from donors implicated in other
allograft-associated infection cases. The enforcement authority
of the New York State Commissioner of Health enabled the Blood
and Tissue Resources Program surveyors to conduct an on-site
inspection of the tissue bank where several deficiencies were
noted, including the failure to perform recovery culture
testing. The Wadsworth Center, the department's public health
laboratory, isolated Clostridium septicum in tissues from two
donors implicated in allograft-associated Clostridium
infections. No remaining tissues associated with the Lykins
case donor were found.
The department also assisted CDC in identifying potential
additional cases of post-transplant allograft infections by
contacting physicians who had used tissue from implicated
donors for transplantation. Since confidentiality requirements
prohibited us from sharing the patient names with CDC, we
needed to contact these physicians directly.
The number of allograft-associated Clostridium infections
per one million population was found to be statistically
significantly lower in New York State compared to the remainder
of the country; 0 vs. 0.06 per million with a highly
significant p-value of 0.0009--highly significant.
CryoLife maintained two inventories of tissue for release;
one suitable for New York State patients and a second one for
patients in other States. Tissues from only two of the
implicated donors would have met the requirements for tissue in
the New York inventory. Tissue from six of the donors,
including the donor in the Lykins case, would have been
disqualified for distribution to New York. This likely
contributed to explaining why there were no known cases of
allograft-associated Clostridium infections in New York. We
believe that New York State regulations have played a
significant role in protecting the State's patients from such
adverse transplant-related outcomes.
Based on our experience, we believe that a mechanism to
ensure documentation of disposition of all tissues must be
established and enforced so that donors may be traced in cases
of adverse events, and all recipient outcomes must be reviewed
and followed up as necessary. The 1985 LifeNet incident, which
was discovered and reported in 1991 in which numerous tissues
were distributed from a donor in the window period of HIV
infection, illustrates the need for accurate accounting for all
allografts distributed by a tissue bank and issued for
transplant by the hospital. In this case, 6 of 54 distributed
tissues could not be accounted for by the transplanting
hospitals.
New York State's rigorous requirements for licensure and
recordkeeping by transplantation facilities are aimed at
ensuring accurate tracking to each recipient. States that
operate tissue bank oversight programs complement Federal
efforts in this most important public health area. New York
State has established a partnership agreement in place with the
FDA's New York District to share inspection documents, and
other reports and documents, and minimize duplicated effort.
We commend your endeavors to address this critical public
health concern. While tissue banking is clearly in need of
Federal oversight and uniform minimum standards, any
potentially deleterious effects of imposing overly restrictive
standards on the tissue supply, we believe must be balanced
against the proven benefits of such standards to the public
health. Specifically, it is unrealistic to expect tissue banks
to be able to guarantee the absence of contamination in a donor
when tissues are processed aseptically. It must be acknowledged
that since some tissues are in short supply, patients' health
could be adversely affected if potentially draconian
regulations further diminish the tissue supply.
The FDA's existing rules for tissue banks and progression
toward good tissue practices represent a valuable step toward
enhancing tissue bank oversight nationwide. The established
benefits of such standards in this area are abundantly clear.
The New York State program has identified several cases in
which unsuitable donors have been rejected and recipients thus
protected by adherence to the State's rigorous standards.
However, we do remind you that any regulatory scheme must
remain flexible enough to quickly adapt to the rapidly
escalating changes in this field.
Thank you very much for the opportunity to comment.
Chairman Collins. Thank you, Dr. Linden. Your testimony is
very helpful to us and I want to congratulate New York State
for coming up with a regulatory framework that has helped
protect patients in your State.
There are two points in your testimony that I want to
explore a little further with you. First, I find it astonishing
that CryoLife actually kept different batches of processed
tissue in its supply; those that were suitable for New York
State and those that could be used elsewhere. That may not be
illegal but it certainly is questionable that different batches
of tissues are sent to a State with a good regulatory scheme
than are made available to States, and that is the vast
majority of States that do not have a regulatory framework in
place.
Do you think that this is an isolated example or do you
think that other tissue banks may also have separate procedures
that are followed if the tissue is going to New York State?
Dr. Linden. The majority of tissue banks, the 130 licensed
outside New York, use the same standards for everybody. They do
not have separate inventories. I cannot say whether CryoLife
was the only one. There may be a small number of others, but
the majority just meet our standards for everyone. But from a
legal standpoint we need to allow that because our jurisdiction
is protecting the people of the State of New York.
Chairman Collins. But in the case at least of CryoLife,
CryoLife was doing different procedures to meet your stricter
standards and thus, I would argue that the patients in New York
State were at less risk of getting contaminated tissue, as the
complicated study, which I am not sure I followed on p-values,
seems to indicate. Is that a fair statement?
Dr. Linden. We believe that is the case and we believe that
everyone in the United States should benefit from the same
standards. We do not encourage facilities that have two
different inventories, but we do allow it.
Chairman Collins. The second point that I want to follow up
with you on to make sure that the Committee fully appreciates
what you said is, you said in your statement that absent its
own jurisdiction or assistance from other Federal agencies,
that the CDC had to come to New York State public health
officials in order to conduct the investigation into Brian
Lykins' death; is that correct?
Dr. Linden. For Brian Lykins' case, no, they were able to
handle that with the Minnesota and Georgia State health
departments, and it is my understanding the facility cooperated
fully in the Lykins case. It is when they got into looking into
other reported infections, which exceeded 25 eventually, at
that point the facility was no longer willing to voluntarily
cooperate, so an agency with authority was needed, and we in
fact did have to use our subpoena power.
Chairman Collins. But I think your point is, and I am
reading from your testimony on page 3 and it actually refers to
the Lykins case as well, that in order to get the additional
samples that the Federal Government did not have adequate
authority; is that accurate?
Dr. Linden. You probably should be asking my colleague.
Chairman Collins. Actually, why don't I ask Dr. Solomon
that. Is it difficult for the CDC in a case like this where the
tissue bank is under no legal obligation to report adverse
events and to cooperate with you, to do the kind of tracing and
careful investigation that needs to be done?
Dr. Solomon. Yes. Throughout this investigation there was
an obvious sense of urgency to identify any risks to health and
safety. From the outset, CDC was working closely with a number
of partner public health organizations, including the State
health departments as mentioned by Dr. Linden and the FDA. At
each stage of the investigation we had the opportunity to call
on the resources of these public health partners who do have
the authority, the legal authority to obtain information and
materials.
We were very fortunate that Dr. Linden and her staff have a
very experienced and very proactive program so that at one
point, obtaining some documents and specimens through the
resources and capabilities of the New York State Department of
Health was the most expeditious and the quickest way of
obtaining that material. We are very appreciative of her
efforts, as we are of the efforts of the other partners,
including the Minnesota and Georgia health departments and the
FDA. That kind of close collaboration is critical for all of
our investigations.
Chairman Collins. Dr. Solomon, you mentioned in your
testimony that in the course of the investigation that you
discovered that there had been tissue donation from this one
cadaver that went to nine patients in eight States; is that
correct?
Dr. Solomon. That is correct, yes.
Chairman Collins. Indeed, in just the Brian Lykins case
there are three States involved. The tissue came from a donor
in Utah. It was processed in Georgia, and the surgery was in
Minnesota. Is that accurate?
Dr. Solomon. Yes, it is.
Chairman Collins. Does this not make a strong case for
uniform Federal regulations?
Dr. Solomon. We are eager to see any kind of regulation or
other type of activity which will help reduce the risks to
patients. We are very grateful that New York State has that
type of regulation in place.
Chairman Collins. One more question, Dr. Solomon, before I
yield to my colleagues. I have a list that our Committee
obtained from CryoLife of some 20 cases involving tainted
tissues or allegations of tainted tissues. Eighteen of these 20
ended up in some sort of court case in lawsuits. Under the
existing regulations, it is my understanding that CryoLife has
no obligation to report these 20 cases to the CDC or the FDA.
Do you believe that there should be a Federal requirement for
adverse events to be reported? Should there be mandatory
reporting of adverse events by tissue banks?
Dr. Solomon. We have dealt with the issue of mandatory
reporting more broadly on the patient safety front for
sometime. CDC gets most of its surveillance and other reporting
through State health departments and directly from health care
providers or patients as well as health care facilities.
Manufacturers and other processors more routinely do their
reporting to FDA. I think it would be more appropriate for FDA
to comment on their relationship with manufacturers and tissue
processors.
Chairman Collins. Senator Pryor.
Senator Pryor. Thank you. Dr. Solomon, if I can follow up
on something you said a few moments ago about New York. You
mentioned you are grateful that New York has standards in
place. Are you pretty familiar with those standards?
Dr. Solomon. I am not intimately familiar with New York
State's standards specifically.
Senator Pryor. Do you think that the New York standards
should be adopted as the national standard?
Dr. Solomon. My familiarity with the New York standards
specifically are not sufficient for me to comment on whether
all of those should be adapted as national standards. Clearly,
as Dr. Linden testified, the New York standards do protect
patients in New York State. Specifically, whether those
standards would be applicable point by point federally is
something that I just do not have information on at this time.
Senator Pryor. Dr. Solomon, I know you are not completely
familiar with them, but is there anything in the New York
standards which you would change, or you think is unnecessary,
or that you would strengthen? Are you aware of anything, given
your limited knowledge of them, that you would change about the
New York standards?
Dr. Solomon. I am not aware of them sufficiently to be able
to say specifically if there are elements that would not be
adaptable. But from what I understand from Dr. Linden, many of
those standards are consistent with what both CDC has proposed
and FDA has proposed throughout this investigation.
Senator Pryor. That is fair. I know that you are not
holding yourself out to be extremely knowledgeable of those
standards. I understand that.
Dr. Linden, let me ask you about New York's standards. Do
you consider them the most stringent and the most thorough in
the country?
Dr. Linden. We like to think so.
Senator Pryor. Do you think they should be adopted as the
national standard?
Dr. Linden. They certainly could not be adopted--the
statutory authority the FDA has is completely different from
ours, so the format needs to be different. I think that
certainly to the extent that our standards capture the accepted
practice in the community, justified in the medical literature,
that many of those elements would be important to be included
with the FDA's approach, and indeed they are.
Senator Pryor. Are you aware of any holes in the New York
standards that you think the State of New York should fix?
Dr. Linden. Certainly, we are always looking to improve our
regulations. We, in fact, have been actively working with the
associated medical schools in New York to strengthen
considerably the technical standards for the use of whole
bodies in medical education where we have had few standards in
the past.
On the transplant side, certainly we continue to watch for
improvements in technology, possible availability this summer
of testing for West Nile virus. We are always looking to
improve. I cannot think offhand of a specific hole, with the
exception of making the comment that we really regulate
services, the people who collect and process and distribute the
tissue, and the users, which we feel is a critical part of our
program which I believe FDA might not even be able to reach
under their authority. FDA regulates products.
So as I said, the approach is different and they have
emphasis on certain issues like validation that is a little bit
different from our approach.
Senator Pryor. Now walk us through that here for just a
moment. Explain the point you are making about the critical
nature of this.
Dr. Linden. We have found that the users, that is the
transplant sites----
Senator Pryor. Now when you say users, do you mean the
doctors who are performing the transplant?
Dr. Linden. Yes, the hospitals, the ambulatory surgery
centers, and physicians' offices that are actually
transplanting or using these tissues, to make sure that they do
not get them mixed up, which has happened, that they go to the
right person, that there is adequate informed consent. I made
the point that some of these tissues, including the type of
femoral condyle used in Mr. Lykins' surgery, cannot withstand,
at the present time, the types of viral and bacterial
inactivation methods that are available, such as gamma
radiation. Maybe there will be other processes in the future.
But some of these tissues are very valuable. If we simply
eliminated them, orthopedic surgeons would be very upset, and
patients would not be able to get the type of life-enhancing
surgeries they have. But we feel that the informed consent, so
that the recipient knows the risks and in consultation with the
physician can weight those is very important. So that is one of
the emphasis of our program.
Senator Pryor. On a typical tissue--and I know that this
may be an unfair question because there are lots of different
kinds of tissue. But how many tests are done, say on a bone
that is going to be transplanted? How many tests are done on
that? Is that an easy thing to do? Is that an expensive thing
to do? What are we talking about here?
Dr. Linden. Are you talking about testing of the bone
itself or of the donor?
Senator Pryor. That is a good question. Both of those. How
do you do that?
Dr. Linden. The donor's blood, and a pre-mortem specimen is
preferable, is tested for a lot of the same things that blood
donors are tested for, plus a few more, particularly depending
on what the tissue is. A particular concern today since we are
talking about bacterial contamination, a culture of a sample
taken at the time of recovery of the tissue and before the
tissue is subjected to antimicrobial solutions is something
that we require and was absent in some of the cases that we
have talked about here today. So that would be testing of the
tissue itself.
In the case of eye tissue, for example, there needs to be
an analysis using a slit lamp to determine whether it is
suitable for transplant and that sort of thing. These are
tissue-specific tests that are done to heart valves. There are
slightly different things.
Senator Pryor. Thank you, Madam Chairman.
Chairman Collins. Thank you. Senator Carper.
OPENING STATEMENT OF SENATOR CARPER
Senator Carper. Welcome. How are you? Thanks for joining us
today.
Dr. Solomon, that is a nice-looking uniform you have got
on. I almost saluted when I came in. Are you a captain as well?
Dr. Solomon. Yes, sir.
Senator Carper. I used to be a captain in the Navy.
Whenever I see your folks walking around in uniforms it brings
back some good memories. But I was never a doctor.
I missed your testimony. I was involved in another meeting
right out in the anteroom with other doctors from Delaware who
are here. We talked about an issue, actually an issue involving
medical malpractice. The question is whether or not that is
something that States should deal with or we should deal with
it at the Federal level. It sounds to me, Dr. Linden, you have
decided in New York to deal with the issue of handling of
tissue and the safe use thereof, try to deal with it on a State
level instead of waiting for us in Washington to come up with
regulations. Is that correct?
Dr. Linden. Yes. We really got started in the tissue in the
mid 1980's, I think largely as a result of the HIV crisis which
was particularly acute in New York and there was really
recognition that tissues are yet another way that infectious
diseases could be spread.
Senator Carper. Are there other States who have followed
suit or preceded you with development of some of the kinds of
regulations?
Dr. Linden. I believe we were the first, but Florida----
Senator Carper. It is good being first. That is a motto in
Delaware, it is good being first.
Dr. Linden. Yes, it is good to be first. Florida also has a
comprehensive program, although it does not cover reproductive
tissues is my understanding. California also has a law, but
last I heard their technical standards had not been adopted
yet. There were some issues there. Other States such as New
Jersey do certain of the tissues. I believe ours is the most
comprehensive and it was the first.
Senator Carper. In my old job as Governor of Delaware I was
the chairman of the National Governors Association and I always
used to say that States ought to be laboratories of democracy,
and in some cases States will come up with a particular
approach, could be welfare reform, could be education, that
might serve as a role model for us on a national level. Is
there any reason to believe that what you have developed in New
York or in some other State could be a role model for us, or a
model for us to try to replicate at a national level?
Dr. Linden. I do not think it can be replicated as is, but
certainly many of the components can be and in fact have been.
We have shared our regulations with FDA, and I have served on
some of their advisory committees. We have worked with them
closely. As I mentioned, we have a partnership agreement with
the district office. I believe that they have in fact
considered some of our suggestions and incorporated them into
their existing regulations and proposed regulations.
Senator Carper. Given what you have learned in the
development and implementation of your regulations, what
lessons are there for us at the Federal level, major lessons
for us at the Federal level that you would like to leave me
with today?
Dr. Linden. Certainly checking everything and not making
assumptions is very important. You cannot just adopt the
standards and just think that everybody is going to follow
them. They might not know about them, particularly when you are
getting into regulating physicians, which is actually an area
we are getting into. So that everything really needs to be
verified. We think the on-site inspection process is very
important.
Senator Carper. How does your enforcement mechanism work?
Or do you have enforcement mechanism?
Dr. Linden. Yes, absolutely. Routinely, following a survey
we will cite deficiencies and usually they are correct. For
egregious situations such as one that I described in my
testimony of two young men operating a semen bank using only
themselves as donors, we filed charges. We have filed charges
in some cases where there are improprieties or very severe
deficiencies that are not corrected.
Senator Carper. Thanks. Dr. Solomon, I missed your
testimony, as I said earlier, and I would appreciate it if you
would just take maybe a minute or so and just recap for me the
most important things that you would want us to garner from
your contributions.
Dr. Solomon. Certainly. Thank you. The main issues have to
do with both our ability to conduct investigations, to follow
up on investigations, and to encourage the implementation of
the types of prevention measures that are in place in New York
and that have been proposed by the FDA.
Another element is the surveillance capability and the
prevention capability that goes with the public health function
and with the prevention research function that allows us to
gather the kind of information and that is so useful in
following up on these kinds of problems and implementing very
rapid responses to protect public health.
Senator Carper. Do I understand that the FDA has developed
regulations of its own for our country; is that correct?
Dr. Solomon. Certainly FDA has proposed a set of
regulations and guidelines and I think we will be hearing about
that later.
Senator Carper. What is the timeline at FDA, do you know,
in terms of accepting public comment, modifying the regs?
Dr. Solomon. I am not familiar with that. I am sorry.
Senator Carper. Maybe we will find out later. Again, our
thanks to both of you for being here. Thanks for your
contributions.
Chairman Collins. I want to thank you both for your
testimony and we will now turn to our third and final panel
today. We have one witness, Dr. Jesse Goodman, who will be
testifying on behalf of the Federal Food and Drug
Administration. Dr. Goodman is the director of the FDA's Center
for Biologics Evaluation and Research. He is also, I am told, a
specialist in infectious disease and a practicing physician.
Dr. Goodman, before I have you give your testimony today I
so want to acknowledge the fact that I believe you have only
been in your current position since January, so obviously this
is a problem that you inherited as opposed to created. But
nevertheless, I hope you understand how frustrating it is for
me personally and for those of us who have worked on this issue
for years now, to find that we are no closer to final
regulations, or virtually no closer than we were when I held a
hearing on this issue 2 years ago. To hear the tragedy endured
by the Lykins family I know moved you as well. So with that
introduction, I would ask that you proceed with your statement.
TESTIMONY OF JESSE L. GOODMAN, M.D.,\1\ DIRECTOR, CENTER FOR
BIOLOGICS EVALUATION AND RESEARCH, FOOD AND DRUG
ADMINISTRATION, U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES
Dr. Goodman. Thanks very much, Madam Chairman, and Members
of the Committee. Thank you for the opportunity to be here
today on this important matter.
---------------------------------------------------------------------------
\1\ The prepared statement of Dr. Goodman with an attachment
appears in the Appendix on page 61.
---------------------------------------------------------------------------
You really introduced me but just as you said, since
January I have been director of the Center for Biologics at
FDA, and I am also an infectious disease physician. So I am
familiar with these problems and in fact have been involved in
treatment of individuals who get infections after tissue
transplants.
CBER, the Center for Biologics, is the FDA center that is
responsible for regulating many types of human tissues and
cells transplanted during medical procedures. We also have some
other very important public health responsibilities in terms of
blood, vaccines, and other novel therapies. I really do
appreciate and share the concern of the Chairman and the
Committee Members that we do everything we can in this area.
Let me assure you that Commissioner McClellan and I are very
committed, while new in our roles at FDA, to doing what we can
to advance the field of tissue safety.
Also I really want to convey to the family and friends of
Brian Lykins how sorry I certainly am for their loss. As a
father, I can only begin to imagine how this has affected them.
Again, while there is nothing that I can say here that will
take that away, I do want them to understand the high level of
commitment we have to do what we can to prevent problems like
this in the future.
In my testimony I am going to briefly provide some
background on human tissues and their use, discuss some of the
safety concerns and their evolution, and in fairness, describe
some actions that we have already taken under existing
regulations as well as the actions we plan to take to enhance
tissue safety.
Transplanted human tissue products have the potential to
treat or cure a wide variety of health conditions. Over the
past decade, advancing technology has expanded the therapeutic
uses of tissue-based products. As we heard from Senator
Collins, it is estimated that over 800,000 tissue transplants
will be performed this year and, fortunately, the vast majority
of these have very positive outcomes. In fact these products
have dramatically increased patients' quality of life in ways
that were previously unheard of. Senator Pryor's experience is
a positive example and we would like to see everyone have that
experience and certainly that is what we are working towards.
Cells and tissue have new uses. They can also be used in
combinations with drugs or devices for doing things like
delivering gene therapies. So there is a lot of promise here,
and there is a potential to provide treatment for diseases as
diverse as cancer, Parkinson's disease, even diabetes and other
serious conditions.
However, with the increased uses of human tissues has come
a heightened public awareness of the need for appropriate
regulations. During the 1980's there were reports of multiple
incidents of transmission of the chronic neurologic disease,
Creutzfeld-Jakob disease by brain-covering allografts. A 1992
report documented seven HIV infections occurring from a single
donor. And in the 1990's, possible transmission of Creutzfeld-
Jakob disease through corneas and eye tissues was reported.
Now most recently, and this is very relevant to the tragic
case we are hearing about today, it has become increasingly
apparent that tissues are also subject to contamination from
other agents like bacteria and fungi. These are unlike the
viruses like hepatitis and HIV which come from donors who were
not aware, or from a system that was not aware they carried a
disease. These risks may have little to do with the donor.
Rather, they may relate largely to how the tissue is handled,
processed, and then tested.
As part of the FDA's efforts to address tissue safety, in
December 1993 the agency published an interim rule for human
tissue intended for transplantation. This rule provided
specific donor suitability and testing requirements for
relevant human tissues. Like actions we had taken to improve
blood safety, FDA was acting primarily to counter the
transmission of HIV, hepatitis B, and hepatitis C. This rule
also provided for the inspection of tissue banks and the recall
and possible destruction of unsafe human tissue. In fact events
that later occurred with CryoLife, as we will hear.
These efforts were part of our risk-based regulatory
approach to tissues, recognizing the importance of these
tissues and maximizing benefits while minimizing risks with the
whole goal in the end being promoting public health.
Now I would like to report on eight areas of agency
activities since the Committee's last hearing 2 years ago on
this subject. These include many actions taken in response to
the need to help better prevent the types of problems that led
to Mr. Lykins' very tragic outcome.
First, the death of Brian Lykins and other reports of
infections in recipients prompted collaborative investigations
by FDA and CDC, as you have heard, and in some cases involving
the State of New York. Extensive testing at CDC implicated
CryoLife tissue in the fatal infection and other reported
infections. This led to a comprehensive inspection of CryoLife,
the tissue bank that processed the implanted tissue.
As an urgent response to these investigations, FDA also
decided it was critical to take additional steps now, not to
wait for regulations necessarily, to control the threat of
bacterial and fungal contamination during manufacturing. In
March 2002, we issued a guidance for immediate implementation
concerning requirements for validating procedures for
processing human tissues under existing regulations. This
guidance and the accompanying outreach to industry and
professionals emphasized important steps believed necessary to
reduce the risk of contamination.
Second, our CryoLife inspection uncovered numerous and
significant violations of FDA regulations. You have heard some
of these today. When CryoLife failed to respond adequately to
these deficiencies, FDA issued an order for retention, recall,
and destruction of tissue in August 2002. This resulted in a
recall of 7,913 tissue products. Further actions by FDA and CDC
resulted in the firm committing to take appropriate steps
necessary to ensure the safety of the tissues it supplies.
Third, the FDA, which had conducted--if we go back to the
year 2000--we conducted 93 tissue establishment inspections
then. We conducted 132 in 2001, increased that to 165 in 2002,
and in fiscal year 2003 plans call for conducting over 200
inspections. I am pleased to be able to report that as a result
of this activity, FDA has now inspected approximately 95
percent of the 162 registered tissue processors. By the end of
fiscal year 2003, our Office of Regulatory Affairs plans to
have completed inspections of 487 of the 512 registered tissue
establishments. This includes not just processors but
establishments that may test or ship or distribute or store
tissue. Again, this is about 95 percent.
These increasing activities in recent years resulted in
2001 to 2002, for example, 99 investigator reports noting
compliance deficiencies that warranted attention. We believe
that these inspections and reports are already helping to
increase awareness, correct deficiencies, and ensure that
better practices are followed, including proper practices to
prevent contamination such as we have heard about today.
Fourth, in October 2002, we created a new office, an Office
of Cells, Tissues and Gene Therapies which coordinates
regulatory and review activities for tissue products.
Fifth, the emerging challenges of chronic degenerative
neurologic diseases such as CJD and variant CJD, or mad cow
disease, prompted us to issue a draft guidance regarding
appropriate donor deferral for donors.
Sixth, very related to this, on October 22, 2002 FDA issued
a rule to classify human dura, which is brain lining, as a
Class II device in order to establish controls to assure
safety.
Seventh, In order to achieve a more robust surveillance
system, FDA is continuing to work with CDC to stimulate adverse
event reporting and to investigate reported events. CDC, as you
have heard, has unique capabilities to conduct such
surveillance. And we are working on our own and with CDC to
obtain adverse event information, including from health care
databases.
Eighth, working collaboratively with tissue manufacturers
and trade and professional associations to identify new safety
issues and improve tissue practices is also an important
component. With this goal in mind, FDA has dramatically
increased outreach activities in recent years in an effort to
anticipate and avoid safety problems.
I should mention that this includes highly productive
interactions with some of the professional associations,
including the one Senator Collins mentioned, the American
Association of Tissue Banks, as well as the eye banks and
reproductive medicine associations. These associations have
gone a long way through their voluntary programs to improving
standards in their industry. Many companies, but not CryoLife,
participate in those standards.
In addition to these activities, as you have alluded to,
FDA advanced three regulatory proposals. The first rule
established suitability determinations for donors of human
cells and tissues. The second rule regards good manufacturing
practices. And the third rule, which became final in January
2001 required the registration and listing of the tissue
establishment. In fact this rule has already provided important
information to direct and manage our risk-based inspection
activities. It is a success, I think, of the publication of
this rule that we have been able to really enhance the
inspections and reach the 95 percent of targeted folks.
Under FDA's proposed regulations we would maintain this
complete database of tissue products and establishments. We
would provide more comprehensive detailed requirements designed
under good tissue practices to help assure high quality during
manufacturing, to further helping to prevent bacterial and
fungal contamination.
We would require establishments to maintain complaint files
and investigate complaints, and to report adverse events and
product deviations to the FDA; issues that have been identified
here. The proposed rules would establish tracking requirements
to allow the agency to find recipients of implicated tissues if
needed. The proposed rule would also augment existing
requirements for screening and testing of donors for relevant
communicable diseases. This would also help us to rapidly
respond to new infectious disease threats such as West Nile
virus which is something we have been devoting a lot of energy
to in our center.
While we have made substantial progress in this effort, the
donor suitability and good tissue practice rules, as alluded to
here, are continuing under review and discussion. Given that
these regulations will create significant change, we want to be
sure both that they are effective and that we achieve the
proper balance of enhancing safety and quality while not
causing undue burden or complexity that would inhibit the
development or availability of products that benefit Americans.
In fact we want these rules also to be flexible enough to
permit the use of new and better technologies to do things like
sterilize tissues or improve safety.
As you heard from some of the testimony, we want to be sure
that as we do these rules we do not create a situation of
shortages or non-availability of certain tissues that actually
could hurt people if they needed the tissues. So we do want to
get the right balance here.
We do believe that the extensive process of comment and
input that has taken place will help us achieve these
objectives. We are not sitting on this. We are actively engaged
in moving forward. We have taken significant steps to make
tissues safer than they were 2 years ago.
However, and even though they are rare, tragic adverse
events like that of Brian Lykins--and as you said, it is not
just an adverse event. This is something that really affects
human beings. That is why I do this. Tragic events like this
are devastating, and we are committed to doing what we can to
prevent them. When a patient has a procedure involving a tissue
product, we want to do our part to help make sure that patient
can be as confident as possible that the product will be safe
and free from any preventable risk of contamination.
I have been very active working to resolve remaining issues
and I am committed to doing everything I can to help in this
effort. I would be glad to answer any questions.
Chairman Collins. Thank you very much, Dr. Goodman. I guess
what I was hoping to hear from you today was that the previous
FDA officials blew it and that you were going to promise me
that within a time certain we would have the regulations. I
understand you might not want to comment on the actions of your
predecessors, but I want to go through a bit of a timeline with
you just so you can better understand the frustration that many
of us are feeling on this issue.
The FDA's first regulation of tissue banks actually goes
back to 1993. But it was in 1997 that the FDA started looking
at the very issues that we are talking about today. In May
2001, 2 years ago almost to the day, I chaired the hearing at
which your predecessor Dr. Zoon testified. She told me the FDA
was committed to completing the regulations. I thought it was
imminent at that point. There was testimony at that hearing
that clearly said that the adequacy of tissue supply was not a
concern, and indeed when you look at the number of transplants
which has soared, some more than 800,000 last year alone made
available in the marketplace, I am not sympathetic to the
argument that somehow the FDA regulations are going to cause
shortages.
When I had the hearing, as I said, 2 years ago, I got a
commitment from Dr. Zoon that the regulations would be issued.
After repeated phone calls throughout the remainder of that
year when nothing happened, I wrote in February 2002 to the
FDA. I expressed my frustration, the agency was taking such an
inordinate amount time to complete its work, because its work
was good. It knew what to do. It had come up with a reasonable
protocol. All we were asking was that it be made final, that it
be made effective.
I asked when the regulations would be completed. The
answer--actually, I wrote again. That was in December 2001, I
wrote to the acting principal deputy commissioner. I did not
even receive a reply to that letter. In February 2002, I again
wrote to FDA. This time I received a reply 2 months later in
April and the answer was, we do not know. We do not have a date
for publication and implementation of the final rules. Again,
this is 5 years later at that point.
In March 2002, we had a report from the CDC after Brian
Lykins' death in November 2001 in which the CDC said, the
findings in this report have important implications for patient
safety and indicate that Federal regulations and industry
standards on processing and quality control methods need to be
enhanced and implemented. So here we have the CDC calling for
implementation.
In October 2002, I asked Commissioner McClellan at his
nomination hearing about this issue. Over and over again I have
asked. I have written everyone I can think of. I have a stack
of correspondence. We have called. When is this going to
happen? The evidence is overwhelming that the FDA has come up
with a good approach. We have examples in three States of
effective regulation. So if there are some issues remaining,
could we not look to the experience of those three States? When
are we going to finalize these regulations?
Dr. Goodman. I share your concern and some of your
frustration and I do appreciate it. When I started as center
director, I know that within those first few weeks I said to
staff, and when I was able to share it with Dr. McClellan, that
I thought this issue and moving forward should be a very high
priority. It is on my list of high priorities. It is not
through lack of attention right now. I do not see a problem
there.
There is a new commissioner. They are complex rules. We
want to do it right. I personally feel that the framework which
has evolved with a lot of outside input and discussion with
folks like the tissue banks, with our colleagues at CDC and the
States, with a lot of comments and input I think it is a good
direction and deals with appropriate issues in a number of
areas that I would like to see us deal with. So I am very
committed to doing that. We are working, the new commissioner
and I are working actively on that now and hope to resolve some
of those issues.
For some of the reasons you have said and some of the past
experience, I do not control the exact timeline and also would
not want to give you one that is inaccurate. Also, I think that
we want to come up with the right product, as I said here, to
meet our common goals, the goals to deal with some of these
areas where we could have improved standards and regulation.
Chairman Collins. Dr. Goodman, I do not doubt your personal
commitment and I do not doubt your sincerity, and I do not
doubt your expertise at all. But we have to act. I cannot allow
more Brian Lykins to die because we did not have regulations in
place. Every expert with whom I have consulted has told me that
they believe that had those regulations been in place and had
CryoLife followed them, we would not have had the death of
Brian Lykins. That is just so troubling to me.
Dr. Goodman. Right. I would like to respond to that because
those are very important points. One is that we too want to do
everything we can to prevent bad outcomes from medicines,
medical procedures, and in this case from tissues. I agree with
that totally.
What I do want to emphasize is that we are in agreement
that there are areas where what can be done through regulation
can be improved, and that some of those would help prevent
problems like Brian Lykins' death. That is particularly what
drives me and makes it important. I do not want to see more of
that.
But what I also want to point out is that FDA's actions at
CryoLife and in response to the investigation conducted in
collaboration with CDC where under existing regulation we did
show that in fact CryoLife was violating existing standards and
rules. Our view is not just a guidance but they were violating
principles that are there in our regulations and those are the
basis of our activities.
Now, that said, there are ways in which elements of the
proposed rules provide additional layers of protection and
augment that existing authority in substantive and real ways
that I think could add value to the public health process.
Those are the things that I am committed to trying to move
forward.
Chairman Collins. My time on this round has expired so I am
going to yield to my colleague, Senator Pryor. But when we come
back, I am going to direct to the deposition of CryoLife in
which it said it did not have to report to the FDA of adverse
events. It did not have to follow the regulations because they
were just guidance and they were not effective, they were not
in effect. I think that is very troubling and should be to you
as well.
Dr. Goodman. I agree. We can discuss that, for sure.
Chairman Collins. Senator Pryor.
Senator Pryor. Thank you, Madam Chairman. I must tell you,
Dr. Goodman, I am not really satisfied with most of your
answers today. The reason I am not is because, by and large,
you have given us answers related to process, not action. I
want to know what you are going to do to get these regs out.
Dr. Goodman. Again, I appreciate your concern. I am not
somebody--sometimes we have processes that we need to assure we
take the right action and to assure we get the action done.
Senator Pryor. This has been pending at your agency for a
long time.
Dr. Goodman. Right. I appreciate the frustration over that.
As I said, in answer to your second question, I have engaged
the commissioner and his office, I am working very diligently
and deliberatively to resolve any issues so that we can move
forward on the key things here. So I agree with you on that.
Without in any way diluting the importance of that work we need
to do, I also would like to say that it has been very important
to me looking at this issue even in the time since I have been
center director to assure also and to let you know that under
our existing authority we have not been doing nothing. We have
dramatically gone out there and increased inspections.
The inspectors we have out there have been trained in
procedures and issues related to exactly the kind of problems
that led to this tragic outcome. As a result we are seeing, for
instance, more voluntary recalls, more actions, and we believe
that even our ongoing actions, which are contributing to
improving quality and helping prevent such events.
Do they achieve all the things that would have been
achieved under the proposed rules if they were finalized? No.
For that reason your comment is very important and I
acknowledge and share your interest in moving forward.
Senator Pryor. What issues are left to be resolved at the
agency before you get these out?
Dr. Goodman. Again, we have just recently briefed and
engaged Dr. McClellan and staff, and the commissioner, who is
new, and his staff in the commissioner's office, on these
issues. There are quite a number of elements of these rules. It
is not one single thing or another. We want to be sure we are
placing the priorities in the right place, the things that will
enhance patient safety while not causing undue burden, get the
right balance here and move forward.
Senator Pryor. But specifically, what obstacles are left
within the agency to do that?
Dr. Goodman. I think the only obstacles are identifying
issues where those kinds of concerns are and then resolving
them in a way that can get us to the satisfactory end point. I
think I do not have a specific list here. This process has been
moving forward and quite a number of unresolved issues I think
people have come up with solutions for them.
Senator Pryor. Is there any reason why these regulations
cannot be released in the next 90 days?
Dr. Goodman. I think that we at FDA--again, I understood
Senator Collins' point of view too in terms of moving these
forward. I think we do have some work to do on them. Again, I
am going to work on those, and work with the commissioner on
those within the next 90 days and try to do everything we can
to move forward in a constructive way.
We are not, also, the only parties to this obviously.
Everything we do is reviewed legally within the agency and the
Department, and at a policy level in the Department. Now we are
trying, and we plan to engage collaboratively in that process
to make this more effective and move it forward. But I agree
with you. We are going to do everything we can during the next
90 days to move things forward.
Senator Pryor. Do you need any additional statutory
authority to move forward?
Dr. Goodman. I am not aware at this time that statutory
authority is at issue here. We feel under the Public Health
Service Act, in terms of protecting people from communicable
diseases that we have authorities, and that the proposed rules
largely build on those authorities. So we do feel we have the
authority.
Senator Pryor. I am interested in Senator Collins'
questions here in a few moments about the deposition relating
to CryoLife and I would really like to hear and delve into that
and know what is said. But one question I have for you is,
given the violations that CryoLife was engaged in, and I guess
has admitted to at this point I guess, why are they still in
business?
Dr. Goodman. I think that is a good question. What I would
say is that FDA has taken a number of actions with respect to
CryoLife. Included in those actions in terms of permitting them
to continue to release tissue were a number of steps in an
agreement reached with them. First of all, just let me say that
as I mentioned, they were required by our action to recall a
large number of their tissues and they entered into agreement
with us to take the needed steps to assure better safety in
their tissue processing.
Also during the interim period while they were taking these
steps, a number of extra safeguards were put into place through
this agreement including many of the things that CDC and Dr.
Linden from the New York State Health Department alluded to.
This includes the things we wanted to see valid, I say valid
pre-processing culture of these materials, appropriate
disposition of materials which failed, valid culturing of
materials after processing, and again, appropriate disposition
of material that failed, and a commitment to create and
validate their own procedures to do this.
So there was quite a significant discussion and a
substantive agreement reached in order to, what we felt was to
ensure needed elements that a safety program was in place there
and that overcame what we felt were, as I said, quite serious
violations even of the existing standards.
Senator Pryor. I am out of time. Thank you, Madam Chair.
Chairman Collins. If you need additional time, feel free to
proceed.
Senator Pryor. I was just going to ask with regard to
CryoLife, as part of the agreement that the agency reached with
this company, is there an ongoing monitoring to assure that the
FDA has assurance that they are complying?
Dr. Goodman. Yes, there are ongoing inspections, there are
meetings. So the answer is yes. We are still concerned. They
have steps in the right direction, but these interim procedures
are still in place in terms of the additional culturing and
other procedures with their materials. But they have taken
steps. Those steps are not finished, and we are going to watch
this carefully as this goes forward. We are quite concerned
about this.
Just getting back to the availability issue, this is one
area where we did hear from a number of surgeons and others who
use certain of their products for what they felt were essential
and lifesaving issues. Part of what we did with CryoLife was
make sure--this again addresses Senator Collins and the Lykins
family comments. Part of what we did in CryoLife was work with
them to be sure that users were also informed about some of
these issues with their products and could themselves help make
an informed risk-benefit situation in the situation they are
in.
Again, I think we have taken substantive action in this
case. But again, as I said, I think some of the components of
the proposed rules will, we hope, prevent and better deal with
future situations like this.
Senator Pryor. Madam Chairman, I will make this the last
question. You mentioned a minute ago that you still have some
concerns about CryoLife. They are taking some steps. They are
not completely there yet. Yet the agency is allowing them to
still be engaged in the business. Why not force them to clean
it up first before they re-enter the business?
Dr. Goodman. There are two components to that. One is,
because they have not completely finished all their progress on
the various things in their agreement with the agency, they are
taking additional steps that would not normally be required in
terms of these outside cultures and oversight and agreements of
what they will do in response to these cultures with us. So
there are additional measures in place to provide assurance
that these kinds of problems are dealt with. So that is the
first component of that.
The second is just to state--and I do not want to equate
these problems with all problems observed in all FDA
inspections or whatever, but in most cases there are different
kinds of levels of concerns and observations in different kinds
of inspections, and very frequently when FDA makes observations
of concerns like this a company will move quickly to correct
those in a manner that gives us assurance that the product is
safe and will remain safe. In this case some of those steps
have been taken but not all, so there is a need to have
additional steps in place.
Senator Pryor. Thank you.
Chairman Collins. Thank you very much, Senator Pryor.
Dr. Goodman, CryoLife was well aware of problems related to
infections of some of the tissue that it was providing long
before Mr. Lykins died in November 2001. The corporation's
internal reports reflect that in May 1998 the company received
a report from a surgeon indicating that a patient had a problem
with an allograft. Cultures indicated the growth of Clostridium
bacterium. The patient then required the removal of the
allograft due to continued problems with infection. In the year
2000 there were at least six complaints to CryoLife regarding
bacterial infections. In 2001 there were 10 complaints at least
regarding bacterial infection, and one of hepatitis C
transmission from an allograft. I mentioned earlier that I have
a list of 18 lawsuits that have been filed against the company
as a result--each case involving tainted tissues.
Now the details of each of these complaints vary but there
is clearly a pattern indicating a problem. There is one common
notation made by a CryoLife employee on each of the complaint
reports. I want to quote it to you. It says, ``orthopedic
allografts are not classified as medical devices as defined by
FDA regulations and therefore are not reportable.'' So CryoLife
was all too aware that the serious problems that had been
reported by surgeons, and other health care providers to the
company did not have to be reported under current FDA
regulations.
Should it not be mandatory for tissue banks to report
adverse events such as these to the FDA?
Dr. Goodman. I would like to see reporting of adverse
events that the tissue banks and processors are aware of to the
FDA. I think it could be helpful, as you allude to, in
identifying problems ahead of time, and it is an element of the
proposed rules. I agree with you.
I cannot comment on the motivation or anything like that,
but you are right. And not just adverse events. It is important
that another component of what has been proposed is that
complaints are investigated and records kept of those
complaints. So even if something is felt not by a company or a
surgeon even not to be due to a graft or some other medical
procedure, it is information that can be helpful to FDA who may
have information from other companies, other sectors of
industry to identifying a problem. It might not even be a
problem at one company. It might be a problem with something
being done elsewhere.
So we do feel this is information that is helpful. It has
been helpful in helping make other kinds of medical products
safe. So I share your desire that we have such information and
that we get it in an effective way.
Chairman Collins. Again, I think that proposed requirement
for mandatory reporting just makes good sense and needs to be
put into effect. That is not a complicated requirement to put
into effect.
Dr. Goodman. Frankly, I think a lot of the issues about
complaints, etc., these are good quality practices that
irregardless of the FDA any good company should be following.
But I agree with you, we cannot always count on that.
Chairman Collins. After Brian Lykins died his family filed
a lawsuit against CryoLife and during that process, as I
alluded to earlier, an executive of the company was deposed.
During his deposition he made reference to the fact that the
FDA had not imposed final regulations regarding what industry
practices should be, but instead had issued what he called only
non-binding guidance. Does it trouble you to learn that a
tissue bank like CryoLife, which clearly does not follow ideal
practices, is citing the FDA's failure to issue regulations as
a defense?
Dr. Goodman. Of course it troubles me. One comment I would
make is it is not infrequent for firms under FDA investigation
or with whom actions have been taken that a firm might not
like, it is not uncommon for them to question those actions or
question the authority for those actions. Everybody loves us.
Irrespective of those kinds of comments I would say that we
believe or we would not have taken the recall action, that we
have clear and strong legal authority to do that irregardless
of their comments. I am disturbed by their comments and I want
to do everything we can to be sure that people do not believe
that and to, in the ways we need to, enhance our activities,
but I do not buy that.
Chairman Collins. When FDA did its inspection and issued a
form 483, FDA inspectors noted 12 objectionable conditions
identified at CryoLife. CryoLife's written response to the FDA
does challenge FDA's authority. When questioned about that in
the deposition the executive said, ``there was a guidance
document issued. They were not formal regulations. They were
opinions, and they were not in effect at the time.''
One of my frustrations is I do not want there to be any
doubt about your authority. I do not want a bad actor to be
able to tie the FDA up in court because you have not gone
through the final steps of issuing all the regulations. We need
to clear this up. We need to end any doubt about your
authority. We need to have clear regulations in place, and I
believe the FDA has the right approach.
It is interesting that in the 6 years that these proposals
have been pending, it is not as if FDA has proposed changing
them in any formal way. In fact the American Association of
Tissue Banks, the American Red Cross have endorsed the
regulations. We need to get on with the job.
Dr. Goodman. I hear you and I appreciate those comments. I
appreciate all of them and I understand your concerns. I do
want to emphasize that while CryoLife may have questioned our
authority in this case, this authority is the interpretation of
the chief counsel of the FDA and the actions of the FDA, and we
do not think there is question about authority in this case.
That does not in any way mean that many of the proposals in the
proposed rules are not helpful, will not help industry do a
better job, will not help FDA do a better job. That is what we
want to aim for, Dr. McClellan and I, helping industry and the
FDA do a better job to help make tissues safer. I agree with
that.
Chairman Collins. Dr. Goodman, I do want to thank you for
coming today. I appreciate the fact that you sat through the
entire hearing so that you heard firsthand the Lykins family
testimony which I am sure you will agree that the death of
their son is such a tragedy. If by acting to implement these
regulations the FDA can prevent future cases like Brian Lykins,
or future cases of disease and infection, we need to help you
get that job done. If there are obstacles I ask again for FDA
to come to us. That was a request that Senator Durbin and I
made 2 years ago. If there is some new statutory authority that
you need, as Senator Pryor asked you about, or if there are
more resources, come to us. But let us get the job done.
I hope I have from you today, or else I will not let you
go, a commitment, a personal commitment to work with us to get
these regulations, which I view as absolutely vital to public
health, implemented without further delay.
Dr. Goodman. First of all, thank you. I am personally
committed and will make a commitment to you to do everything
that I can and is within my power, which is not, as you know,
everything in the world. But I will do everything I can that is
within my power to move this forward. This is a high priority
to me.
I think as we look at the proposed rules and as I work with
Dr. McClellan and the commissioner's office we really do want
to identify for sure what are the key things that we can do and
we need to do to help improve safety here and move those
forward. So I am giving you my commitment that I am going to do
everything I can to try to do that.
Chairman Collins. I thank you for that commitment and you
can be assured that I am going to hold you to it. I know again
that you have only been on the job for a short time, but
working together I am convinced that we can make a difference
in this area. Again, thank you for being with us this morning.
Dr. Goodman. Thank you.
Chairman Collins. Before adjourning the hearing, I also
want to say a special thank you to the Lykins family. Steve,
Leslie, and Tammy spent time with me in my office yesterday as
well as having talked to the staff. I am so impressed and moved
by their courage and their determination to make something good
out of the very worst tragedy that any family could suffer
through. I just want to publicly again thank them for their
courage and for their commitment, and to assure them that we
will continue to work on this important issue.
I also want to thank my staff for its hard work. I am
optimistic today that we are going to move forward, but I felt
that way exactly 2 years ago, so this is an issue we will
continue to follow.
The hearing record will remain open for 15 days for the
submission of questions or any additional materials. I want to
thank my colleague, Senator Pryor for sharing his personal
experience and for being here for this hearing. The Committee
hearing is now adjourned.
[Whereupon, at 11:56 a.m., the Committee was adjourned.]
A P P E N D I X
----------
[GRAPHIC] [TIFF OMITTED] T8247.001
[GRAPHIC] [TIFF OMITTED] T8247.002
[GRAPHIC] [TIFF OMITTED] T8247.003
[GRAPHIC] [TIFF OMITTED] T8247.004
[GRAPHIC] [TIFF OMITTED] T8247.005
[GRAPHIC] [TIFF OMITTED] T8247.006
[GRAPHIC] [TIFF OMITTED] T8247.007
[GRAPHIC] [TIFF OMITTED] T8247.008
[GRAPHIC] [TIFF OMITTED] T8247.009
[GRAPHIC] [TIFF OMITTED] T8247.010
[GRAPHIC] [TIFF OMITTED] T8247.011
[GRAPHIC] [TIFF OMITTED] T8247.012
[GRAPHIC] [TIFF OMITTED] T8247.013
[GRAPHIC] [TIFF OMITTED] T8247.014
[GRAPHIC] [TIFF OMITTED] T8247.015
[GRAPHIC] [TIFF OMITTED] T8247.016
[GRAPHIC] [TIFF OMITTED] T8247.017
[GRAPHIC] [TIFF OMITTED] T8247.018
[GRAPHIC] [TIFF OMITTED] T8247.019
[GRAPHIC] [TIFF OMITTED] T8247.020
[GRAPHIC] [TIFF OMITTED] T8247.021
[GRAPHIC] [TIFF OMITTED] T8247.022
[GRAPHIC] [TIFF OMITTED] T8247.023
[GRAPHIC] [TIFF OMITTED] T8247.024
[GRAPHIC] [TIFF OMITTED] T8247.025
[GRAPHIC] [TIFF OMITTED] T8247.026
[GRAPHIC] [TIFF OMITTED] T8247.027
[GRAPHIC] [TIFF OMITTED] T8247.028
[GRAPHIC] [TIFF OMITTED] T8247.029
[GRAPHIC] [TIFF OMITTED] T8247.030
[GRAPHIC] [TIFF OMITTED] T8247.031
[GRAPHIC] [TIFF OMITTED] T8247.032
[GRAPHIC] [TIFF OMITTED] T8247.033
[GRAPHIC] [TIFF OMITTED] T8247.034
[GRAPHIC] [TIFF OMITTED] T8247.035
[GRAPHIC] [TIFF OMITTED] T8247.036
[GRAPHIC] [TIFF OMITTED] T8247.037
[GRAPHIC] [TIFF OMITTED] T8247.038
[GRAPHIC] [TIFF OMITTED] T8247.039
[GRAPHIC] [TIFF OMITTED] T8247.040
[GRAPHIC] [TIFF OMITTED] T8247.041
[GRAPHIC] [TIFF OMITTED] T8247.042
[GRAPHIC] [TIFF OMITTED] T8247.043
[GRAPHIC] [TIFF OMITTED] T8247.044
[GRAPHIC] [TIFF OMITTED] T8247.045
[GRAPHIC] [TIFF OMITTED] T8247.046
[GRAPHIC] [TIFF OMITTED] T8247.047
[GRAPHIC] [TIFF OMITTED] T8247.048
[GRAPHIC] [TIFF OMITTED] T8247.049
[GRAPHIC] [TIFF OMITTED] T8247.050
[GRAPHIC] [TIFF OMITTED] T8247.051
[GRAPHIC] [TIFF OMITTED] T8247.052
[GRAPHIC] [TIFF OMITTED] T8247.053
[GRAPHIC] [TIFF OMITTED] T8247.054
[GRAPHIC] [TIFF OMITTED] T8247.055
[GRAPHIC] [TIFF OMITTED] T8247.056
[GRAPHIC] [TIFF OMITTED] T8247.057
[GRAPHIC] [TIFF OMITTED] T8247.058
[GRAPHIC] [TIFF OMITTED] T8247.059
[GRAPHIC] [TIFF OMITTED] T8247.060
[GRAPHIC] [TIFF OMITTED] T8247.061
[GRAPHIC] [TIFF OMITTED] T8247.062
[GRAPHIC] [TIFF OMITTED] T8247.063
[GRAPHIC] [TIFF OMITTED] T8247.064
[GRAPHIC] [TIFF OMITTED] T8247.065
[GRAPHIC] [TIFF OMITTED] T8247.066
[GRAPHIC] [TIFF OMITTED] T8247.067
[GRAPHIC] [TIFF OMITTED] T8247.068
[GRAPHIC] [TIFF OMITTED] T8247.069
[GRAPHIC] [TIFF OMITTED] T8247.070
[GRAPHIC] [TIFF OMITTED] T8247.071
[GRAPHIC] [TIFF OMITTED] T8247.072
[GRAPHIC] [TIFF OMITTED] T8247.073
[GRAPHIC] [TIFF OMITTED] T8247.074
[GRAPHIC] [TIFF OMITTED] T8247.075
[GRAPHIC] [TIFF OMITTED] T8247.076
[GRAPHIC] [TIFF OMITTED] T8247.077
[GRAPHIC] [TIFF OMITTED] T8247.078
[GRAPHIC] [TIFF OMITTED] T8247.079
[GRAPHIC] [TIFF OMITTED] T8247.080
[GRAPHIC] [TIFF OMITTED] T8247.081
[GRAPHIC] [TIFF OMITTED] T8247.082
[GRAPHIC] [TIFF OMITTED] T8247.083