1
1
AThis transcript has not been edited or corrected,
but appears as received from the commercial transcribing service. Accordingly, the FDA makes no representation
to its accuracyY@
2
3
4 FOOD AND DRUG ADMINISTRATION
5 CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
6
7
8
9 BIOLOGICAL RESPONSE MODIFIERS
10 ADVISORY
COMMITTEE (BRMAC)
11 Meeting 36
12 DAY TWO
13
14
15
16
17
18
19
20
21 Gaithersburg, Maryland
22 Friday, October 10, 2003
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1
PARTICIPANTS:
2 BRMAC MEMBERS:
3 MAHENDRA S. RAO, Acting Chair
National Institute on
Aging
4
JONATHAN S. ALLAM
5 Southwest Foundation for Biomedical Research
6 BRUCE R. BLAZAR
University of Minnesota
7
DAVID M. HARLAN
8 National Institute of Diabetes and Digestive
and Kidney Disease
9
KATHERINE A. HIGH
10 University of Pennsylvania
11 JOANNE KURTZBERG
Duke University Medical
Center
12
ALISON F. LAWTON
13 Genzyme Corporation
14 RICHARD C. MULLIGAN
Harvard Medical School
15
ANASTASIOS A. TSIATIS
16 North Carolina State University
17 ALICE J. WOLFSON
Wolfson &
Schlichtmann
18
TEMPORARY VOTING MEMBERS:
19
JAMES F. CHILDRESS
20 University of Virginia
21 LYNNE L. LEVITSKY
Harvard Medical School
22
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1 PARTICIPANTS
(CONT'D):
2 TEMPORARY VOTING MEMBERS (CONT'D):
3 ABBEY S. MEYERS
National Organization for
Rare Disorders
4
CAROLE B. MILLER
5 St. Agnes Healthcare
6 W. MICHAEL O'FALLON
Mayo Clinic
7
DANIEL R. SALOMON
8 The Scripps Research Institute
9 ROBERT S. SHERWIN
Yale University School of Medicine
10
JANET H. SILVERSTEIN
11 University of Florida College of Medicine
12 CONSULTANTS:
13 JOHN J. O'NEIL JR.
LifeScan, Inc.
14
CAMILLO RICORDI
15 University of Miami School of Medicine
16 GUESTS/GUEST SPEAKERS:
17 BERNARD J. HERING
University of Minnesota
18
JAMES SHAPIRO
19 University of Alberta
20 THOMAS L. EGGERMAN
National Institute of
Diabetes and Digestive
21 and Kidney Diseases
22
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PARTICIPANTS (CONT'D):
2 GUESTS/GUEST SPEAKERS (CONT'D):
3 JAMES BURDICK
Health Resources and
4 Services Administration
5 FRANCISCA AGBANYO
Health Canada
6
FOOD & DRUG ADMINISTRATION
(FDA) PARTICIPANTS:
7
JESSE L. GOODMAN
8 Center for Biologics Evaluation
and Research
9
KATHRYN CARBONE
10 Center for Biologics Evaluation
and Research
11
RAJ PURI
12 Center for Biologics Evaluation
and Research
13
CAROLYN WILSON
14 Center for Biologics Evaluation
and Research
15
ANDREW BYRNES
16 Center for Biologics Evaluation
and Research
17
NANCY MARKOWITZ
18 Center for Biologics Evaluation
and Research
19
STEVEN BAUER
20 Center for Biologics Evaluation
and Research
21
22
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PARTICIPANTS (CONT'D):
2 FDA PARTICIPANTS (CONT'D):
3 AMY ROSENBERG
Center for Drug
Evaluation
4 and Research (CDER)
5 EMILY SHACTER
Center for Drug
Evaluation
6 and Research
7 GAIL DAPOLITO
Executive Secretary
8 Center for Biologics Evaluation
and Research
9
ROSANNA L. HARVEY
10 Committee Management Specialist
Center for Biologics Evaluation
11 and Research
12 BRMAC #36 FDA PLANNING COMMITTEE MEMBERS:
13 PHILIP NOGUCHI
Center for Biologics
Evaluation
14 and Research
15 CYNTHIA
RASK
Center for Biologics
Evaluation
16 and Research
17 DARIN WEBER
Center for Biologics
Evaluation
18 and Research
19 DWAINE RIEVES
Center for Biologics
Evaluation
20 and Research
21 KEITH M. WONNACOTT
Center for Biologics
Evaluation
22 and Research
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PARTICIPANTS (CONT'D):
2 BRMAC #36 FDA PLANNING COMMITTEE MEMBERS
(CONT'D):
3
NICHOLAS I. OBIRI
4 Center for Biologics Evaluation
and Research
5
RICHARD McFARLAND
6
STEPHEN GRANT
7
SUSAN LEIBENHAUT
8
JOHN ELTERMANN JR.
9
JOHN FINKBOHNER
10
SARAH KIM
11
SUSAN ELLENBERG
12
GHANSYAM GUPTA
13
ROBERT MISBIN
14
15 C O N T E N T S
16
AGENDA SESSION: PAGE
17 Current Status of Clinical Islet 7
Transplantation
18
Allocation of Pancreata for
Whole 65
19 Organ and Islet Transplantation
20 Ethical Considerations in Allogeneic 115
Islet Transplantation
21
Clinical Development of
Islet Products 151
22
* *
* * *
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1 P R O C E E D I N G S
2 (8:13 a.m.)
3 DR. SHAPIRO:
Good morning. On
4
behalf of Dr. Camillo Ricordi, and
5
Dr. Bernhard Hering, and myself, and many
6
other members involved with total islet
7
transplant activity. It is a
great pleasure
8
to provide this information today to the FDA
9
as we consider moving forward with a
10
possibility of a BLA.
11 I'd like to emphasize that we come
12
to you today with a long history of research
13
and progress in islet transplantation over
14
now three decades. With the
first
15
successful islet transplantation and
16
reversal of diabetes in rodent models by
17
Dr. Paul Lacy and his colleagues back in the
18
early 1970s.
19 The success at the University of
20
Minnesota with islet auto‑transplants in
21
the 1970s, and in fact it's worth mentioning
22
that today there are islet autografts that
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are functional beyond 18 years maintaining
2
insulin independence with no concerns
3
regarding the health of those patients
4
receiving islet autografts ‑‑
5 (Power plug pulled)
6 DR.
SHAPIRO: As I was saying,
7
the 30 years of research and then the 18
8
years of success with islet
9
auto‑transplants, and then the development
10
of the automated method by Dr. Camillo
11 Ricordi
introduced and published in 1989,
12
and then the first series of patients
13
receiving allo transplants using the
14
automated method in 1990; the success at
15
Giessen and more recently in Minnesota by
16
Dr. Bernhard Hering and his group, and also
17
in Geneva and Milan, with 50 percent insulin
18
independence rates reported in the
19
mid‑1990s.
20 The introduction of the low
21
antitoxin liberase soclazinaes (?) enzyme;
22
and then the work from Edmonton, the
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multi‑center trial, and now with subsequent
2
refinements and techniques and periodicals
3
including the use of culture and the
4
two‑layer method for perforlodectorine (?)
5
transportation and oxygenation of pancreases
6
during transportation.
7 So with this recent success that
8
clearly, and the FDA's aware of this,
9 there's been an
enormous interest and a
10
large number of new institutions moving
11
forward with islet transportation.
We are
12
aware now of at least 75 new centers across
13
the world trying to develop processes for
14
islet isolation or clinical transplant
15
programs.
16 So if we lay on the map the
17
current activity in islet transplantation up
18
to the present time, and we look at the
19
centers involved with islet transplantation
20
North America and in Europe now, within the
21
Edmonton Protocol and beyond the Edmonton
22
Protocol now, there are over 300 patients
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treated since 1990 with clinical islet alone
2
transplantation, or with islet after kidney
3
transplantation, too.
4 Now what is common between the
5
three of us and our data at three
6
institutions and a number of institutions as
7
well is that we have common protocols.
We
8
have identical patient selection criteria
9
for islet‑alone transplants.
We have common
10
methods for patient evaluation and the
11
schedule of testing.
12 We have common methods, as you
13
heard yesterday, for islet processing using
14
the Ricordi method across centers.
We have
15
common methods for maintaining islets in
16
culture. We have common methods
for
17
transplant techniques; standard
18
anti‑coagulation protocols for
19
peri‑transplant management; standard
20
post‑transplant screening for complications,
21
including bleeding and thrombosis.
Standard
22
post‑transplant monitoring; and standard
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definitions of what we regard as being
2
success and failure with an islet
3
transplantation.
4 We have common criteria for
5
patient selection. We pick
patients for
6
islet‑alone transplantation who have Type 1
7
diabetes for more than five years.
Where
8
there is independent evidence that a patient
9
is failing despite total compliance with
10
maximum alternative medical therapy, in
11
other words, insulin.
12 The process for patient selection
13
is typically in layers, with a primary
14
screen, a secondary screen, two
15
diabetologists involved independently with
16
islet programs completing a review prior to
17
acceptance by an islet program for further
18
work‑up; and generally, a multi‑disciplinary
19
team approach for assessments so that a
20
patient who ends up being listed for islet
21
transplantation clearly has been through
22
many separate screenings to get to that
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point.
2 Our inclusion criteria for
3
islet‑alone transplantation generally
4
include an age between 18 and 65, c‑peptide
5
negative, capable of understanding risks and
6
benefits of treatments including evidence of
7 good compliance.
8 We only take patients who have
9
complications of Type 1 diabetes that
10
include frequent hypoglycemia, metabolic
11
lability, or very occasionally, evidence of
12 progressive
secondary complications. We
13
have a large number of exclusion criteria.
14
I won't go through these in detail except
15
just to point out maybe body mass index
16
greater than 28; insulin requirements
17
greater than .7 units per kilogram per day;
18
untreated prolific retinopathy or evidence
19
where there is inadequate insulin
20
compliance. In other words, with
a
21
hemoglobin A1C greater than 12 percent; or
22
untreated Addison's disease or untreated
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sialic disease that might confirm the
2
interpretation of hypoglycemic unawareness.
3 So how do we select our patients
4
with hypoglycemia or metabolic lability?
5
Our patients have to have Type 1 diabetes,
6
as mentioned, with insulin therapy that's
7
essentially failed, where patients have
8
reduced awareness of hypoglycemia, as
9 defined by an absence
of adequate autonomic
10
symptoms and a plasma glucose level at 58
11
milligrams per deciliter, indicated by two
12
or more episodes of hypoglycemia requiring
13
third‑party assistance within 12 months.
14 Or patients who have metabolic
15
instability, characterized by erratic
16
glucose levels that interfere with daily
17
activities, and/or requiring two or more
18 hospital visits
for diabetic ketoacidosis
19
over the proceeding 12 months.
20 Intensive insulin management is
21
defined as monitoring glucose values at home
22
at no less than four times each day, and by
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the administration by three or more insulin
2
injections each day. This has to
be
3
monitored in close cooperation with an
4
endocrinologist or primary care physician.
5 More recently, we've tried to
6 develop more
objective criteria for
7
assessment of both hypoglycemia and
8
lability. Dr. Edmond Ryan, a
diabetologist
9
and medical director of our program at
10
Edmonton has really developed this Ryan
11
index, which is hypoglycemic score, and a
12
lability index that replaces the former
13
scoring system that we used, which was
14
called the mean aptitude of glycemic
15
excursion.
16 Just to show you very briefly, the
17
hypoglycemic score sheet is essentially
18
filled out by the patient, and we record the
19
number of episodes and how this interferes
20
with the patient's activities;
whether they
21
become confused, whether the patient had
22
developed seizures, whether they have to
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require outside help to treat.
Essentially
2
a score is developed from this.
3 Really just to emphasize here,
4
here is a population of a control cohort in
5
Edmonton who have Type 1 diabetes in the
6
general diabetes clinic. Here
are pre‑islet
7
transplant patients that have a much higher
8 hypoglycemia
score. Just to make the point
9
that islet transplantation is successful,
10
one year after the islet transplant, you can
11
see that this hypo score is brought down to
12
zero.
13 With
regard to assessment to
14
metabolic lability, it's too early in the
15
morning for me to fully explain the
16
mathematical approach to the lability index.
17
But just to say this does provide robust
18
data, and again, to illustrate to you how
19
the lability index demonstrates.
Here again
20
is our Type 1 diabetes controls.
Here are
21
our patients before an islet transplant that
22
have a much higher index of lability
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compared to the normal Type 1 diabetic
2
populations. So these are again
a highly
3
selected subset of patients.
Then after
4
islet transplantation, the lability index is
5
corrected down to zero at one year.
6 How do we define insulin
7
independence? I know this was
one issue
8
that was raised in some of the questions
9
that were passed to us before the meeting.
10 Essentially, we
regard the sustained graft
11
function with adequate endocrine metabolic
12
reserve after complete discontinuation of
13
exogenous insulin, while maintaining a
14
normal hemoglobin A1C.
15 There has to be independence from
16
insulin, and this is defined by adequate
17
control of glucose when a patient is not
18
using insulin; where the hemoglobin A1C is
19
less than 6.5 percent; where
the fasting
20
blood glucose level does not exceed 140
21
milligrams per deciliter more than three
22
times a week using the morning fasting
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glucose level; where the two‑hour
2
post‑prandial glucose levels using any
3
post‑meal glucose value does not exceed 180
4
milligrams per deciliter more than four
5
times in any one week.
6 A participant may occasionally
7
have elevated blood sugars in response to an
8
intercurrent illness, or when the tacrolimus
9
level is high, but this period has to be
10
less than the total of 14 days in order to
11
calculate this as a patient who is
12
insulin‑dependent.
13 To emphasize, in our program at
14
Edmonton, we've transitioned from research
15
to being regarded to as clinical standard of
16
care. Our non‑research
program is funded as
17
of April 2001 by the same mechanism that
18
funds hearts, lungs, or livers for
19
transplantation in Alberta by the government
20
of Alberta through the Providence‑wide
21
Services Committee, after a full independent
22
and critical appraisal committee review of
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the program data.
2 So we are regarded as a clinical
3
standard of care in Edmonton.
This covers
4
only the non‑research transplants. We do of
5 course continue
to do research funded by the
6
Juvenile Diabetes Research Foundation, by
7
the NIH, and by other organizations, too.
8 The standards for non‑research
9
islet processing are currently in evolution
10
with Health Canada, and we're working
11
closely with Health Canada, just as the
12
process is moving forward with the FDA in
13
the U.S. to try to get similar standards in
14
place.
15 The immune protocols are generally
16
based on sirolimus, low‑dose tacrolimus and
17
diclisimap (?), but we are willing to vary
18
this and we can vary this for our
19
non‑research patients since the
20
immunosuppression protocol's, just like with
21
heart, lung, or liver transplant, are
22
individualized as needed by the patient.
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This is not specifically restricted or
2
mandated by the government. So
we are able
3
to used approved or off‑label drugs as
4
appropriate for the management of our
5
clinical islet patients.
6 We accept referrals from across
7
Canada. You can see, again, just
to
8
emphasize the point that we're very
9
selective in who we pick for an islet
10
transplant. Ten percent of the
patients
11
referred for islet transplant, no more
12
than 10 percent, end up on the islet
13
transplant list. Just to show
you the
14
distribution between the three indications,
15
hypoglycemia, and hypoglycemic unawareness
16
forms the bulk of the referrals at 70
17
percent, lability 25 percent.
18 So at the University at Alberta
19
now, we've moved on from the first seven
20
patients we've transplanted now.
We now
21
have a consecutive cohort of 58 patients
22
treated. This just shows you the
follow‑up
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for these patients; with a median follow‑up
2
now of 21.5 months. There are
now five
3
patients beyond four years after transplant.
4
You can see here the first 15 patients
5
received fresh islet transplants.
Working
6
together with Dr. Ricordi and Dr. Hering, we
7
then switched our program from fresh
8
transplants to cultured islet transplants.
9 So you can
see we have data on
10
patients receiving cultured, with a total
11
of 35 patients, versus 20 patients receiving
12
fresh transplants. Most of our
patients
13
require two procedures to provide insulin
14
independence. So 24 patients
here you can
15
see had two islet procedures.
There are
16
five patients that have had a third islet
17
infusion.
18 So how can we compare the data
19
between fresh and cultured clinical islet
20
preparations? I know we covered
some of
21
this yesterday, so I'll be brief.
Improved
22
safety and reduce pac cell (?) volume is one
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clear advantage of the use of islet culture.
2
Together with the enhanced opportunity for
3
completion of product‑released criteria, as
4
you heard from Dr. Hering yesterday.
5
Certainly from the patient's perspective,
6
this increases the practicality of the
7
procedure. Not only does it
allow islets to
8
be shipped between centers, but it also
9
means that the patient does not have to live
10
in the transplant center while they're
11
listed.
12 Data that Dr. Camillo Ricordi and
13
his group in Miami shared with us is
14
reporting insulin dependence following
15
cultured islet transplants, where they have
16
either been transplanted in Miami or shipped
17
to the beta group in Houston.
Here, their
18
survival rate for insulin independence is 80
19
percent at one year, for a total of 19
20
patients transplanted.
21 If we compare our data in Edmonton
22
with the first 16 patients with the next 35
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patients treated with cultured islet
2
preparations, we see no difference in
3
outcome at one year. With
cultured patients
4 receiving cultured
first islet
5
transplants, 90 percent of these patients
6
are insulin‑free at the one‑year time point.
7
Whereas with the non‑cultured first
8
transplants, 95 percent of patients are
9
insulin‑free at the one‑year time point,
10
with no statistical difference between
11
these two groups; again indicating that
12
culture is certainly not detrimental to
13
outcome.
14 Our outcome at two years, 79
15
percent are insulin‑free at two years with
16
cultured islets. Four years ‑‑
and these
17
are fresh islet. Two of the
first three
18
patients are still insulin‑free at the last
19
analysis. Four‑year graft
survival by
20
c‑peptide secretion shows for our entire
21
series that 88 percent of patients remain
22
c‑peptide positive at four years.
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1 Data again from the University of
2
Miami shows that islet after kidney
3
transplantation can be equally successful.
4
Here's an example of three patients
5
receiving islets after kidney transplants,
6
all three of whom are completely
7
insulin‑free with the complete absence of
8
hypoglycemia.
9 So if we pool our data at the
10
three sites, Miami, Minneapolis, and
11
Edmonton, for cultured islets, we now have a
12
cumulative total of 75 patients treated.
13
Ninety‑nine percent of these patients
14
demonstrate primary islet graft function.
15 One‑year C‑peptide secretion is
16
evident in 96 percent of patients.
One‑year
17
insulin independence rates are evident in 85
18
percent of these patients. These
outcomes
19
clearly match the current success rate of
20
the pancreas alone transplantation across
21
the U.S.
22 Complications including main
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portal vein thrombosis have not been seen in
2
this series of patients. There
is no main
3
portal vein thrombosis. We have
seen the
4
left portal vein branched on, but only at
5
our site in Edmonton, not in Miami or
6
Minnesota in three cases. So the
risk
7
overall is at 4 percent. There
have been no
8
deaths, no cancers, no lymphomas, no CMV, no
9
EBV infections to date.
10 Again, showing the collaboration
11
between the three centers, we routinely now
12
use the transplant bag rather than the
13
syringe for islet delivery, to make sure
14
that we have uniformed product that is not
15
exposed to additional risks in the radiology
16
department. We can show you
sustained
17
evidence of graft function over time, really
18
evidenced by normalization of hemoglobin
19
A1C.
20 This shows our cohort of islet
21
transplant patients at one, two and three
22
years data showing normalization of
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hemoglobin A1C less than 6.1 percent.
If we
2 compare this to
consecutive patients
3
undergoing pancreas transplantation at our
4
own institution, we see virtually identical
5
hemoglobin A1C function out to three years.
6 If we compare the hemoglobin A1C
7
in our non‑cultured versus cultured islet
8
preparations, again we see no difference in
9
outcome, with normalization of hemoglobin
10
A1C in both transplant groups.
11 We see
evidence of sustained
12
C‑peptide secretion over time.
So these
13
patients are generally not losing C‑peptide
14
secretion. If you look here,
these are the
15
fasting C‑peptide levels.
These are the
16
stimulated C‑peptide levels.
Again, showing
17
stable data shown here across three years of
18
follow‑up.
19 We're currently in the process of
20
working with Miami and Minnesota to complete
21
prospective quality of live and cost utility
22
studies. These are in evolution
of the
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present time. Just to show you
one example,
2
the hypoglycemia fear score is significantly
3
reduced after islet transplantation and
4
remains stable over time.
5 Complications after islet
6
transplantation can occur despite this being
7
a minimally invasive procedure.
Here's a
8
list of complications encountered at our own
9
site the University of Alberta.
We've had
10
an unusually high incidence of liver bleeds,
11
at 14 percent. This has been
entirely due
12
to the fact that we were giving a loading
13
dose of aspirin just before the patient
14
received their percutaneous procedure, to
15
try to improve islet engraftment.
16 Since we've recognized this
17
complication, the use of aspirin has been
18
withdrawn from our protocols.
Other
19
complications that occur commonly include
20
mouth ulceration, in 87 percent of patients;
21
dyslipidemia, in 44 percent of patients that
22
respond to statin therapy; transient rises
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1
in liver function tests. And we
do see
2
changes on the MRI scan, with steatosis in
3
the liver in about 23 percent of patients.
4
Again, no deaths, no cancer, no lymphomas,
5 no CMV.
6 I mentioned the bleeds that have
7
occurred after transplant.
Here's a patient
8
having a laparoscopy for a bleed that
9
occurred at the site of puncture in the
10 liver. This is a preventable complication.
11
We believe this is the technique developed
12
at the University of Miami where a
13
collagen‑thrombin plug is placed in the
14
catheter tract.
15 The
University of Miami has had no
16
further bleeding using that approach.
In
17
Edmonton we've been developing a Nd:YAG
18
Laser for a very similar approach really to
19
ablate the liver. This is in a
large animal
20
model, but we've been using this in patients
21
to seal the catheter tract.
22 At the University of Minnesota,
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also, in a consecutive series of 20
2
consecutive patients there, not a single
3 bleed when the
combination of coils and
4
gelfoam are used to mechanically and
5
physically ablate the catheter tract.
So
6
this is a preventable complication, in our
7
opinion.
8 Data from the International
9
Multicenter Trial of the Edmonton Protocol,
10
I'm showing you data that has been presented
11
and has been in the public forum since May
12
of this year, when this data was presented
13
at the American Society of Transplantation
14
meeting, ATC meeting. The
objectives of the
15
ITN trial was to replicate the Edmonton
16
Protocol at multiple sites; provide a base
17
of qualified islet centers for future ITN
18
tolerance trails; and really to define the
19
challenges of applying one common protocol
20
for patient selection, islet preparation,
21
and immunosuppression across multiple
22
centers.
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1 Also with the ITN to potentially
2
explore mechanisms of islet acceptance and
3
rejection in collaboration with the
4
tolerance assay subgroup.
5 A total of nine sites moved
6
forward with this trial. This is
three
7
sites in Europe and the five sites in North
8
America. We look at the success,
it
9
certainly has been variable by site, but
10
what we can say very clearly from this data
11
is the Edmonton Protocol has been
12
successfully replicated by a number of
13
sites. Not by everybody.
14 But this really illustrates the
15
challenges involved with preparation of
16
islets and with the clinical care of
17
patients. Now this data shown
here with
18
four sites not delivering insulin
19
dependence; again, I would emphasize this is
20
data reported in May 2003. This
data has
21
not been subsequently updated, and there's
22
no question this data has improved since
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1
then. But subsequent analyses
are pending.
2
I'd also draw your attention to a letter in
3 correspondence in
today's issue of "The
4
Lancet," and I'll just read it to you.
5 "As co‑principal investigators of
6
the ITN Multicenter trial, we wish to
7
clarify the importance of the preliminary
8
analysis. A 90 percent insulin‑free
rate
9
was noted in three centers with longstanding
10
expertise in islet preparation and in
11
clinical use of immunosuppression, not only
12 at the Edmonton
site where the protocol
13
originated.
14 The average rate of insulin
15
independence among the remaining six
16
clinical sites was 23 percent, including one
17
site with an interim success rate of 67
18
percent. Thus, the Edmonton
Protocol has
19
been replicated successfully at other
20
clinical sites, and in some cases with a
21
high degree of success. Although
this data
22
is preliminary, we view this result as a
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positive one, which confirms the great
2
benefits to patients of islet
3
transplantation and provides additional
4
justification for continued investigation of
5
islet transplantation as a treatment for
6
brittle forms of Type 1 diabetes."
7 Finally, I draw your attention to
8
data emerging from the University of
9
Minnesota, with truly a remarkable series of
10
now 20 patients treated with successful
11
single donor islet transplants for Type 1
12
diabetes. Dr. Hering may address
this
13
further in discussion. But
essentially, in
14
order to achieve single donor islet
15
transplant success, there were seven
16
strategies implemented, including excluding
17
pancreas organs from donor organs aged 50 or
18
higher; limited ischemic injury of islets by
19
processing within eight hours, sometimes
20
quite a bit less than that time, to optimize
21
islet function; avoiding islet toxic
22
reagents during the islet processing, using
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1
culture of islets as we've mentioned to
2
allow pre‑transplant initiation of
3
immunosuppression; providing potent
4
prophylactic anticoagulation and aggressive
5
insulin therapy prior to transplant; and
6
increasing the immunosuppressive and
7
anti‑inflammatory potency of the induction
8
of immunosuppression while avoiding
9
calcineural (?) inhibitors in maintenance of
10
immunosuppression.
11 This shows the remarkable success
12
of these patients undergoing this form of
13
transplant. Here's a patient
with a single
14
donor islet transplant at the University of
15
Minnesota with totally normal oral glucose
16
tolerance test and perfect glycemic control
17
across one year of follow‑up.
18 Thank you for your attention.
19 DR. RAO:
Thank you, Dr. Shapiro.
20
Any questions for Dr. Shapiro?
21 DR. RIEVES:
Hi there. My name is
22
Dwaine Rieves. Could you very
briefly
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provide a perception, share some of your
2
thinking regarding some of the clinical
3
benefit in your studies, in your procedures,
4
beyond perhaps the avoidance of exogenous
5
insulin? You've touched on
improvement in a
6
fear index, and I suspect that you also have
7
thoughts about other clinical outcomes that
8
these patients may have achieved.
Can you
9
comment on that?
10 DR. SHAPIRO:
Certainly. I would
11
say that most patients who come to us for an
12
islet transplant, their aim isn't to attain
13
insulin independence. It may be
the
14
program's aims, but it's certainly not many
15
of the patient's aim, sort of suffering from
16
severe hypoglycemia. Most
patients have no
17
problem staying on a small amount of insulin
18
if needed in order to rid themselves of the
19
day‑to‑day difficulties and challenges of
20
recurrent hypoglycemias.
21 I would emphasize to you that
22
these patients are at quite high risk when
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they face recurrent hypoglycemias.
For
2
example, at our three sites, there have been
3
in fact three deaths in patients that were
4
listed for islet transplant from
5
hypoglycemia. I mentioned to
you, we
6
haven't had any deaths after an islet
7
transplant. So clearly these
patients are
8
at added risk because of their recurrent
9
hypoglycemias.
10 In other words, in our sense, even
11
with just one islet transplant, as long as
12
the patient's maintained c‑peptide
13
secretion, their risk of hypoglycemia is
14
completed obviated, so they have very much
15
more stable glucose control, and in fact
16
rapid correction of hemoglobin A1C even
17
though they're requiring at that point small
18
doses of insulin. So from the
patient's
19
perspective, there clearly is a benefit from
20
that.
21 If you're asking about what are
22
the longer‑term benefits of a successful
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islet transplant in terms of secondary
2
complications, I think that is a harder one
3
to answer right now. We
currently use the
4
surrogate endpoint of correction of the
5
hemoglobin A1C; we would expect that if
6
patients maintain a hemoglobin A1C within a
7
normal range over time, they will enviably
8
have reduced progression and maybe reversal
9
of some of the secondary complications in
10
exactly the same way as that's been shown
11
with successful whole pancreas
12
transplantation.
13
But we don't have long‑term
data
14
really to prove that at the present time.
15
That will emerge, but I suspect just like in
16
pancreas transplantation, it may take 10 or
17
maybe 15 years to really prove that point.
18 DR. EGGERMAN:
Yes, Tom Eggerman,
19
NIDDK. I noticed you had an
incidence or
20
prevalence of steatosis of like 22 percent.
21
I'm wondering if all that changed over time
22
in terms of severity as well as prevalence.
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1 DR. SHAPIRO:
So this is a finding
2
that is recognized on ultrasound with
3
heterogeneity of the liver, and it's
4
recognized when we screen all of our
5
patients by MRI scan over time;
6
approximately 22 percent of patients have
7
changes on MRI scan compatible with mild
8
steatosis. Occasionally, it can
be more
9
than mild.
10 The patients have a normal liver
11
function test however, and we see this as
12
being a direct physiological impact of high
13
dose local insulin secretion in the liver.
14
It's an interesting physiological
15 observation, but
we don't think it has any
16
clinical concern beyond that.
17 The reason we say that is that
18
islet autotransplant patients also have
19
these changes. I mentioned to
you that
20
there are patients now out beyond 18 years
21
after an islet autotransplant with these
22
kinds of changes too that have not led to
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any clinical difficulties.
2 So it's an observation. I can
3
tell you too that we have a patient that
4
lost c‑peptide secretion over time who had
5
changes of the steatosis. When
she lost her
6
c‑peptide secretion, she completely resolved
7
the steatosis. So we think this
is related
8
to high local insulin and it's a reversible
9
phenomenon.
10 DR. EGGERMAN:
But is there a
11
steady increase over time, or is it ‑‑
12 DR. SHAPIRO:
No, it seems to
13
remain stable.
14 DR. EGGERMAN:
In terms of
15
prevalence as well as severity?
16 DR. SHAPIRO:
Well,
17
cross‑sectional data is really unavailable
18 to us now. Longitudinal studies are in
19
progress. I don't think we have
the
20
evidence so far to say it's getting worse
21
over time. It may be getting
better.
22 DR. RAO: I
noticed you showed
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this correspondence letter where there was
2
difference between the success rate at the
3
three centers versus the other multicenter
4
trial runs. Is there any
speculation why
5
there was that difference?
6 DR.
SHAPIRO: Again, I would
7
emphasize that the data presented is
8
extremely preliminary. It has
changed and
9
evolved over time. I think it
really
10
illustrates the fact that new islet
11 transplant
centers are moving forward.
12
There's a considerable learning curve in the
13
manufacturer of islets that we all know and
14
recognize.
15 Despite tremendous support
16 provided, with
the three of us traveling to
17
each institution to train as institutions
18
moving to the three sites to learn the
19
techniques, not every center has been able
20
to deliver good islets. That's
one factor.
21 I think the second factor is that
22
basic management of clinical
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immunosuppression in some cases has led to
2
rejection when patients were not maintained
3
in perfect target range of tacrolimus or
4 sirolimus after
transplants. In other
5
words, some patients lost islet function as
6
a direct result of rejection.
7 DR. RAO:
Maybe to expand on that
8
question just a little bit. You
had
9
measures of potency that were talked about
10
in terms of the manufacturer of the product.
11
In some sense, those should have been
12
predictive of what the islets would do at
13
different centers if there's an appropriate
14
SB. Was there any sort of
correlation when
15
you said that there was a learning curve and
16
despite the fact that there was huge
17
training, the difference was completely
18
learned?
19 DR. SHAPIRO:
Well, I would
20
comment that on the first look of that data
21
didn't show any obvious factor or any
22
evidence from the potency assays, but again,
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that was very preliminary data.
We have a
2
lot more data accrued since the initial
3
analysis. I think in subsequence
analysis
4
maybe something will emerge in terms of
5
evidence of impacted potency or islet mass
6 in terms of
correlation with clinical
7
outcome. That data is pending
currently.
8 DR. SHERWIN:
Jim, you haven't
9
shown data looking at actual insulin
10
secretion in these people. I
just wonder
11
how normal is the actual secretion of
12
insulin, beginning by the glucose levels
13
first.
14 DR. SHAPIRO:
Of course. We have
15
accrued a fair amount of metabolic data with
16
Dr. Ryan in our group and Dr. Pati (?)
17
looking at insulin and oral glucose
18
tolerance, intravenous glucose tolerance,
19
and response to arginine (?) challenge.
20
What I can tell you from our own
site data
21
is that most patients have impaired glucose
22
tolerance. Some patients have
normal
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glucose tolerance. If a patient
can
2
maintain insulin independence with a normal
3
hemoglobin A1C, but have an impaired glucose
4
tolerance, and that really is a reflection
5
of the fact that still some of our patients
6
have a marginal islet implant mass that's
7
sufficient to allow them to discontinue
8 insulin. So insulin secretion is not
9
normalized in most patients.
10 I think Dr. Hering might want to
11
comment though, because I think his data,
12
where virtually all have been able to
13
achieve a normal oral glucose tolerance I
14
think speaks to the point that probably in
15
his data, these patients have much more
16
endocrine reserve.
17 DR. HERING:
This is again very
18
preliminary. But just to
indicate the fact
19
that you can achieve fairly good metabolic
20
control after islet transplantation.
In a
21
very small group of recipients that were
22 monitored for
one year, at one year
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post‑transplant, 80 percent of patients
2
showed a normal oral glucose tolerance test
3
with two‑hour glucose levels below 140, and
4
actually being between 90 and 120 in most
5
patients. I think this may be
due to
6
careful selection of donor organs and
7
patient selection, but just to illustrate
8
that this can be achieved.
9 DR. SHERWIN:
The people that have
10
impaired glucose tolerance, are they more
11
likely to require insulin subsequently or is
12
that a marker in any way?
13 DR. HERING:
Not necessarily. No,
14
not necessarily.
15 DR. RAO: I just remind all the
16
members and the committee to shut off their
17
speakerphones.
18 DR. HIGH: I
just wanted to ask,
19
in terms of risk/benefit in this sort of
20
procedure: If somebody rejects
their
21
transplant if they stop taking their
22
immunosuppressive regimen, are they
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essentially left exactly as they were before
2
the transplant? So in other
words, there's
3
no downside risk to rejecting it; they're
4
just the way they were before they started.
5 DR. SHAPIRO:
Thank you for that
6
question. From a practical
sense, patients
7
that completely lose graft function and
8 become c‑peptide
negative are usually back
9
at square one. So if they had
severe
10
hypoglycemias beforehand, they lose complete
11
graft function, they're back where they were
12
and they're no worse.
13 The only theoretical risk to the
14
patient is if they were to become sensitized
15
with a high panel reactive (?) antibody, so
16
if they were to progress to develop kidney
17 failure and need a
kidney transplant, it
18
might in theory be difficult to match them.
19 If we look at the data in practice
20
however, there's one patient of ours that
21
lost c‑peptide function that had a high peak
22
PRA at 67 percent after the islet
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transplant. This is resolved
down to 2
2
percent currently. So overall, I
would say
3
the risk of sensitization, provided this
4
careful management and careful weaning and
5
withdrawal of immunosuppression, the risk of
6
the sensitization is not high.
7 DR. LEVITSKY:
Given that many of
8
these patients seem to be on the edge
9
metabolically in terms of their glucose
10
tolerance, do you give them any sort of
11
special nutritional counseling?
What is the
12
nutritional regimen that you like to keep
13
them on?
14 DR. SHAPIRO:
Well, it depends on
15
what the metabolic control of the patient is
16
like. If patients have a normal
oral
17
glucose tolerance test, they can usually
18
tolerate a normal diet and have no problems
19
whatsoever. If patients have
impaired
20
glucose tolerance and elevated blood sugar
21
levels, we do have a dietician involved with
22
the program who would maintain the patient
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on a diabetic diet. Beyond that,
there
2
would be no major restrictions.
3 DR. RAO: Dr.
Silverstein, did you
4
have ‑‑
5 DR. SILVERSTEIN:
I did have a
6
question about compliance. Have
you had a
7
problem with noncompliance in any of our
8
patients? If so, are there any
predictors
9
that you could note for noncompliance with
10
their regimen post‑transplant?
11 DR. SHAPIRO:
Maybe Dr. Ricordi
12 would want to
comment on that, too. We have
13
had one patient that really had very severe
14
hypoglycemias before his transplant, was
15
clearly quite difficult to assess.
We
16
anticipated there would be potential
17
problems afterwards. This
patient was
18
therefore not included in a research trial,
19
but was in a more clinical standard of care
20
protocol.
21 That patient continues to take his
22
immunosuppression, but has not really
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complied with close post‑transplant
2
monitoring. I think these
patients really
3
are very similar to other transplant
4
patients. What we do to try to
avoid these
5 kinds of challenges
is have a detailed
6
psychological and psychosocial evaluation of
7
our patients before transplants so that we
8
can try to anticipate some of those
9
challenges afterwards.
10 DR. RICORDI:
We had one case in
11
which we just had to stop immunosuppression
12
because the patient was not tolerating the
13
drugs, so that we raised in discussion
14
whether we should test immunosuppression
15
regimen before islet transplant to identify
16
people that don't.
17 Because it's very individual, the
18
response. Some patients tolerate
it very
19 well and others
have problems. Some adapt
20
and some just don't cope. But I
wanted to
21
comment on the fact on what is normal islet
22
function of islets transplanted in a liver
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and the immunosuppression, because this is
2
very important.
3 You cannot compare it with normal
4
islet function in a non‑diabetic subject,
5
because even in organ transplant recipients
6
who are not diabetic who undergo maintenance
7
immunosuppression with calcineural
8
inhibitors, like in some of these protocols,
9
you clearly have impaired insulin secretion.
10 This is because of the
11
diabeticogenic affect of some of these
12
immunosuppressive drugs. As the
13
immunosuppressive protocols will improve
14
with new agents, you will see less of this
15
chronic deleterious affect on islet
16
function. There are results from
17
Dr. Hering, who has new protocols that point
18
in this direction. We also have
preclinical
19
data in nonhuman primates showing that if
20
you avoid the diabetic immunosuppression,
21
the islet function to a liver is identical
22
to that of a native pancreas, and that
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actually improve over time for the first
2
year post‑transplant.
3 So those are very important
4
indications that I think even if islets in
5
the liver is a different physiologic
6
setting, so you that we may expect some
7
little differences in glucose metabolism or
8
insulin secretion; that the problem of
9
chronic toxicity will be most likely
10
resolved with the use of less toxic
11
immunosuppressive drugs.
12 MS. BIRDIE:
Hello. I would like
13
to introduce myself. My name is
Ellen
14
Birdie. I have received
"the product." I
15
received the product at NIH with Dr. Dave
16
Harlan in June of 2001. I would
like to
17
make a comment and address the issue of the
18
fear of hypoglycemia. Dr.
Shapiro mentioned
19
that they had a graph to try and measure
20
what the effect of that is.
21 I would be off the graph, because
22
that fear is an overriding fear that
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permeates your whole life. You
never know
2
when you may pass out and be on the
3
crumbling edge of the hypoglycemic cliff
4
with no warning at all. Before
transplant,
5
this often happened to me while I was
6
driving the car. Often on 495,
in the
7
middle of the road, or on back roads, where
8
I would just stop the car and pass out.
One
9
time, I passed out for three hours.
10 So that fear is hard to measure
11
what effect that has on your whole life and
12
your whole life of everyone else around you;
13
your friends, your relatives, who are
14
consistently monitoring you all the time to
15
make sure that you are okay.
16 So I would just like to stress the
17
importance of not having that fear anymore.
18
I don't know how you could even begin to
19
measure that. Thank you.
20 DR. RAO: Dr.
Eggerman.
21 DR. EGGERMAN:
Yes, I was
22
wondering if there was any differences
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between those patients that are
2
insulin‑independent and those that remained
3
significantly c‑peptide positive but require
4
some insulin in terms of the degree of
5
hypoglycemia unawareness.
6 MR. SHAPIRO:
As I mentioned,
7
patients that have either partial graft
8
function or complete graft function, neither
9 patient is faced with
episodes of
10
hypoglycemia. If you're asking
me of
11
response of an islet transplant to correct
12
hypoglycemic unawareness, I think that's a
13
different question.
14 We do
have data, and we've
15
published this data in patients who we've
16
taken controls and patients with Type 1
17
diabetes, we've taken the normal population,
18
and looked at the stepped hypoglycemic
19
clamp. What we've shown is that
even though
20
patients are clearly not facing evidence of
21
hypoglycemia at all, in an artificial
22
situation with a stepped hypoglycemic clamp,
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patients do not have complete restoration of
2
hypoglycemic responsiveness or glycogen
3
responsiveness, or epinephrine
4
responsiveness after islet transplantation.
5 So it would appear that even
6
though the alphacell function isn't
7
physiological, I should say, in islet
8
transplant patients when the islets are in
9
the liver, the clinical impact of a
10
partially successful islet transplant, where
11
there is dynamic insulin
response in
12
accordance to glucose levels, these patients
13
are not facing hypoglycemic reactions.
14 DR. SHERWIN:
James, though I
15
wouldn't be quite as cavalier as that, in
16
the sense that patients probably remain
17
unaware or at least their counter‑regulatory
18
systems are still not quite normal, even,
19
surprisingly, after the treatment.
So they
20 may have mild
changes, not enough to be
21
clinically important, that we can tell.
22 But they may actually have lower
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glucose at certain times of the day, after a
2
large carbohydrate meal, for example, and
3
would be unaware of that.
Whether that is
4
of any consequence clinically is something
5
else. I don't know, but it's
possible.
6
Until you have a good sensor and do
7
continuous monitoring in the outpatient
8 setting.
9 DR. SHAPIRO:
Thank you for that
10
point. We accept that.
11 DR. HERING:
If I could comment, I
12
think there's good technology as we you
13
know. A continuous glucose
monitoring
14
system which will ‑‑
15 DR. RAO: You
lost your mic.
16 DR. HERING:
Which should clearly
17
allow better evaluation of glucose control
18 in hypoglycemic episodes.
But I wanted to
19
emphasize also that islet transplants can
20
restore epinephrine secretion in response to
21
hypoglycemia and can restore normal symptom
22
perception. We have documented
this and
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published this in transplantation many years
2
ago, and it may not be a consistent finding
3
in every single person.
4 But this study in which we
5
compared patients undergoing a stepped
6
hypoglycemic clamp test before and after
7
islet transplantation clearly documented the
8
possibility that this can be restored to
9
normal.
10 DR. RAO:
Tom.
11 DR. HARLAN:
In a recent New
12
England Journal article looking at the
13
incidence of renal insufficiency in
14
non‑kidney transplant recipients, they
15
reported, depending on the organ
16
transplanted, an incidence of anywhere
17
from 7 to 21 percent of nuance at renal
18
insufficiency. I wonder if you
could
19
comment on the incidence of that
20
complication in the islet transplant
21
population.
22 MR. SHAPIRO:
Of 58 patients, we
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have two patients that have evidence of
2
elevated creatinine. Did not
require
3
dialysis, but clearly have progressed with
4
their renal insufficiency, with significant
5 underlying diabetic changes, with impaired
6
creatinine clearance prior to their
7
acceptance to the program.
8 The means and the rest of the
9
group of patients really have unchanged
10 creatinines over
time. The one measurement
11
that we are concerned about is the degree of
12
proteinuria in patients.
Occasionally we do
13
see accelerated proteinuria in patients that
14
have microbminuria (?) when
referred for
15
islet transplantation.
16 I can think of one patient in
17
particular that had secretion of .2 grams
18
for 24 hours prior to transplant.
This rose
19
to 2 grams for 24 hours. Went on
to
20
tacrolimus and sirolimus immunosuppression.
21
This patient in fact was taken off sirolimus
22
and given higher dose tacrolimus, and in
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fact the proteinuria result is back down to
2
baseline presently.
3 DR. HERING:
If I could comment.
4
I think both patients showed not long
5
proteinuria before islet transplantation but
6
also had evidence of impaired kidney
7
function, as measured by impaired creatinine
8
clearance. So I think patients
had advanced
9
kidney disease. Those patients
should
10
probably be excluded from participation as
11
long as calcineural inhibitors are used in
12
protocols.
13 DR. SHAPIRO:
Dr. Hering, you're
14
absolutely right. The protocols
in fact
15
have been modified since our earlier
16
experience with that. So we now
exclude
17
patients that have microbminuria or who have
18
evidence of significantly impaired
19
creatinine clearance.
20 DR. RICORDI:
I think this is a
21
very important point that Dr. Hering raised,
22
because it is important to distinguish what
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are side effects or complications related to
2
the islet transplant, or what could be a
3
result of the particular kind of
4
immunosuppressive agents used.
In the case
5
of the calcineural inhibitor and who can
6
benefit from that, you have to exclude
7
patients who already have progressing kidney
8
disease.
9 But it's not to say that in the
10
future, when you have other normal
11
flotoxic (?) agents in the battery of
12
agents, these patients will become
13
candidates, because actually one of the
14
objectives of islet transplantation will be
15
to prevent progression of neuropathy and
16
intervene early in the course of the disease
17
before you need a kidney transplant.
18 DR. O'FALLON:
In your map, you
19 showed patients
being referred to you from
20
all over Canada. If I remember
the correct
21
number, you said about 10 percent of them
22
pass through your screening process.
What
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proportion of them were ultimately
2
transplanted, and for those who weren't
3
transplanted, what were the reasons why they
4
weren't transplanted?
5 DR. SHAPIRO:
That's the dynamic
6
snapshot of our data, so I think it
7
was 1,200 patients who had undergone
8
primarily screening, and 10 percent of
9
patients, as you correctly identified, were
10
listed for an islet transplant.
At the
11
present time, we have approximately 70
12 patients on our islet
transplant, waiting
13
list, actively awaiting islet transplants
14
from across Canada.
15 Currently, I would say the
16
patients that we turn away for islet
17
transplant have applied for primary screen
18
but maybe have been found to have c‑peptide,
19
or have Type 2 diabetes, or have
20
insufficient cardiac reserve, or have
21
inadequate renal reserve.
Patients with
22
inadequate renal reserve, we don't always
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turn down. In fact, we tell
them, just like
2
Dr. Ricordi mentioned, that there are new
3
protocols and development and we will keep
4
their names on file and contact them again
5
when we have protocols active that
6
calcineural inhibitor are free.
7 I don't have an up‑to‑date
8
breakdown for you as to exactly what
9
patients were turned away for what reasons.
10
That could be analyzed for you.
11 MR. RAO:
There are no more
12
questions. Thank you, Dr.
Shapiro. We'll
13
go to the next speaker. I'd like
to take a
14
moment and have the new members of the
15
committee introduce themselves, starting
16
with Dr. Silverstein.
17 DR. SILVERSTEIN:
Hi, I'm Janet
18
Silverstein, a pediatric endocrinologist
19
from the University of
Florida.
20 DR. RAO: Dr.
Rieves.
21 DR. RIEVES:
Hi. My name is
22
Dwaine Rieves. I'm chief of the
clinical
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branch with the FDA's cell and gene therapy
2
group.
3 DR. VINER:
I'm Dr. Norm Viner.
4
I'm the clinical trial application unit head
5
at Health Canada, BGTDU, which is the
6
equivalent to CBER.
7 DR. RAO: Our
next speaker is
8
Dr. Jim Burdick. He already
spoke
9
yesterday. He's from HRSA, and
he's going
10
to speak a little bit more on the allocation
11
of pancreata for whole organs and islet
12
transplantation. We have the
mandatory I
13
guess PowerPoint break. Were
there any
14
other questions for any of our speakers?
15 I had one question for any of the
16
three centers. Do you ever
consider looking
17
at immune‑typing the cells themselves when
18
you harvest them, or try and match it with
19
patients in any fashion?
20 DR. SHAPIRO:
Generally, we list
21
our patients by blood group only.
We do not
22
actually match. We actually
type, and
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occasionally, we'll do a prospective
2
cross‑match. Certainly one
benefit of
3
culture, as opposed to fresh transplant, it
4
does provide an opportunity to do a
5
prospective cross‑match.
We do have some
6
patients now listed that have been
7
sensitized by previous pregnancies or blood
8
transfusion. Those patients do
get a
9
prospective for cross‑match and we try to
10 actually match to avoid similar antigens.
11 DR. RAO: I
noticed that in
12
several of your cases, you have to do more
13
than one transplant. Do you find
an
14
increased problem when you do the second or
15
is the success rate pretty much the same?
16 DR. SHAPIRO:
It's virtually the
17
same. So after one transplant,
the
18
patient's insulin requirements will
19
typically fall by about 50 to 60 percent.
20
The second islet transplant will typically
21
bring that down to zero. We
don't see
22
evidence of sensitization between the first
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or second transplant. We don't
see issues
2
or challenges generally in patients
3
receiving a second transfusion.
4 DR. RAO: Any
antibody monitoring
5
that you look at?
6 DR. SHAPIRO:
We do look at
7
antibodies. We do flow
screens. We do
8
auto‑antibody screens for gas 65, ICA 512,
9
and MIAA. We do that before
transplant and
10
at different time points after transplant to
11
see, if the outpatients have evidence of
12
deteriorating graft functions,
to see if
13
there's evidence of suggestion that these
14
patients might have recurrent auto‑immunity.
15 DR. BURDICK:
Since we're spending
16
a minute here about the auto‑immunity issue,
17
because I think that as far as I know, that
18
hasn't been addressed, and of course that is
19
of concern. But the clinical
observation
20
that liver transplantation or things
21
involving the liver somehow are often able
22
to mute the immune response. Now
that's
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semi‑soft science in general, but it's
2
certainly an important clinical conviction.
3
I wonder if it's possible that you're having
4
an effect on auto‑immunity that would be
5
good by the fact that they're sitting in the
6
liver. Is there any way to look
at that, or
7
have you thought about that at all?
8 DR. SHAPIRO:
Thank you, James.
9
It's a nice concept that when we deliver
10
islets or antigen intraportly, that it might
11
lead to clinical tolerance to auto ----
12
antigens. But I agree with you
that the
13
science surrounding that is soft.
I would
14
say far more important in fact is the fact
15
we have these patients on potent
16
immunosuppression, and for example, the
17
combination of low dose tacrolimus and
18
sirolimus, we tested in the NOD auto‑immune
19
mouse model and found it to be extremely
20
effective as long as the medications are
21
maintained in preventing recurrence of
22
auto‑immunity or primary auto‑immune
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destruction of islets in that model.
2 So I think the dominant force is
3
in fact the presence of immunosuppression,
4
rather than the fact that the islets are
5
delivered at an intraportal site to the
6
liver.
7 DR. SHERWIN:
James, you commented
8
on the fact that you had to use statins in a
9
number of patients. Just curious
about the
10
degree of change in the lipid profile.
And
11
have you looked carefully at the size of LDL
12
and things that might give you a sense of
13
atherosclerotic risk in these patients.
14 DR. SHAPIRO:
Dr. Eddie Ryan I
15
think could comment on that far better than
16
I could. We certainly have done
detailed
17
studies in terms of lipid profiles, and
18
we've done serial screens for carotid
19
intimal thickness to see if there's evidence
20
of progression or reversal of
21
atherosclerosis in the carotid vessels.
22
Those studies are underway presently.
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1 Dr. Hering, do you have any
2
comment?
3 DR. SHERWIN:
How much does the
4
LDL go up?
5 DR. SHAPIRO:
Predominate changes
6
been in cholesterol, and we followed the
7
diabetes target guidelines for initiation of
8
therapy. When we initiate statin
therapy,
9
it reverses to normal in the vast majority
10
of cases.
11 DR. SHERWIN:
This is seen with
12
other types of transplants, am I right?
13 DR. SHAPIRO:
It is. Go ahead,
14
Dr. Harlan.
15 DR. HARLAN:
I just have a couple
16
comments on questions that were raised.
One
17
is, two of our patients elected to
18
discontinue immunosuppression.
One because
19
of progressive renal insufficiency, despite
20
no proteinuria prior to transplant, and
21
despite normal creatinine clearance prior to
22
transplant; another because of
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Rapamyacin‑induced numimytis (?).
So we
2
have seen the elevated creatinine despite
3
normal kidney function as far as we could
4
measure prior to transplant. In
both of the
5
cases that elected to discontinue
6
immunosuppression, we saw sensitization
7
that's persisted. So it's ‑‑
8 DR. RAO:
Define "sensitization."
9 DR. SHAPIRO:
Sensitization means
10
that the recipient has learned to recognize
11
donor tissue. So that if those
patients
12
needed a transplant down the road, it could
13
be more difficult to find a suitable donor
14
for them. So what we always, in
obtaining
15
informed consent, inform people that if it
16
fails, they may not be just back at
17
baseline, that it could be more difficult if
18
they needed a transplant down the road.
19 DR. RAO:
Thank you.
20 DR.
BURDICK: Good morning, again.
21
I'd like to start by just noting that
22
there's been back and forth about exactly
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what the material is that we're talking
2
about and what it's going to be called.
3
Whether it's a product, clearly has been
4
established, it is. I'd just
like to
5
emphasize that I think the important thing
6
is we're all on the same page.
We want a
7
treatment which will involve this entity
8
that's been declared a product.
9 But we want something that's
10
effective and it's safe. It's
clearly going
11
to be dominantly, I think, a public process,
12
with very definitely the appropriate federal
13
oversight. So we don't want to
let any
14
particular name get in the way of that
15
desire.
16 Today, what I want to talk about
17
is what is happening with the marvelous new
18
promise that is as yet a promise, but it's
19
coming closer, in terms of the actual
20
treatment process which is being done
21
through the OPTN that our division oversees
22
in HRSA.
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1 Just to review, this is under the
2
NOTA, the Organ Transplant Network,
3
specified through the National Organ
4
Transplant Act, and also through the Social
5
Security Act. An important point
that we
6
need to come back to is the prohibition
7
against purchase or sale of transplantable
8
organs. The main arm in this in
terms of
9
the community is the voluntary process that
10
the OPTN has underway with also the
11 potential for
CMS intervention for certified
12
centers if centers do not participate
13
appropriately.
14 This is what the makeup of the
15
transplant field in this country is at
16 present. You can see historically of
17
course, kidney is the big one.
But there
18
are many centers doing a small number of
19
pancreas transplants, and 37 declared
20
pancreas islet cell programs.
This has
21
changed. You've seen a more
recent slide.
22
There is no membership process of islet
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1
programs at present in the OPTN.
2 But the OPTN clearly, and
3
therefore the community, clearly feels that
4
this falls under the realm of the other
5
things that are being done with organ
6
transplantation.
7 The KP committee that has members
8
on it and which is very sensitive to issues
9
in whole organ and islet cell transplant has
10
this process underway. In fact,
recently
11
issued for public comment their policies
12
that are proposed, and those responses are
13
now being viewed, and the board will meet
14
again in November to think about this more.
15 Let me just stop for just a second
16
and mention that part of the OPTN process is
17
that in order to list patients on the
18
deceased donor list, and therefore receive
19
organs, a program has a series of criteria
20
they must be in compliance with, including
21
membership, including professional staff
22
that have had appropriate training and
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background, and many other process things
2
about the program.
3 Then the member must be conformed
4
to policy of the OPTN. Finally,
the
5
institution's data are reviewed and members
6
that fall out, that are not doing
7
sufficiently well by the criteria
8
established by the OPTN membership
9
committee, are reviewed and process is taken
10
as necessary if it's felt there are poor
11
results that the OPTN wishes to provide
12
penalties against.
13 This is very a effective process
14
in maintaining a situation in which organ
15
transplants are used optimally in the
16
country.
17 So this is the process that is
18
envisioned for islets as well.
So the rules
19
would be that the hospital doing the islet
20
transplant must be in a center approved for
21
whole pancreas transplants. As
with
22
everything else, data must be provided.
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1
Remember, these data are national, complete,
2
and reviewed twice a year. So
what is
3
available to the community, and as an aside,
4
to the FDA, is not a surrogate
of some sort
5
or another that is processed or other things
6
for outcomes, but the outcomes.
It's the
7
country's outcomes.
8 What happens to the islets? How
9
they are going to be able to handle the
10
actual implantation or the transplantation
11
and the other issues that have been raised
12
all must be clear. All patients
must be
13
listed on the computer waiting list,
14
centralized waiting list, with allocation
15
rules that we'll talk about in a minute.
16 OPTN members, and I'll stress that
17
OPTN members, in order to participate in the
18
process, that includes all organ procurement
19
organizations and all transplanting
20
programs, shall not provide organs to
21
non‑member transplant centers.
Now, those
22
issues are included here because by
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