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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1
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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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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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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implication, the islets in this regulatory
2
setting are being treated as organs.
3 At present, there are 164 islet
4
candidates listed. Now, this I'm
sure is
5
higher. Well, actually this is
quite up to
6
date. It's interesting that
there are 70 in
7
one institution in Canada, which says
8
something about the field at this point.
9
But it's also that you don't need very many
10
potential recipients of a given blood group
11
and you have enough potential recipients for
12
what donor comes along, because we're
13
already starting to see the tip of the
14
iceberg of the difference between supply and
15
demand, I think. As we said,
there are a
16
little over 1,000 whole organ pancreas
17
transplants done per year in the U.S. now.
18 How to allocate the islets is
19
going to be undergoing evolution over some
20
years. I'll show you that going
from a
21
situation in which only whole organ claims
22
get first priority to a mixture is what has
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been appealing and what is put out for
2
public comment. There is a
concept within
3
the allocation rules, because this country
4
is very heterogenous in many ways, and
5
sometimes the standard rules across the
6
country might be improved in some way or
7 another by some
local change or use of a
8
variance for that, so variances could be
9
applied to islet allocation.
10 Probably not terribly relevant for
11
this discussion, but there are variances
12
that are allowed for the purposes and under
13
the settings that are described here.
But
14
at any rate, aside from such variances, the
15
candidates for a pancreas, and that will
16 include islets
as this comes along at
17
present, are ranked by waiting time, highest
18
priority for whole pancreas. We
try to
19
place the whole gland first.
20 If the pancreas cannot be placed
21
nationally, then it will be offered in a
22
similar way, locally, regionally, then
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nationally by waiting time, blood group, of
2
course, for clinical islet transplantation,
3
and finally clinical research, if either of
4 those can produce a
home for the gland.
5 This is interesting in light of
6
some other stuff you've seen today.
But
7
mixing a blend of physiology and sort of
8
logistic fairness, the committee came up
9
with a proposal ‑‑ it's interesting,
10
PowerPoint turned a "less than" to a pair of
11
scissors. I'm going to have to
think about
12
this for a second.
13 I'd like to know how to do that
14
intentionally. I'm sorry I have
to
15
remember; I think that's a less than.
Okay,
16
that's a greater than, so this is a less
17
than. Donor age less than 50
years and BMI
18
less than 30 kg/m2. This is sort
of the
19
general cutoff for centers using whole
20
pancreas for transplantation.
21 It involves a combination of the
22
issues that are really terribly complicating
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in whole organ transplantation and cause so
2
much trouble. It's one of the
reasons
3
there's so much enthusiasm for something
4
different, that is the islets.
Also, you
5
want a low BMI, because it is felt that if
6
there's a lot of fat deposition in the
7
gland, there is higher likelihood of
8
post‑transplant problems.
9 So in that case, it goes out for
10
whole pancreas with kidney or by itself. Or
11
combined solid organ islet, which has a
12
special case, often, say, a liver‑islet,
13
because it's a given patient who needs both
14
and there are some advantages to doing a
15
combined transplant in several settings,
16
it's been found. Then further
pancreas and
17
then finally islet.
18 The important point is that if
19
those two criteria are not met; that is, if
20
the donor age is beyond the point of time
21
that would be optimal for use for whole
22
gland, or if the pancreas is fatty, it turns
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1
out that there is some enthusiasm that the
2
islet separation works better in this
3
setting. Now, if clearly here,
Dr. Shapiro,
4
and Dr. Ricordi and others are clearly not
5
necessarily going to be in favor of this
6
down the road. So I think it
will be a
7
tension between whole gland and islet
8
transplant for the moment, and that will be
9
an evolution. I mean, this is
something
10
that needs to get sorted out.
Changed,
11
removed, whatever.
12 But at any rate, this then goes
13
for first a local pancreas gland if
14
possible, because that's a particularly
15
quick and appropriate thing to do, but then
16
islet comes next. So the point
is by basing
17
it on these mixture of things, a difference.
18
And this is what is out for public comment
19
and what will be thought about.
20 The OPTN feels strongly that the
21
kind of oversight that it's been providing,
22
and the way this is intertwined with its
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general mission and contractural purpose, it
2
means that there's going to be a problem
3
with non‑member institutions doing islet
4
transplants. Remember, it is a
transplant
5 with the need for
immunosuppression. Those
6
issues have already been brought up.
This
7
is a natural way for the public and the
8
public health interest to best be served, is
9
to have it under this aegis.
10 There's also a concern about
11
research allocation resulting then in a
12
pancreas being used for clinical islet
13
transplantation, and that's something that
14 clearly the
organization wishes to avoid.
15
And I'm sure the FDA would be in sync
16
because of the process and quality control
17
issues that it would raise.
18 So they must be allocated through
19
the allocation system.
Therefore, if a
20
pancreas is initially through that algorithm
21
I showed you allocated for research, but
22
then there's a desire to transplant the
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1
islets, let say the islets are separated and
2
they look great by all the
criteria being
3
discussed; it has to be reallocated through
4
the OPTN system. At present,
that holds
5
because member institutions are also members
6
for other reasons; that is, they have to
7
have a pancreas transplant program as well.
8
OPOs are obviously bound by this, so the
9
pancreas can't leave the OPO under other
10
circumstances at any rate.
11
But remember that the
pancreas,
12
and by implication the islets, are allocated
13
to a specific patient. The
allocation is
14
based on a set of issues, including how well
15
it's going to work and how fair the process
16
is. There is a concern about
cost and
17
reimbursement with regard to the prohibition
18
against buying and selling organs.
That is,
19
the NOTA Section 301, which is now in the
20
Criminal Code and is clearly a legal issue.
21 There are several things that we
22
can see are issues listed here.
How to
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decide which way to tip the system; I think
2
as islet transplantation matures, that will
3
become a non‑issue if it
matures in the way
4
we all hope. Information,
program
5
expertise, these are the issues the OPTN is
6
dealing with.
7 So this is me, and I'd like to
8 continue to be part of this discussion. I
9
think also Laura St. Martin and my bunch and
10
I both feel this is a very important thing
11
for us to continue to work with you about.
12
I should apologize. I have to
leave before
13
the end of the morning for another meeting,
14
but you can get a hold of me for future
15
things.
16 Maybe one final sort of thought
17
about the fundamental issue, I think the use
18
of the term "product" is appropriate as long
19
as it doesn't interfere with the biology
20
that we're dealing with. In
particular, as
21
this still represents in some ways an organ,
22
and if there is the issue of supply and
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1
demand that I would think might occur,
2
obviously the patients we've seen generally
3
listed so far have been under these very
4
tight protocols, and a large, greatly
5
increased number of patients should be able
6
to benefit from this, then the allocation
7
will become probably as fierce as any of the
8
controversies that are at issue in organ
9
transplantation. And I think the
OPTN,
10
under HRSA oversight, is the place for that
11
trouble to occur. So thanks for
your
12
attention.
13 DR. RAO: Any
questions from the
14
committee?
15 DR. RICORDI:
I just have a couple
16
of comments. I was surprised
actually to
17
see that it still stands, the fact that it
18
is proposed that islet transplant can be
19
performed only at centers that do pancreas
20
whole organ transplantation. I
participated
21
in the initial discussion on this when I was
22
a member of the American Society of
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Transplant Surgeon Council. I
think there
2
is no rationale at all, and actually would
3
be a major impediment to the progress of
4
islet transplantation, especially if you've
5
seen in other chapter of the proposed rules
6
that even the marginal donors of age
7
above 50 or BMI over 30 have to be first
8
offered to the local whole organ pancreas
9
transplant programs.
10 In a way, that is a way to make
11
sure that you have a direct competition in
12 place whose
expertise is not required at all
13
to perform an islet transplant.
Because if
14
anything, you need a liver transplant.
15
Surgery on the islet don't go in the ----
16
process vascularized organ, and I think this
17
is really something that, if not horrifies
18
me, make me really think about the whole
19
process and the reason that there is this
20
constant attempt to keep islet
21 transplantation
under the shade or underfoot
22
of pancreas transplant would be like to say
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that every democratic senator can be elected
2
only in a state where there is a republican
3
governor or vise versa, like as an approach.
4
The other comment is
that the fact
5
that 70 patients are on the waiting list in
6
Canada and only 164 are on the waiting list
7
in the United States is related to the fact
8
that in United States, we are all under
9
INDs. So if I have a protocol
with FDA that
10
allows me to transplant only 6 patients
11
or 12 patients, I cannot morally accept 200
12
patients on the waiting list when I know I
13
can only treat only 6 of them.
14 So we close recruitments, and this
15
is a limitation. If this
procedure would be
16
approved in the United States, I'm sure that
17
the number of patients on the waiting list
18
will be higher than those on pancreas
19
transplant lists.
20 MR. RAO:
Your comments are
21
well‑taken. I'm sure the
FDA's taking heed
22
of those issues.
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1 MR. HERING:
Dr. Burdick, I would
2
like to thank you for your superb
3
presentation. You really raised
all the
4
important issues, including the very recent
5
discussion of the proposed modifications to
6
allocation policies.
7 If I may, I would just like to add
8
a few data to really illustrate the point
9
that we want to make. I think it
is
10
important to consider timing of allocation.
11
We discussed yesterday that the single most
12
important factor is determining outcome of
13
islet isolation, and presumably
14
auto‑transplantation, are pancreas
15
procurement and also pancreas preservation.
16 The islet transplant community is
17
therefore very concerned that timing is
18
considered in allocation algorithms, to the
19
point that islet transplant programs are
20
often an opportunity to use what is
21
considered state of art and really maximize
22
utilization of current technology, so that
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1
really, we can maximize the effective use
2
off a very scarce resource.
3 Now if I then look at results, or
4
the pancreas disposition for diseased donors
5
recovered between 2000 and 2002 in the
6
United States, and I have the data here
7
available, there were 18,249 donors.
Now,
8 donors with a BMI
of 28 or higher, there
9
were some 5,600 donors. BMI 31
and higher,
10
there were 2,072 donors. Now, if
I look at
11
this subgroup of donors that are overweight
12
or obese, 77 percent of those pancreases
13
from those donors were not recovered at all.
14
Those are perfectly suitable pancreases for
15
islet transplantation, but are considered
16
less appropriate for pancreas
17
transplantation.
18 I think the data actually support
19
that point. About 10 percent of
donor
20
organs from this subgroup of donors were
21
used and recovered for pancreas
22 transplantation.
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1 So I think it is fair to say that
2
there is substantial underutilization of
3
organs from donors that are obese or
4
overweight. Those are perfect
donors for
5
islet transplantation, because we have
6
documented over and over again that islet
7
yields are very high, and that we can
8
achieve very acceptable results after
9
transplantation.
10 So for this reason, we like to
11
propose a modification that would consider
12
timing of allocation, but would not limit
13
the use of those organs in the pancreas
14
transplant community. What we
consider is
15
that allocation of those organs to a
16
pancreas transplant recipient should be
17
completed by four hours before incision is
18
made, so that if this pancreas is turned
19
down for medical reasons or other reasons by
20
pancreas transplant programs, that the offer
21
can be made to an islet transplant program
22
or to an islet transplant recipient so that
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we can really utilize this pancreas.
2 What happens in real life at this
3
point in time is that a lot of time is taken
4
to place this pancreas, and an islet
5
transplant program is very often if not
6
almost always informed about the
7
availability of this pancreas hours after
8
procurement has been completed.
So this
9
pancreas can no longer be used.
10 So I think we could optimize
11
allocation, and without compromising the
12
ability of pancreas transplant programs to
13
use this pancreas, and really increasing the
14
availability to islet transplant patients
15
without really modifying the policies too
16
much. So we would like to make
this point.
17
And I think the implications for islet
18
transplantation, islet transplant recipients
19
would be profound. But the
implications for
20
pancreas transplant recipients would be
21
minimal.
22 DR. BURDICK:
Well, thanks. You
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know, I'm sure that I agree with the things
2
you're saying. The comment
period for the
3
OPTN is closed, but if you haven't gotten
4
your message to them and want me to help get
5
that, I certainly would be glad for you to
6
get a hold of me. But I think
for the FDA's
7
point of view, these issues will continue to
8
be hashed out. It's very much an
evolution,
9
as I told you. This may very
clearly not
10
fly, what has been put out so far; that's
11
fine.
12 But if as a product there's an
13
issue of ownership and there's a
14
possibility, as has happened over the
15
history of transplantation, that individual
16
centers that are fantastic and are doing
17
wonderfully but sort of grab it and start
18
doing things a bit on their own, and then
19 the community
finds that they don't quite
20
think what's happening is fair, there's a
21
problem. That's why I think that
there's a
22
place for this oversight.
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1 That will evolve and maybe the
2
islets will turn out to be clearly just a
3
product very different from a organ and this
4
will all evaporate, and that could work just
5
fine, too. I'm just talking
about what the
6
practical sort of societal issues might be.
7 That's all.
8 DR. RIEVES:
I do have a question.
9
I didn't raise my hand though.
Dr. Burdick,
10
this is a fascinating area, because as
11
everyone has mentioned, we're talking about
12
products. Islet products are
unique
13
compared to drugs and biologic therapies in
14
many respects, but yet we have to follow our
15
regulatory standards. I want to
be sure I
16
walk away with a clear message as things
17
stand right now. This is not
necessarily a
18
request for comments as it directly applies
19
to FDA, because FDA does not generally take
20
cost considerations under review in
21
licensing products. But it has
major
22
implications for our sponsors.
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1 If I understand correctly, HRSA
2
regards islets currently as organs.
3
Consequently, currently, the NOTA
4
regulations prohibit the purchase of islet
5
transplants, meaning conceptually, there is
6
not a marketable, in the traditional sense,
7
product, if I'm understanding correctly.
8
Also somewhat unique to drugs and biologic
9
products, HRSA procedures somewhat regulate
10
or control or influence, if you will, of the
11
distribution of the product, getting at some
12
of the questions comments.
13 Am I correct in this
14
understanding? So our sponsors
of islet
15
products have multiple guidances,
16
influences, perhaps regulations that they
17
have to comply with beyond FDA.
Meaning
18
that they essentially do not have
19
"marketable" products in the same sense that
20
we think of marketable products.
Their
21
distribution is somewhat controlled beyond
22
the extent that traditional biologic
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products are controlled. Could
you comment
2
on that understanding?
3 DR. BURDICK:
Two things. That's
4
precisely the issue that I've been talking
5
about. You got it. Secondly, I have not
6
been part of the KP committee discussions
7
and the islet cell transplanters' input and
8
so forth. I don't know how
mature this is.
9
It may be that a sufficiently persuasive
10
argument against including it in the rubric
11
that I have described is going to be made or
12
has been made.
13 I think my point is that until
14
it's clear throughout the country, if you
15
will, that that point has been made and the
16
change is acceptable from the present
17
situation ‑‑ there is plenty of sentiment at
18
present that the islets are not typical
19
product in the way the FDA views a product,
20 and there are
people here who can answer
21
more of what they're likely to be saying to
22
the OPTN and it's a process in evolution.
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1 DR. SALOMON:
There's a lot of
2
stuff on the table right now, and obviously,
3
you don't want to hear me rattle on for 20
4
minutes on it. But I feel
strongly about a
5
number of things here. Number
one, I
6
strongly support what Bernhard has been
7
saying. Bernhard, Camillo,
myself, Richard
8
Nazick sent a detailed proposal to the KP
9
committee in public response.
That data
10
that Bernhard was referring to comes from
11
UNOS released data.
12 So at least it's the best you guys
13
have given us to go by. It was
presented,
14
discussed, and the decision by the KP
15
committee was to disagree and continue to
16
say that still, it's still in priority to
17
whole organ programs.
18 The compromise, just to be clear,
19
that Bernhard articulated a few minutes ago
20
is something that's come subsequently
21
through discussions, and we'll try and go
22
back to the KP committee and get this done.
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But your support and your input in this
2
would be very important.
3 The second and the last thing I
4
want to get into is really important.
That
5
is, this is exactly what I was talking about
6
yesterday. When I talked about
one of the
7
complicating things about this whole field
8
right now is that you're in transplantation,
9
and then you're into this product and
10
manufacturer part, and then you're back into
11
transplantation.
12 A half a dozen different issues
13
that are on the table right now relate to
14
that. Number one, do you need a
pancreas
15
program in order to do an islet program? I
16
think that's ridiculous. Do you
need
17
skilled physicians who know how to take care
18
of transplant patients and use
19
immunosuppression? Absolutely.
20 Second issue, do you need to have
21
pancreas procurement and pancreas for islet
22
governed by the OPTN? I think
you do,
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because I think right now at least, it's
2
really impossible for me to see a system
3
that works equitably when you still have
4
pancreas programs and islet programs that
5
doesn't interface seamlessly with the OPTNs.
6
So I totally agree with that point.
7 But lastly,
here's again the
8
issue. The FDA has said this is
a product,
9
we're going to deal with it, and the whole
10
field now is under this IND and all the
11
consequences of that. Okay,
fine. These
12
guys have worked really hard.
The field's
13
worked really hard to deal with that, and in
14
a constructive way, I think made tremendous
15
progress. However, the OPTN says
no, we're
16
organs. The OPTN has to insist
that this
17
organ, because if they say that it's tissue,
18
then they don't regulate it anymore.
And I
19
just explained to you why the OPTN cannot
20
allow that.
21 So they're at an absolute
22
loggerhead. Then when we go to
CMS and say,
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well, how much are you charging use to do a
2
whole organ so that we make islets out of
3
it? They go, well it's an organ,
so you got
4
to pay $18,000 to $20,000 for it.
5 DR. RICORDI:
Twenty‑seven.
6 DR. SALOMON:
How much?
7 DR. RICORDI:
27,000.
8 DR. SALOMON:
That's what you have
9
to pay in Miami.
10 DR. RICORDI:
But that's not the
11
same.
12 DR. SALOMON:
It's less expensive
13
to live in California. But
seriously, he's
14
right. I'm giving you a median
range. We
15
looked at it and it goes from about $18,000
16
to $25,000. It's ridiculous,
because when
17
we do a whole organ pancreas at San Diego,
18
microprogram would pay $18,000 or $20,000
19
for the pancreas. But it's a
passthrough,
20
through our kidney aquisition fund, through
21
CMS.
22 As long as the OPO is charging us
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a reasonable amount of money and they're
2
under audit and it's all fair and I'm on the
3
board and we can handle all that, it's no
4
problem. But when we want to
think about
5
setting up an islet program, it's killing
6
us, because we don't get any funding for it.
7 What's
happening is we then have
8
to go and get JDRF and NIH dollars that
9
should be going to support research and
10
advancing science; we have to go beg on our
11
knees to philanthropists who should be
12
moving science forward so we can buy $18,000
13
organs. I mean, this is
nonsense.
14 But when we go to CMS, they go,
15
you know, we don't know. It's
organs. We
16
can't really change
things. We don't have
17
time. We've got lots of other
things to
18
worry about.
19 So, I'm done here, but this
20
obviously has got me going. The
issue here
21
is if we want to complete the loop, all the
22
stakeholders have got to get their act
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together. I mean, I think the
FDA's view of
2
this has been positive and appropriate.
Not
3
everybody agrees with that, but I think it
4
has been. I think the OPTN
absolutely has
5
got a point. I think CMS has got
to get on
6
board. There's a whole lot of
stakeholders
7
waiting for this to get sorted out.
8 MR. RAO:
Before you get up, I
9
think this issue may be retreated by several
10
people and make their comments before you
11
respond.
12 DR. MULLIGAN:
Actually, this does
13
not exactly involve this. I know
how
14
powerfully important your organization is,
15
and it essentially controls the raw
16
materials for this whole activity.
17 In a sense, I would think that it
18
really controls the pace of the whole
19
development of the technology, and that's a
20
very, very powerful position to be in.
So
21
I'm curious. Could you tell us
something
22
about the decision‑makers here.
How are
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they picked, what kinds of people they are?
2
Because I would think that it could have a
3
tremendous impact. Very simply,
if you have
4
people that like whole pancreases, but don't
5
like islets, you're going to have a very
6
different point of view and
allocation. How
7
democratic is the process? How
do they get
8
elected? How long do they sit
there? Or
9
how much history is there in this whole
10
thing?
11 DR. RAO: Hold
that question.
12
There are several people who requested to
13
ask questions, and I'm going to ask them if
14
it's directly related, to do that right now
15
so that we can have a common response.
16 DR. KURTZBERG:
I think that this
17
is an incredibly important issue.
I agree
18
with everything that Dan said. I
think this
19
goes beyond islet cells, and putting aside
20
the question of how you define something as
21
an organ or a tissue, which is confusing. I
22
think that the FDA needs a new category that
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isn't licensing, but that allows
2
authorization or sanctioning of a particular
3
therapy so that third‑party reimbursement
4
can go forward, but doesn't make it a
5
for‑profit business for selling organs.
6
That category doesn't exist right now.
7 But if there was a new kind of
8
designation that said islet cell
9
transplantation or whatever cellular therapy
10
product we're talking about, transplantation
11
is sanctioned and is recognized as standard
12
of care, but you don't make money on that
13
organ and it's not really a license product,
14
that would be a different designation, but
15
it would allow the third‑party pairs in CMS
16
or whoever to say that yes, this is part of
17
patient care and this should be reimbursed.
18 I think that's where the FDA has
19
to go with all of these cellular products so
20
that they don't become a business for
21
profit, but so that patient care can be
22
reimbursed.
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1 DR. RAO: Dr.
Sherwin.
2 DR. SHERWIN:
I'm amazed. I've
3
learned a lot today. This was
very helpful,
4
because I had no sense, even though I was
5 present of the
American Diabetes
6
Association, what was going on.
What really
7
strikes me is that I suspect the people that
8
deal with this issue are the transplant
9
community. When you're dealing
with
10
diabetes, the people that deal with the
11
patients are the diabetologists, and the
12
endocrinologists.
13 I think we have the best
14
perspective as to how to allocate organs for
15
our patients, and not surgeons who simply
16
treat the patient for a short period of time
17
and don't deal with the whole patient.
So I
18
was absolutely struck by this situation. I
19
think it's a very unique situation.
20 We deal with patients over an
21
extended period of time, and we have to deal
22
with issues that I think are quite complex,
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and I think we have probably the best
2
perspective of how to deal with that.
So I
3
would ask again, how you make your decisions
4
about who makes these decisions about
5
pancreas versus islet transplants?
6 DR. RAO: Dr.
Eggerman. Is this
7
directly related to this whole issue right
8
now?
9 DR. EGGERMAN:
Right. Just a
10
quick question in terms of what the basis
11
was of them making the designation of organ
12
versus tissue or cellular therapy; if this
13
was something in terms of established in
14
terms of regulation or was this just a
15
policy or what that was, because that
16
certainly addresses how it might be
17
addressed.
18 DR. RAO: Dr.
Harlan, do you have
19
a specific comment to this?
20 DR. HARLAN:
I do, and I wish to
21
support the comment that islets being
22
subservient to pancreas is problematic.
I
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wish to support the comment from
2
Dr. Kurtzberg that thinking of a new way to
3
reimburse for this product is a very, I
4
think, fruitful avenue of investigation.
5
The specific point I wish to make is on I
6
think your penultimate slide, Dr. Burdick,
7
it said pancreas transplantation is now a
8
proven therapy. In this city,
where the
9
famous quote is "depends on what the
10
definition of 'is' is" was said, I would say
11
it depends on what your definition of
12
"proof" is.
13 We have an analysis that's been
14
discussed in professional circles that looks
15
at an end point of patient survival; looking
16
at patients listed for pancreas transplant,
17
those who get it, and those who don't.
We
18
find that you're more likely to survive, if
19 you're listed
for a pancreas transplant, so
20
you fill all the criteria that we've heard
21
about, and you don't get the transplant over
22
a four‑year time interval, so long as kidney
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function is normal. So I'm an
equal
2
opportunity conservative observer of all
3
therapies.
4 I'm fairly conservative in my
5
views of islet transplant, but I'm equally
6
conservative in my views of pancreas
7
transplant. I think we have to
at least
8
keep open the question of just how proven a
9
therapy it is, and echoing what Dr. Sherwin
10
said.
11 DR. RAO: Dr.
Burdick, you now
12
have heard several comments directly related
13
to this.
14 DR. RICORDI:
Can I make one last
15
one, very short? It's just that
there is
16
currently no representation from active
17
islet transplant program on the
18
kidney‑pancreas committee when you refer
19
that this could have been discussed in that
20
occasion.
21 Also to express how my concern,
22
and I'm sorry if I lose my traditional
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diplomacy at times, is that to give a very
2
defined example. We received an
offer
3
for 51‑year old pancreas; with this rule has
4
to be offered before to whole organ pancreas
5
programs, and we arrived to the limit where
6
the pancreas surgeon was not doing the
7
procurement. He decides well, I
decide when
8
I have visual confirmation tomorrow morning
9
when I get that if I use it, or if it can be
10
offered to islet.
11 That was clearly a wasted organ.
12
So this is just an example of how hundreds
13
of organs that could be valuable, not just
14
for transplantation but also for research
15
purposes. There is tons of
diabetes
16
research depending on islets that are
17
distributed for research that are equally
18
important.
19 My anger or concern is that I want
20 to make every
pancreas count, either for
21
clinical pancreas, clinical islet, or
22
research. But we can not accept
as a
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community that hundreds of pancreases are
2
wasted because of lack of timing in the
3
location and these kind of lobbying battles.
4 DR. BURDICK:
Thank you. The
5
biggest single block to this moving ahead
6
right now is not the board of directors,
7
it's not anybody's fault. It's
just that
8 the field is
very early and you have the
9
mass in terms of intellectual and
10
experiential activity here in the room
11
before you, and it's something that needs to
12
have more of an impact on the country than
13
it has.
14 Maybe I could go to Dr. Ricordi
15
first. I'm not quite sure why
there isn't
16
somebody who is in islet transplantation on
17
the KP committee, but it's certainly
18
something that HRSA will look into, I
19
promise. But it's not a
surprise, because
20
this is happening fast and it's new.
21 I know from the work that you've
22
been doing for many years that it doesn't
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seem like it's happening fast, but it has
2
not gotten out in the way that you've
3
presented it.
4 Let me just go through a few other
5
things. I think that there are
now data
6 that both whole
organ transplantation and
7
islet transplantation do make a difference.
8
Exactly how much difference and how to
9
select patients and so forth are big issues.
10
There are so many problems in both of these
11
areas still at this point that it's hard to
12
deny Dr. Harlan's skepticism, and I agree
13
with that.
14 However, I think we should
15
consider them both proven therapies, with
16
the caveat that I said that if islets can be
17
made to work even nearly as well as whole
18
organ, and it looks like they're going to
19
be, they're far better as a therapeutic
20
approach.
21 Now, Dr. Salomon, we're going to
22
continue discussions. I pretty
much agree
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with what he had to say. I
actually
2
described yesterday somewhat about the board
3
of directors. Tell me if I have
only a
4
minute left or something, because there are
5
a lot questions. I'll try to go
through
6
this quickly.
7 For the last 20 years, there's
8
been a process that has been overseen
9
closely, with some friction and sparks, but
10
often things going very, very smoothly
11
between the government and the private
12
contractor. It is not a bunch of
transplant
13
surgeons. It has about 50 percent
14
transplant professionals on the 40‑ or 50‑
15
member board of directors. The
others
16
are ‑‑
17 DR. RAO: Is
there anybody from
18
the diabetology or endocrinology?
19 DR. BURDICK:
Well, let me address
20
that. The way the policies occur
is through
21
a series of committees. KP has
been talked
22
about this: Liver, intestine, there's
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cardiac. The cardiologists have
a great
2
deal of input in the deliberations and the
3
issues that come to the thoracic transplant
4
committee. Diabetologists,
nephrologists,
5
and others for the kidney‑pancreas.
6
Hepatologists for liver transplantation, and
7
in fact, the president of the board this
8
year is a hepatologist from the Mayo Clinic.
9 And I should say that this
10
represents 50 percent of the representation.
11
The others are ethicists. Dr.
Childress can
12
tell you he's served in these committees:
13
patients, community representatives.
The
14
community people now are there for three
15 years because of
having a chance to sort of
16
get used to a lot of the technical things.
17 The other people are voted through
18
the regions in the country to be on
19
committees, and then as members of the
20
board, and they're there for two years.
So
21
that's the structure.
22 There's a lot of care to the sort
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of heterogenous representation that I think
2
everybody would want. It's a
very
3
responsible group that takes this very
4
seriously. I'm not aware of
sustained
5
attacks by anybody who's come in close
6
contact with this who would say it's not
7
working very well.
8 You asked
about terminology.
9
"Organ" is actually in Stedman's Medical
10
Dictionary, "a somewhat independent body
11
part that performs a special function." I
12
think there's nothing more intelligent I can
13
say than that. I've talked about
14
Dr. Harlan's and Dr. Ricordi's.
15 DR. RAO: Can
I ask Phil to
16
respond in particular also to what Joanne
17
Kurtzberg said.
18 DR. NOGUCHI:
Yes, thank you.
19
Dr. Burdick, if I don't get a chance to
20
thank you before you leave today, we really
21
appreciate your presence and your courage
22
and being able to actually address all these
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issues.
2 Just parenthetically, I would just
3
have to say that what Dr. Burdick has gone
4
through here is typically what FDA goes
5
through on a continual basis, but very often
6
we're not even allowed to speak in return.
7
We have a lot of sympathy for all the points
8
being addressed here.
9 One of the things that I think
10
that this really does illustrate, and it is
11
a major reason why the BRMAC has been
12
constituted and will continue to be expanded
13
in its unique role in cell tissue and gene
14
therapy, is in fact that we are seeing an
15
intersection where many different interests
16
are coming together, where in fact, as those
17
of us who have had some interaction with
18
HRSA and with the UNOS system, as FDA has
19
always known about itself and UNOS knows
20
about itself, and HRSA knows about itself,
21
good‑minded people think about the same way.
22
We have different laws and regulations and
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restraints, but we by in large usually do
2
come out ultimately to similar types of
3 conclusions.
4 I wanted to address the issue of
5
product, because I've been thinking about
6
that. There clearly is a whole
industry
7
called blood banking, which is non‑profit,
8
which is not sold. You cannot
buy blood,
9
but you pay for the services.
It's a system
10
that has its own flaws. In a non‑profit
11
situation, no matter what happens, expenses
12
rise, and then how do you actually maintain
13
the quality? That's clearly a
major, major
14
issue.
15 But we do have precedence where
16
with the concept of a product, nobody owns
17
blood, but it's given freely, and it's
18
distributed not freely, but with somewhat
19
minimal costs, and yet the impact on public
20
health is tremendous as well as some of the
21
unfortunate events that happen.
22 We do have actual experience in
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FDA in terms of reimbursement.
There's a
2
whole class of products called medical
3
devices in which actually much of it is
4
reimbursed during the investigational stage.
5
That is not to say that we can automatically
6
extend this across all FDA‑regulated
7
products. However, I think there
are those
8
of us within and without the agency who
9
would really like to explore that a little
10
bit further.
11 Some things, such as these which
12
cross from transplantation into cellular
13
products, ultimately gene therapy and other
14
things as well, clearly some form of
15
societal commitment to the actual process of
16
investigation is warranted, and how we get
17
there, again, is not a singular agency kind
18
of approach, but is dependent on all of us
19
here, and others who aren't here as well.
20 Just to say in terms of the issue
21
of multiple oversight or overlapping
22
oversight, Dan Salomon knows this well, as
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do others on the committee, when we talk
2
about gene therapy, we have additional
3
intersections with the National Institutes
4
of Health which have had very interesting
5
and sometimes stormy discussions, but again
6
at the end of the day, we do come out with
7
very similar approaches and opinions about
8
what has to be done.
9 So I think that is a clear message
10
for us at FDA to open and extend even more
11
our interactions with HRSA and with the
12
transplant community in general.
I have
13
been at some of those UNOS meeting where in
14
fact the community participants have
15
ironically done what many of us at FDA would
16
like for many things is, well, why can't you
17
tell us what the outcomes are at each
18
individual centers so that we the patients
19
can judge better for ourselves where we
20
would like to go? There's been
very
21
interesting discussions as to back and forth
22
about that.
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1 I think I'll just try to end here
2
to just say that this particular discussion
3
that we've had, although I didn't quite
4
expect it would necessarily generate this
5
interaction, clearly, it has touched
6
everyone's passion for trying to make sure
7
that the right thing gets done.
8 If we have organs that aren't even
9
harvested but could literally save people's
10
lives, that's an issue that needs to be
11
worked on. This is not an FDA‑alone
issue.
12
It's not a HRSA‑alone issue.
Clearly, it is
13
all our issues, especially as Dr. Kurtzberg
14
keeps pointing out, where is the rest of
15
society to really commit to making these
16
things happen? This will cost
money. This
17
will cost funding. This will
cost
18
dedication and effort. It will
cost making
19
new rules and regulations. None
of which is
20
going to be easy given all the increased
21
responsibilities that we have.
22 But I think
this is perhaps a good
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time for us to say this conversation will be
2
continued. I regret we can't
continue too
3
much of it more here. But I
think it is a
4
good segue right into Dr. Childress's next
5
discussion, which I think really gets back
6
at the whole heart of what we're talking
7
about: Is this an FDA‑regulated
product.
8
No, this is a resource and this is one of
9
many resources that are now being developed
10
that needs to be delivered. It's
our duty
11
here to help us get to that point.
12 I hope I've at least answered a
13
couple questions and maybe pointed this to
14
some of the discussion for the rest of the
15
morning.
16 DR. KURTZBERG:
I really
17
appreciate that response, but I have a
18
question. What process will take
this
19
forward? I don't understand
quite how to do
20
it. Does the government need new
21
legislation? Do these agencies
have to come
22
together with CMS or whatever?
How would
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that happen?
2 DR. SALOMON:
I personally have
3
been talking to different people that
4
represent the different groups, FDA, JDRF,
5
NIH, NCRR, the Islet Consortium Group that I
6
participate in. The only thing
that makes
7
sense to me is for some sort of
8 stakeholders' meeting that brings together
9
the endocrinology community, the transplant
10
community, patient community, basically all
11
those who have a stake in this area, and
12
just reasonably sort through what are very
13
clear barriers.
14 As I've tried to say, each of the
15
different pieces is okay by themselves and
16
internally consistent with the missions of
17
these groups. It's just that
when you take
18
them altogether, you suddenly realize some
19
of the contradictions that are here.
We
20
just need to get everyone together and say
21
here are a bunch of patients with a bad
22
disease, let's work it out.
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1 DR. KURTZBERG:
It's more than
2
just this disease and these patients.
It's
3
a policy that has to be established.
4 DR. RAO: I
really wanted to
5
emphasize that, that it's really a policy,
6
which we might have to visit the same issue
7
many, many times depending on whether you
8
use stem cells or any other tissue.
We look
9
at Parkinson's Disease, anything, and this
10
might be the sort of ---- so it would be
11
very worthwhile working out a good policy of
12
how people can talk together.
13 On that note, I'll ask
14
Dr. Childress for the next issue.
15 DR. CHILDRESS:
Well, I think it's
16
a pleasure to be here. Let me
start a
17
little different way than I planned to.
18
Aristotle once said that ethics and politics
19 have to be
treated together. He did a book
20
on ethics and he did a book on politics, and
21
they were seen as basically part of the same
22
work.
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1 I think you heard a discussion
2
this morning that suggests how indeed ethics
3
is often imbedded in a larger discussion
4
about politics, by which I mean issues of
5
control.
6 We are seeing different frameworks
7
within government. We're also
hearing a
8
discussion of different professional roles
9
and responsibilities in this regard.
So my
10
thoughts about ethics today will put the
11
ethical considerations in the context of
12
this discussion rather than being an
13
abstract formulation.
14 I will step back from some of the
15
immediate discussions, offer up some general
16
points, and then come back in and illustrate
17
with some of the discussion we've had today
18
and has gone on elsewhere.
19 Let me also say a word about
20
conflicts of interest. I was a
vice chair
21
of the federal task force on organ
22
transplantation, which formulated the
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guidelines that ultimately became part of
2
the OPTN and the structure for the OPTN. I
3
served on the board of directors at UNOS in
4
the early years, and then subsequently on
5 the ethics committee.
6 But I have not been on the ethics
7
committee for the last, I don't know, three
8
or four years. I've not been
part of this
9
discussion at UNOS, and I've only actually
10
followed it at some distance. So
maybe
11
that's an appropriate type of background for
12
beginning this presentation.
13 Let me also note that we are, as
14
the discussion has indicated, in an
15
evolutionary situation. An
evolutionary
16
situation in terms of the field of science;
17
does it work here in terms of the medicine
18
related to this arena in terms of isolation
19
of islet cells, et cetera.
20 But we're also in a evolution I
21
think in our conceptual frameworks.
I think
22
we've heard a bit of discussion about that
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today because of not only the competing, but
2
overlapping governmental frameworks, we also
3
have some contested and potentially
4
conflicting conceptual frameworks.
In
5
particular, how we think about exactly what
6
it is we're dealing with.
7
So with that in
mind, let me offer
8
a few comments about ethical analysis.
I
9
think much of what we do in ethical analysis
10
does involve looking at general moral
11
considerations. Principle like
benefitting
12
patients, not harming them; maximizing
13
welfare; what we call utility; respecting
14
autonomy; acting justly, et cetera.
15 Much of what goes on in ethical
16 analysis is trying
to make these very broad
17
concepts more specific, because they are too
18
broad to give us very much guidance.
So
19
when we talk about what does utility mean in
20
the context of medicine, in the context of
21
organ transplantation, then we have to make
22
it much more specific or assimilate for
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justice. These principle may
come into some
2
conflict, or there at least may be tension,
3
so we at times have to try to balance them.
4 A lot of what I've experienced in
5
the context of debates in UNOS about
6
allocation had to do with balancing
7
principle, trying to find some way to hold
8
onto all of them in the context
of
9
developing allocation policies.
Of course
10
central in this discussion are the
11
principles of justice and utility.
12 But this is not the only way we
13
engage in ethical analysis. Much
of the
14
discussion that has gone on here quite
15
appropriately has basically appealed to
16
moral precedence or analogies.
We have
17
settled, and it may not be all that settled,
18
moral judgments about certain kinds of
19
cases, and they provide relevant analogies
20
and we'll move into a new area or a rapidly
21
developing area.
22 For example,
much of the
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discussion has preceded my reference to
2
policies toward and judgments about organ
3
transplants and what light they shed on a
4
discussion of islet transplantation.
We've
5
talked about various kinds of analogies.
6
Obviously, with solid organ transplantation,
7
bone marrow transplantation, blood products.
8
There's one we haven't really spent much
9
time talking about and might be useful, and
10 that's to think about the products that come
11
from bone and skin.
12 That's an area under the tissue
13
part that FDA, I believe, regulates in terms
14
of safety, but there are other
15 considerations
that clearly arise there.
16 Of course, the interaction of
17
science and ethics is critical to this.
I
18
think some of the arguments about islet
19
transplantation, about allocation, or about
20
donors, reflect if not scientifically based,
21
at least developing science, where things
22
may not be fully settled yet.
Although
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clearly from what we've heard from the three
2
major centers, a lot is settled, or really
3
strong evidence about a lot of directions.
4 Now, to think just a little bit
5
about justice and utility, two concepts I
6
suggested are very important in thinking
7
about. In particular,
allocation, but more
8
broadly than that justice, giving each
9
person his or her due, what is due that
10
person. Again, since Aristotle,
there's
11
been a recognition that treating people
12
justly at a very minimum on the formal
13
levels means treating equals equally and
14
similar cases in a similar way.
15 But obviously, there's a big
16
problem with that. As someone
said of Vince
17
Lombardi, the late coach of the Redskins and
18
the Packers, he treated all of his players
19
equally, like dirt. You can have
a form of
20
equality, but what's really critical are
21
what are the relevant similarities and how
22
should we respond to those similarities.
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1
Well, the material criteria of justice are
2
basically efforts to specify relevant
3
similarities and differences.
When we're
4
thinking about patient
selection, is need
5
the critical thing? Is the
probability of
6
success critical? Is ability to
pay
7
relevant, et cetera?
8 Now, utility basically means
9 maximizing welfare,
and we're not here
10
talking about social utility, though that
11
might be part of the background.
We're
12
really concentrating I think on medical
13
utility and trying to maximize the welfare
14
persons suffering from particular diseases.
15 But if we're trying to specify
16
medical utility, trying to give it some
17
concrete meaning, what would be most
18
important, again thinking about again
19
maximizing the welfare patient suffering
20
from a particular disease? Well,
need
21
obviously is one consideration.
Probability
22
of success is another.
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1 Now, there are difficulties
2 obviously in
defining and assigning weights
3
to these criteria, whether we're talking
4
about research or the experimental phase, or
5
in actually established therapy.
In
6
particular when we're talking about success,
7
we've already heard a lot of discussion
8
about what should count as success, and
9
clearly there are degrees in relation to
10
islet transplantation.
11
We may set the standard
in certain
12
way for a clinical trial and actually in a
13
different place for therapy, what would
14
count as effective therapy. So
there are
15
difficulties, again, in defining and
16
assigning weights to these, but also,
17
there's a possible tension between them in
18
that urgency of need, at least in several
19
contexts of organ transplantation, may
20
reduce the probability of
success. And how
21
one addresses both of those in relation to
22
each other then becomes a critical matter in
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1
trying to maximize welfare among patients
2
suffering from a particular disease.
3 It's already come up in our
4
discussion. There are issues of
justice and
5
medical utility and allocation.
One has to
6
do with established therapy versus
7
experimental therapy, as we're trying to
8
allocate, say, a pancreata which should have
9
priority, how do we go about setting the
10
standards of allocation. Also,
we've had
11
attention already to the question of the
12
number of organs per recipient, with islet
13
transplant recipients requiring sometimes
14
two, sometimes three organs in contrast to
15
one pancreas in the context of pancreatic
16
transplantation.
17 Now, this has
been debated in
18
different ways in the organ allocation.
19
Clearly even in the UNOS criteria for
20
thinking about islet transplantation, if you
21
saw the priorities that were set, you did
22
have some combined organ transplants, and
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1
then there have been situations with some
2
recipients in the U.S. receiving as many as
3
four or five organs that could have been
4
assigned individually to other recipients.
5
So there is an
important question
6
here about medical utility and justice,
7
about how many organs in fact one has a
8
right to. How far do the claims
go? In
9
terms of medical utility, of maximizing
10
welfare among patients suffering from
11
diseases. You can see also that
you might
12
maximize the welfare by spreading these
13
organs out, getting more people.
But you
14
can see how that debate goes than in trying
15
to think through particular policies.
16 Now, time waiting has been
17
recognized as a non‑medical criterion of
18
justice that is different from medical
19
utility. It's often been used as
a
20
tie‑breaker. It's received
a certain weight
21
in organ transplantation policies in UNOS.
22
Again, often to break a tie.
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1 There are other issues of justice
2
and medical utility. Debates in
particular
3
about other criteria. This is
more broadly
4
in terms of organ transplantation.
Some of
5
these do play a role in the context that
6
we're talking about. I mean, is it
7
appropriate to set an age limit?
It may be
8
appropriate to do that in the context, for
9
example, of a clinic trial. When
is it
10
appropriate to do that in the context of
11
therapy?
12 I might just say another word
13
about age. Sometimes that can
enter into
14
the discussion of sort of as a social
15
utility consideration. I think
we have to
16
be very cautious about that. But
sometimes
17
it may enter in as an appropriate medical
18
indicator, as a surrogate for some other
19
things, but probably would then need to be
20
examined more carefully.
21 Ability
to pay has come up as a
22
considerations in our discussions so far.
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1
Clearly the context in the U.S. is different
2
from the one in Canada. Even
when we talk
3
about being eligible for third‑party
4
reimbursement, we still have to recognize
5
again the 45 million who are uninsured at
6
any one time in the United States, and in
7
any given year, the 20‑plus million who pass
8
through that group of 45 million.
9 The UNOS
proposals, Jim Burdick
10
has nicely discussed already. So
I'll just
11
simply touch on a couple points in relation
12
to them. There was here a
recognition of a
13
need for a more uniformed system because of
14
the large number of variances that have been
15
granted by two OPOs for groups trying to
16
address islet transplantation.
17 The proposed big change has
18
already been discussed, and I won't go
19
through that. Jim discussed this
and other
20
matters quite well. I'll would
just note a
21
couple of other points.
22 After admission, the waiting list
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1
for islet transplants. Priority
would be
2
set by waiting time alone in the proposal.
3
So there's elimination of HLA matching.
4
Elimination of statuses, non‑urgent and
5
urgent. I think this has been a
problem
6 throughout organ
transplantation, and where
7
much of, if there were concerns about
8
justice in the United States related to
9
access to organ transplants, actually much
10
of the concern arises to the level of the
11
admission to the waiting list.
That's where
12
there's a lot more discretion.
13 Once the person's on the waiting
14
list, then the criteria that have been laid
15 out, defended
publicly and developed with
16
public input, obviously with expertise being
17
primary, then those criteria have been in
18
operation. But the admission to
waiting
19
lists has been a much more controversial
20
matter. And I would just note,
and Jim may
21
want to speak to this ‑‑ he's already left
22
so he can't speak to it ‑‑ that I didn't see
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as much in the proposals addressing this.
2 The ownership question, the
3
question of property has been an important
4
part of our discussion. It's
traditional
5
among legal philosophers to think about
6
property as having to do with a bundle of
7
rights of ownership. Some I've
seen list as
8
many as 20 or 25 different aspects of
9
ownership. They include right to
use, to
10
exclude others from using, to transfer by
11
gift, transfer by sale, and so forth.
But
12
there are many situations where we set
13
limits as a society on the exercise of
14
property rights or what will count as a
15
property right.
16 For example, it's my automobile,
17
but I can't go out and set it on fire in the
18
parking lot. There are certain
things
19
society won't let me do. I can't
destroy it
20
that way. In the U.S., we have,
in the
21 National Organ
Transplant Act, banned
22
transfer by sales. That came in
in the
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1
mid‑1980s. Arguably, it
was not illegal in
2
most states following the Uniform Anatomical
3
Gift Act to sell organs until the mid‑1980s,
4
when the National Organ Transplant Act was
5
passed.
6 Who owns donated organs? In cases
7
of directed donation, obviously, this is
8
being directed to a particular individual,
9
then the procurement and transplant team
10
exercise a trusteeship over those organs for
11
that particular individual unless the
12
original donor gives a different direction.
13
But most of the cadaveric or deceased organs
14
are now undirected donation.
15 The task force on organ
16
transplantation, as Jim Burdick mentioned
17
yesterday, offered a philosophical view that
18
we should think about donated organs, where
19
there hasn't been directed donation, as
20
belonging to the community. The
21
professionals involved in procurement and
22
transplantation are trustees or stewards of
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1
those donated organs for the public welfare.
2 Doing this for the public welfare
3
then brings into play both medical utility
4
and also justice. The criteria
used for
5
allocating the organs should be set with
6
expert, but also public participation.
The
7
criteria should be developed in public.
So
8
the comments that have been offered now on
9
the most recent proposals have been public
10
comments and have included not only expert
11
opinion, but, broadly, public responses.
12 Now, I would just note that UNOS
13
in its proposal for allocation is also
14
offering perhaps an optimistic view that it
15 can expand the
donor pool. We've already
16
talked a bit about expanding in moving to
17
over 50 years old and a body mass index
18
over 30 in an effort to reduce the wastage
19
of pancreata.
20 As you've already heard data about
21
how few are obtained even if the
22
individuals, in donating organs, did not
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1
exclude those, they're not obtained with the
2
frequency that should be the case.
Then
3
there's also an interest in, and some
4
supposition about, possibly increasing
5
donation. Now, this has been a
problem in
6
the United States, and this is probably in
7
much of the world, and that is how we can
8
increase the organs. Especially
now as we
9
move into areas like islet transplantation;
10
we not only have the needs that are already
11
being unmet for organs, but also we need
12
more organs.
13 There are several different ways
14
that have been implemented or proposed for
15
obtaining organs. Express
donation is the
16
one we use in the United States by the
17
individual while alive through
a donor card,
18
or documented gift, or by the next of kin
19
after the individual's death.
20 We do have presumed donation for
21
corneas in at least a dozen states when the
22
bodies are under the auspices of the medical
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1
examiner's offices. These have
been held to
2
be Constitutional by the Supreme Courts in
3
Georgia and Florida, and the U.S. Supreme
4
Court let them stand as well without an
5 explicit
hearing. It's not clear whether
6
those really are presumed donations; that is
7
whether the silence really means that the
8
individuals were willing to have their
9
organs used for others, or whether the
10
individuals were silent because they didn't
11
know they had the option. In
which case, it
12
may not be presumed donation but more like
13
routine salvaging, with the possibility of
14
opting out if you are aware that you have
15
that option.
16 Of course, Jim Burdick said we may
17
have to come back to the issue of sales and
18
purchases, which obviously many people
19
proposed as a way to deal with this
20
shortage, but as a way that been excluded in
21
the United States.
22 In conclusion, let me just note
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that I think that as we continue to reflect
2
on these areas, we have to think through the
3
broad general principles that are relevant
4
for our efforts here. In
particular
5
thinking about allocation, I've focused on
6
medical utility and on justice.
7 I think
that there are also the
8
precedents, and part of what we're trying to
9
do in this discussion is see what will
10
really count as a precedent for our
11
reflection here. And that's in
part
12
complicated by virtue of the governmental
13
and professional roles involved.
But it's
14
also complicated because actually, the way
15
we approach a particular area like organ
16 transplantation, and
then how islet
17
transplantation came in, we do transfer
18
concepts and we bring new activities under
19
those concepts, and this is one where I
20
think it is appropriate to have a good broad
21
debate about how best we can understand
22
what's going on.
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1 There's still developments in
2
science that are occurring that will
3
obviously will have an impact on the
4
relevant ethical judgments.
5 In terms of the competing
6
concepts, I would just note, and Phil nicely
7
focused, on some of the issues in blood.
8
Selling blood is still legal, but we don't
9
use it as a practice. But even
when it was
10
used as a practice, it's interesting that
11
there was an effort to keep it from being
12
viewed as a product in a strict sense.
13 So a court opinion addressed the
14
issue of how we should think about liability
15
where the blood ends up being bad.
The
16
court held that this is not a matter of
17
product liability, but rather the provision
18
of blood is a service. We do have
19
inconsistences in the way we go about
20
approaching things, and I think that what
21
we're trying to do, as has already been
22
suggested, is find a way that we can
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1
adequately address the critical and
2 important patient
needs here. And I would
3
emphasize those under medical utility and
4
justice, in a way that address the kinds of
5
constraints and limits as well as directions
6
that are provided by our governmental and
7
professional roles and responsibilities.
8 Thank you very much.
9 DR. RAO:
Thank you,
10
Dr. Childress.
11 DR. MEYERS: I
think the longer I
12
hang around the government, the more insane
13
I get. The FDA is funded not by
a health
14
subcommittee in Congress, but by the
15
Agriculture Committee, because 100 years
16 ago, when it
started, it regulated food,
17
because many people were getting sick from
18
food.
19 So 100 years later, you still have
20
to talk to the Agriculture Appropriations
21 Committee about
funding for the FDA. Now,
22
it turns out that an egg in a shell is
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1
regulated by the Department of Agriculture,
2
but as soon as you crack the egg open, the
3
FDA regulates it. That's
insanity.
4 The same thing is basically
5
happening here, because the FDA wants to
6
regulate the islet, but it can't regulate
7
the whole pancreas. It doesn't
make any
8
sense to me.
9 If these people behind me were
10
developing a drug for diabetes, the FDA
11
would say you have to study it on 2,000
12
to 3,000 people. You could not
even bring
13
it to the FDA for approval without a huge
14 clinical
trial. Yet we're talking here
15
about a maximum of 300 people in the world
16
who've undergone this procedure.
So I'm
17
wondering if you think it's ethical to say
18
well, this is a new very interesting
19
technology, and therefore, we can bend the
20
rules or make a new set of rules for this
21
technology; allow something through with
22
such a small amount of clinical data.
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1 DR. CHILDRESS:
I'm clearly going
2 to turn that
question over to someone else.
3
But I would just say that as I understand
4
it, our task here is not to bend those
5
rules, but actually to do one very specific
6
small things. I'll ask Phil to
respond to
7
that.
8 DR. RAO:
I'll ask you to hold
9
for ‑‑
10 DR. CHILDRESS:
Okay.
11 DR. KURTZBERG:
I had a different
12
question. You alluded to the fact in
13
allocation that ability to pay was
14
important, and that there are 45 million
15
uninsured Americans. But this
goes beyond
16
that, because many of the insured Americans
17
will not have this procedure approved by
18
their insurance company because it is
19
"experimental." So
that's a much bigger
20
issue in the transplantation and cellular
21
therapies field.
22 MR. CHILDRESS:
I quite agree.
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But my point is that when we're thinking
2
about issues of justice, fairness, and
3
equity in allocation, we need to keep in
4
mind that sort of all these circles, and who
5
gets in and who gets out. I quite agree
6
with the point you're making here though.
7 DR. NOGUCHI:
To respond to
8
Abbey's concern here, in no way do I think
9
that we're asking, nor would we ever be
10
asking, for bending of the rules, because
11
the rules have based on well over 100 years
12
of conflict throughout this nation and
13
people have died because of them, and have
14
led to the implementation of these rules.
15 What we are saying is that in the
16
very broadest sense, the Food, Drug and
17
Cosmetic Act gives us authority to regulate
18
articles intended to affect the structure
19
and function of a body, its amelioration,
20
prevention, et cetera, disease, for a
21
specified indication. I think
that is the
22
key; that there are many components to this.
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1
We can approve that which works for a very
2
specific thing or we can improve things for
3
broader indication.
4 In the case of vaccination, we
5
approve it to prevent disease in literally
6
every child that goes to school in this
7
country. Those are all part of
the same
8
rules. We do not bend the rules
for any of
9
them. But we are very specific
in requiring
10
that when something is approved by the FDA,
11 that it works in the
intended indication,
12
that it can be made in a good fashion, such
13
that the practicing physician can take heed
14
and say I expect that this will do the
15
intended effect.
16 We all know that each effective
17
therapy also has adverse events.
But I
18
don't see that we are in any way bending any
19
rules. We are exploring the
edges of our
20
authority. We are asking the questions of
21
does this make sense, or does this not make
22
sense. Dr. Childress has
illustrated to us
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1
very broad basic ethical concepts which are
2
inherit in everything that we discussed.
3
But I assure you, Abbey, we are not going to
4
be bending rules.
5 DR. RAO: Did
you have a comment?
6 DR. HARLAN:
Yes. I'd like to
7
comment on one bullet of one slide that said
8
part of the ethical consideration is
9
comparing existing therapies with
10
experimental therapies. That's
the point
11
that for Type 1 diabetes over the last 20
12
years, and perhaps Dr. Sherwin would
13
comment, the prognosis for this disease has
14
clinically, significantly, statistically
15
significantly, and quite dramatically
16
improved.
17 So that as we consider
18
less‑established therapies in the ethics of
19
this, we have to consider the fact that this
20
is not a disease like x‑links (?) skid, or
21
liver failure, or heart failure.
As bad as
22
it is, and I will with God as my witness say
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there's nobody in this room that wants the
2
cure of the disease more than I do, but it
3
is a disease that is imminently treatable
4
with a excellent long‑term prognosis now
5
much better than it was even 20 years ago.
6
That's statistically documented.
7 DR. CHILDRESS:
We do have
8
justification for going forth with clinical
9
trials. I assume you're not
disputing that.
10
It may be important to have options open to
11
people who may find if there is something
12
that could be successful, that could in
13
terms of their quality of live, et cetera,
14
make a difference.
15 DR.
RICORDI: Yes. As good as
16
these treatments are, there are still
17
over 1,000 people dying everyday from
18
diabetes, and the subgroups that we are
19
addressing are clearly the higher risk.
So
20
I think that is an established point.
21 By my comment was that I think
22
there is a common misconception that when
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you use more than one donor for islet
2
transplant, you're wasting precious organs
3
that could have cured individual
patients
4
through organ transplantation.
Because in
5
fact, this is done with organs that are
6
discarded that are suboptimal.
7 This is an argument that is
8
advanced by pancreas transplant surgeons
9
generally that is becoming common sense a
10
way to ---- islets is for organs, or two or
11
three, or one and half. When
instead the
12
retransplant rate in pancreas
13
transplantation reaches 25 percent; that is
14
done with perfectly good first choice, first
15
pick organs. So I think that is
one thing
16
to consider.
17 DR.
CHILDRESS: Can I respond? I
18
very much agree with that.
Certainly the
19
UNOS criteria that are being proposed are an
20
effort basically to do that, and one could
21
debate then whether specific criteria
22
actually do exactly what they're after,
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1
because in the U.S., we obviously have
2
complications of the local, regional,
3
national, and a lot of other things play
4
into this. But certainly the way
the
5
criteria have developed, they are really an
6
effort to deal with and to incorporate now
7
organs that would not have been otherwise
8
used, and to make them primary in the
9
allocation process.
10 DR. RICORDI:
A proposal that I
11
advanced in discussions with Salomon and
12
others is that you can establish some kind
13
of equal distribution in a small subgroup of
14
donors that are not generally used for
15
pancreas for the first pancreas.
But then
16
if you need a supplemental dose to take care
17
of the last six units of insulin, you can
18
use an organ that wouldn't be used for organ
19
transplant. That would be much
more
20
acceptable, I believe.
21 DR. CHILDRESS:
Right, right.
22 DR. SALOMON:
I think that has to
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amplified. I mean, the data
you've heard
2
today shows that conservatively, 70 percent
3
of pancreas organs every year today are not
4
being used. So the premise that
there is a
5
large number of pancreata that would not be
6
used for anyone that could be used for
7 supplemental
transplants is perfectly borne
8
out by the data. So really what
we are
9
talking about is competing fairly for the
10
good pancreata for the first transplant.
11 DR. CHILDRESS:
I would just note
12
on that, that that figure goes up depending
13
on the age group, too. The age
group of the
14
potential donor. It's about 62
percent
15
overall not obtained, and then as you move
16
in the age group, it goes higher.
17 DR. SALOMON:
Just to reiterate
18
what Bernhard told you, if you take the BMI
19
of 28 or greater, the statistics are that
20
less than 10 percent of those are taken.
21
That means 90 percent are not used.
If you
22
go to 30 or greater, it's 97 percent are not
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taken.
2 DR. RICORDI:
Moreover, if you
3
count the pancreases or the number of
4
recipients that can be done under INDs, for
5
islet transplantations, your counting is
6
between 6 and 12, or maybe 20.
So this is
7
out of the 6,000 possible donors.
It's much
8
more ethically difficult to accept that if
9
you have these few patients on which you can
10
test in your therapy, you impose them to
11
perform that with suboptimal or bad
12
pancreases. That is what you are
trying to
13 address.
14 DR. MULLIGAN:
Yes, from an
15
ethical point, this issue of allocating
16
pancreases for either organ transplantation
17
versus islet cells, is there a case that
18
this composition as a group that makes
19
decisions ought to be looked at in more
20
detail? I mean, you made some
comments
21
about the sense that the community owns
22
these things. Seems to me these
are
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critically important decisions.
2 DR. CHILDRESS:
This I think picks
3
up a point that was made earlier.
I have
4
not looked at the current composition of
5
UNOS. You did hear a few
comments from Jim
6
Burdick, UNOS's board of directors.
But
7
then there are also the committees.
The
8
committees play a very, very important role.
9
And you don't have to member of the board of
10
directors to be on the committees.
So there
11
are different layers of development.
12 Given the size of the board of
13
directors, often a very carefully
14
thought‑out subcommittee report to a
15
committee, and then the committee report to
16
the board of directors will be adopted if it
17
seems to be plausible. So there
are the
18
different levels of participation.
I've not
19
looked at the board composition or the
20
committee composition for our purposes today
21
to be able to make some judgment.
22 But I think the point that's been
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made and I think Jim Burdick heard it as
2
well, to go back and look into this and make
3
sure ‑‑ and the reason you want to make sure
4
that you have representation is you want to
5
make sure that all the relevant concerns get
6
identified and adequately addressed.
7 DR. O'FALLON:
I presume it's true
8
for all organ transplant situations that we
9
recognize that there aren't enough organs
10
for the patients that require the organs.
11
Clearly, the group that you have
12
participated in for these years must have
13
had some very serious ethical discussions
14
regarding this matter. I realize
you
15
presented some of these points, but how do
16
we move forward? This seems like
to me at
17
times almost an impossible ethical dilemma
18
to address.
19 DR. CHILDRESS:
You're approaching
20
it on the procurement side, the shortage
21
scarcity generally. UNOS is
under contract;
22
the organ procurement and transplantation
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network. Much of the discussion
we've had
2
focuses on the allocation issues, because
3
that's clearly a set of issues that will
4
arise when you have situation of scarcity.
5
But then you're quite right, and I just
6
mentioned a couple of points in passing that
7
if you can increase the available supply,
8
then obviously we need to take steps to do
9 so.
10 Interestingly, the proposals over
11
the last 15 years, ranging from required
12
requests to routine referral, to this, that,
13
or the other, have actually only modestly
14 increased the
supply of cadaveric or
15
deceased organs. We in the
United States
16
have moved much more rapidly toward the use
17
of living donors. Now we have
more living
18
donors than we have cadaveric donors; that
19
is acts of donation. Clearly you
get from
20
the cadaver many more organs.
21 I have just listed some of the
22
options in terms of structures or modes of
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transfer. I guess the big
question is, I
2 think we're at the
point of keeping
3
expressed donation as the model for the
4
foreseeable future. It's very
difficult to
5
find effective ways to increase that.
Now,
6
if we're talking about organs for brain‑dead
7
donors, we only have about 12,000 to 13,000
8
of those each year in the United States.
9 So from one standpoint, we may not
10
be doing that badly, getting about half of
11
those. From another standpoint,
50 percent
12
lost to the possibility of benefitting
13
others is a serious problem.
14 DR. RAO: I
think there were
15
several issues raised. It's
something which
16
is sort of awkward in the sense that it's
17
something which is not directly under the
18
control of the FDA even if it was regulated.
19
This is this whole process of allocation.
20 But I want to make sure that we
21
get the issues and allocation clear, in my
22
head at least. There's an issue
of a level
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playing field in the sense of how pancreata
2
are allocated. Whether the
process of islet
3 transplantation or
isolation should be done
4
in a center which also does whole pancreas
5
transplantation; whether one should extend
6
the isolation process so that we can also
7
harvest pancreata or encourage in some
8
fashion harvesting pancreata thick tissue
9
from people with a higher BMI, which would
10
not normally be considered optimal for
11
pancreatic transplantation.
12
And a whole issue in
addition is
13
how does one conform to certain sets of
14
standards in terms of getting reimbursement,
15
working with the OPTN as tissue so that
16
there is an appropriate mechanism for being
17
able to perform the whole process in a
18
reasonable way. Did that in some
sense
19
capture most issues that have been raised in
20
this discussion?
21 DR. RIEVES:
Thanks for your
22
patience this morning. We have
not had a
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break, so it does take a great deal of
2
patience to go through this. My
name is
3
Dwaine Rieves. I'm going to
somewhat shift
4
the gears. We've had a very
interesting
5
discussion that's touched on the complexity
6
of oversight, of cellular products.
7 We've touched on policy issues.
8
We've recognized a number of problems that
9
our sponsors and the governmental agencies
10
are going to have to deal with.
What we're
11
hoping to do though from here on out in our
12
discussion is talk about the clinical
13
science regardless of the policy, regardless
14
of many other issues, the clinical science
15
is proceeding, and is going to continue
16
proceeding.
17 What we want to be confident of is
18
that our sponsors, our investigators, who
19
are conducting this clinical science are
20
performing their science in a manner that
21
FDA, if need be, can verify the results and
22
can interpret the data. So from
here on
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out, we hope to obtain some feedback about
2 the realities, the
tangibles, with respect
3
to clinical testing of islet products.
4 This talk's going to brief, and
5
perhaps it's old news to many people here in
6
this room, but I think it's important that
7
we understand where FDA is coming from and
8
the principle that we apply to evaluating
9
clinical data. In my talk, I'm
first going
10
to talk about the purpose, go over the
11
regulatory background, and briefly touch on
12
the questions.
13 The purpose of our discussion as I
14
had mentioned is to obtain insight,
15
perceptions, thoughts. We want
you to put
16
on your thinking cap. Perhaps
give us
17
recommendations with respect to two aspects:
18
Clinical study design issues. If
a sponsor
19
comes to us with what the sponsor is
20
proposing is "a pivotal
study or a
21
definitive study, a phase three study," we
22
need to be able to give them some feedback.
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1 We're looking to the committee to
2
express opinions on certain aspects of
3
clinical study design, such as endpoints,
4
such as the type of design control, that
5
sort of thing.
6 As you've noted, there have been
7
clinical data collected. The
purpose of our
8
discussion this afternoon is not actually to
9
evaluate that clinical data.
That clinical
10
data was presented largely as to provide an
11
overview, an example of what's being
12
collected in the field. But the
clinical
13
data are being collected, and FDA will
14
probably have to evaluate that data.
So
15
your feedback that we get today will be very
16
useful in interpreting those clinical data.
17 The bottom
line with respect to
18
licensure. FDA examines two
major items.
19
The first is those clinical data must be
20
sufficient for the agency, the advisors, the
21
many people who provide input into the
22
licensure decision, to assess the
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risk/benefit of the product.
2 Secondly, and perhaps just as
3
importantly for our sponsors to remember in
4
the clinical development of their product,
5
those clinical studies must be designed and
6
conducted in a manner such that the sponsor
7
and the agency can work together to describe
8
the use of that product in a label, such
9
that we're able to tell the practitioner
10
what types of immunosuppressants, for
11
example; the other concomitant medications,
12
such that that claim has a reasonable
13
likelihood of being reproduced if the
14
practitioner actually uses that product in a
15
manner similar to its use in the pre‑market
16
clinical studies.
17 Everything I'm saying is coming
18
from a guidance document, or multiple
19
guidance documents actually. If
you go to
20
the FDA website, www.fda.gov/cber in
21
particular in the reading room, and look for
22
guidance documents, you'll find multiple.
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1 Here, I'm citing two of perhaps
2
the most important guidance documents with
3
respect to clinical data gathering with
4
prospects of obtaining licensure.
5 The first one is the guidance
6
called, "Guidance for Industry: Providing
7
Clinical Evidence of Effectiveness for Human
8
Drugs and Biological Products."
That's
9
important, because as you heard yesterday,
10
at the current time, islet products are
11
regulated both as biologic products and also
12
as human drugs. Consequently,
the Public
13
Health Service Act applies to it; the Food,
14
Drug and Cosmetic Act applies to these
15
products.
16 The second guidance is, "Guidance
17
for Industry: Choice of Control
Group and
18
Related Issues in Clinical Trials." The
19
last bullet on this slide highlights another
20
guidance document that's actually relatively
21
new, and is very useful for sponsors who
22
want to obtain "binding" feedback from the
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agency.
2 This guidance document provides a
3
description of the process whereby a sponsor
4
can submit a clinical protocol to the agency
5
and the agency is under a timeline, 45 days,
6
to provide the sponsor feedback with respect
7
to whether that protocol for that study will
8
be sufficient to provide substantial
9 evidence of efficacy
for the product. Those
10
comments, if the FDA determines that that
11
study is acceptable, are binding upon the
12
agency.
13 So two major aspects to clinical
14 development are
products, from an FDA
15
regulatory standpoint, risk/benefit analysis
16
and the ability to write a label.
17 The next several slides concern
18
the risk/benefit assessment. A
dichotomous
19
concern here. One is obviously
safety, but
20
I put substantial evidence of effectiveness
21
at the top of the list, because that's
22
usually the greatest challenge for our
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sponsors in developing their products,
2 because obviously,
a placebo is usually
3
safe. The challenge comes in in
proving
4
that a product is not a placebo, it actually
5
does something. So it's
providing this
6
"substantial evidence of effectiveness" that
7
is so important. This terms
comes directly
8
from the Food, Drug and Cosmetic Act.
It's
9
a very carefully chosen choice of words, as
10
we'll see.
11 The Act, as
well as our
12
regulations, say that this substantial
13
evidence of effectiveness must come from
14
"adequate and well‑controlled
15
investigations." Now, the
risk aspect of
16
this, the safety aspect, the clinical data
17
that go into safety determinations, comes
18
not only from adequate and well‑controlled
19
investigations, but it actually comes from
20
the totality of the clinical database.
It
21
comes from the exploratory investigations
22
leading up to what is commonly called the
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pivotal clinical studies, or what we call
2
adequate and well‑controlled investigations.
3 The next few slides explore the
4
substantial evidence of effectiveness.
5
Expectation. What defines
substantial
6
evidence of effectiveness? It's
an
7
interesting choice of words.
"Substantial."
8
I guess whoever wrote that law could have
9
chosen "reasonable," for example. They
10
could have chosen "any evidence." They
11
could have chosen "some," but they didn't.
12
They choose "substantial."
13 So to address that question of
14
what substantial means, the FDA constructed
15
the substantial evidence of effectiveness
16
document. At the core of that
document is
17
the take‑home message that efficacy or
18
effectiveness is determined from independent
19
clinical studies; meaning that a clinical
20
benefit is reproduced in an adequate and
21
well‑controlled study.
22 You noticed
I've underlined the
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"s" here. It's a
plural. Independent
2
substantiation of findings, meaning more
3
than one adequate and well‑controlled
4
investigation assessing the efficacy of the
5
product. However, if you go to that
6
guidance document, and this is very
7
important for perhaps some of the potential
8
indications that could be constructed from
9
the use of islet products, as well as for
10
many other unusual rare diseases, there are
11
exceptions.
12 The guidance document goes into
13
much greater detail than what I'm touching
14
on here. I'm only hitting the
highlights.
15
The guidance document provides
a very
16
notable exception. When a single
study may
17
be regarded as providing substantial
18
evidence of effectiveness. I'm
going to
19
highlight what that guidance document cites
20
as one example. There are other
examples.
21
But the guidance document says a single
22
study maybe considered sufficient when that
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study shows a clinically meaningful affect
2
on mortality, irreversible morbidity or
3
prevention of a disease with a potentially
4
serious outcome, and when confirmation of
5
that outcome in a second study is
6
impossible. The implication
being that it's
7
ethically impossible to conduct an
8
additional clinical study.
9 The guidance document provides
10
what are called characteristics of a single
11
study. The example from the
guidance
12
document is large multicenter studies, large
13
sample size, multiple centers involved in
14
the clinical study; the single study shows
15
consistent findings in subgroups of the
16
overall population database; there are
17
consistent findings in multiple endpoints,
18
secondary, tertiary type endpoints; the
19
efficacy outcomes are statistically very
20
persuasive. The document notes
that none of
21
these "characteristics" are determinative.
22 For example, having simply a large
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sample size doesn't tacitly mean that that
2
study will be sufficient. The
document
3
emphasizes that the determiner is somewhat
4
more subjective, that the results from that
5
clinical studying in the proposed clinical
6
indication are strongly persuasive.
7 With respect to substantial
8
evidence of effectiveness, that information
9
must come from adequate and well‑controlled
10
studies. So the next few slides
look at the
11
definitions of "adequate and
12
well‑controlled."
Here, I've highlighted
13
what our regulations denote as the major
14
characteristics of "an adequate" clinical
15
study. I group it into three
p's, for
16
example.
17 The first p refers to the product.
18
Somewhat we touched on the importance of
19
this yesterday. For these
adequate and
20
well‑controlled investigations, the product
21
must be manufactured at a point such that
22
the data are interpretable, meaning that
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product is almost the same product that will
2 be distributed post‑licensure.
3 The study agent needs to be
4
standardized for identity, strength,
5
quality, purity and dosage form; language
6
that's applicable to drugs interpreted as
7
safety, purity, potency. The
other "p"
8
applies to the protocol, the prospective
9
nature of the clinical studies.
10 The adequate clinical study needs
11
an acceptable study design in which the
12
protocol sufficiently describes the dose,
13
the evaluations, the endpoint, analyses.
14
There are multiple other components of an
15
acceptable clinical protocol.
16 Finally, how the clinical study's
17
actually conducted. The
performance of the
18
clinical study, such that the clinical study
19
needs to be performed in a manner consistent
20
with good clinical practice such that the
21
data are verifiable. When it
comes time for
22
licensure, FDA can send out inspectors if
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need to be to look at the source documents,
2
the hospital records; can look at the case
3
report forms; can check the case report
4
tabulations and the statements that are
5
actually submitted to the agency.
And that
6
we can cross‑check all that information to
7
make sure there are not transcription errors
8 for example, the
wrong numbers plugged into
9
the data set. It's a very
important aspect
10
of our job.
11 The other component of the
12
adequate and well‑controlled phrase there.
13
The "well‑controlled."
What does that mean?
14
Why is it needed to be controlled?
It's
15
required in order to discriminate outcomes
16
caused by the study agent from outcomes due
17
to other factors. As you can
imagine, the
18
natural progression of the disease, the
19
observer, the patient expectation, the
20
inherent biases we bring to new products,
21
and the impact of concomitant therapies.
22 Within control groups, hopefully
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we can separate out these various items that
2
may influence the outcome.
3 What are the types of control?
4
They can be broadly grouped into two major
5
categories: Concurrent controls
and
6
non‑concurrent controls.
Within the subset
7
of concurrent controls, the controls may be
8
obviously a placebo control; they can be
9
active control, comparison of the
10 experimental agent to
another agent. For
11
example, a new thrombolytic compared to an
12
old thrombolytic.
13 The control could be a different
14
dose. It could be a multiple‑arms
study in
15
which the primary outcome measure is an
16
attempt to examine a dose response effect.
17
A high dose compared to a low dose.
That
18
sort of thing. Or a clinical
study can use
19
a concurrent control where there is no
20
treatment, where the control arm is a group
21
of subjects who receive standard care; they
22
don't actually receive an
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indication‑specific comparator treatment.
2
An approach that's commonly done in cancer
3
clinical studies.
4 Finally, the bullets at the bottom
5
of this slide notice that FDA does consider
6
non‑concurrent clinical controls.
In
7
general, that refers to historical or
8
external controls. As you can
imagine,
9
there's strengths and weaknesses to both
10
types of controls.
11 This slide attempts to come to a
12
conclusion on balance with respect to these
13
strengths and weaknesses. As
noted in our
14
guidance document on controls, we come away
15
with the conclusion that there are
16
substantial strengths to concurrent
17 controls, and there
are substantial
18
weaknesses to historical controls.
19 The strength of concurrent
20
controls is that there is a minimization of
21
bias. In one way of thinking, in
any
22
clinical study, there's always some bias.
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There's bias inherent in the eligibility
2
criteria with respect to how a product may
3
ultimately be used. The beauty
of
4
concurrent controls is that we are able to
5
hopefully control that bias, primarily
6
through the ability to conduct randomization
7
as well as blinding.
8 With historical controls, it's
9
largely impossible to control bias.
There's
10 an inherent
selection factor in the choice
11
of those control subjects.
Consequently, as
12
noted in our document, the use of historical
13
controls is generally recommended only when
14
there is thought to be a profound treatment
15
effect and the course of the disease being
16
examined is highly predictable.
Such as the
17
data are highly persuasive.
18 Then the other aspect of licensure
19
considerations ties into an acceptable
20
safety. We certainly cannot
ignore the
21
safety considerations, even though they
22
perhaps maybe a little bit easier to obtain
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in terms of clinical trial design.
But
2
major considerations in reviewing a clinical
3
safety database ties into consideration of
4
the subject characteristics. For
example,
5
if our sponsors use a laundry list of
6
eligibility criteria such that there are
7
definitive clinical studies are only
8
performed among a very, very select subset
9
of the potential population who may desire
10
to receive this product, is it appropriate
11
in the label to generalize those findings
12
from that very small subset to a larger
13
subset, or should we try to attempt to
14
construct a package insert, a label, that to
15
a certain extent reiterates the eligibility
16
criteria? We prefer not to do
that.
17 We prefer that our sponsors take
18
into consideration the potential
19
generalizability of their data in the design
20
of their clinical study.
21 What about the number of subjects
22
and the extent of exposure in these
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subjects? Should the sample size
be small?
2
Certainly on common diseases, we anticipate
3
seeing small sample size databases.
4 Questions with
respect to the extent of
5
exposure. For chronic diseases,
the
6
question of how long and how great a
7
exposure to the experimental agent should be
8
obtained is always on the table.
That's one
9
of the issues we hope to address this
10
afternoon.
11 Diabetes is a chronic illness. Is
12
it reasonable to license a product where we
13
have clinical data from one year?
Do we
14
need two years before we can sufficiently
15
even address the question of a risk/benefit
16
of assessment. The duration of
follow‑up
17
sufficient for a chronic disease.
18 In
licensure consideration, as I
19
noted, two big aspects: The
ability to
20
assess the risk/benefit, and are the
21
clinical data sufficient for us to write a
22
label.
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1 With respect to the labeling
2
aspects, the label, the package
insert
3
should contain, "a summary of scientific
4
information needed for safe and effective
5
use of the product." That
generally applies
6
to clinical data. Occasionally,
animal data
7
are included in the package insert,
8
especially with respect to reproductive
9
toxicity, the other carcinogenicity‑type
10
issues.
11 Aspects of the label. The major
12
aspects are noted here. There
are subsets
13
within these aspects. The label
14
considerations. The sponsor
should generate
15
clinical pharmacology data.
There is a need
16 for pharmacokinetics, the description of
17
pharmacodynamics of the products.
There is
18
a need for a clinical studies sections.
For
19
islet products, this may be especially
20
important, because that clinical study
21
section would describe the types of
22
immunosuppressives that were used, the
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1
dosages, that sort of thing.
Information
2
that the practitioner will need to have
3
access to to use the product sufficiently.
4
Of course, the label
needs to
5
state the indication and usage, which is
6
sort of at the heart of FDA regulation.
The
7
ability to authorize a sponsor to make a
8
claim about their product. The
label will
9
contain contraindications, describing those
10
situations where the product should not be
11
used. Of course, warnings,
precautions,
12
adverse reactions, overdosage of use.
13 Finally, a
description of the dose, the
14
cellular dose, and the administration
15
directions.
16 Getting back to the core aspect of
17
the label, meaning the indication, the
18 claim, which
conceptually may be one of the
19
benefits of licensure is that there is an
20
imprimatur to make a claim about a product.
21
All indications shall be supported by
22
substantial evidence of effectiveness based
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1
on adequate and well‑controlled studies. A
2
lifting here from the regulations.
3 So the purpose of our discussion
4
this afternoon is not so much to talk about
5
deficiencies in the policies of how these
6
products are regulated. I think
those
7
questions are pretty obvious to everyone in
8
this room.
9 What we're hoping to do is to get
10
insight from the panel members, thoughts,
11
perceptions, recommendations even, such that
12
we can go back to our sponsors, give them
13
feedback and try to advance the field to
14
help FDA help interpret the data our
15
sponsors are generating, as well as to help
16
FDA to try to steer our sponsors into
17
collecting the data such that we can resolve
18
this issues of licensure.
19 As we noted, there's no assessment
20
of the presented data. The
questions are
21
briefly summarized here. The
very first
22
question that we're going to ask the group
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1
to discuss, to comment upon, deals with
2
endpoints for these definitive clinical
3
studies. Is insulin independence
‑‑ meaning
4
simply the avoidance of exogenous insulin,
5
for example, is that a sufficient primary
6
endpoint on which to make a claim of
7
efficacy, for example? Or is the
avoidance
8
of life‑threatening hypoglycemia?
There are
9
many potential indications, endpoints that
10
could be examined here. We need
feedback on
11
those issues.
12 Other clinical development
13
concerns are noted in question number two.
14
It deals with the requisite length of
15
follow‑up. Is there a
certain period of
16
time that FDA really should have follow‑up
17
even before we make that assessment of a
18
risk/benefit. Meaning at least
one year,
19
for example. At least two
years. Give us
20
your thoughts, perceptions on the duration
21
of follow‑up.
22 The
use of historical controls.
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1 It's going to be
a pretty obvious question.
2
Is it applicable? Is it
reasonable to use
3
historical controls in this setting?
Do you
4
envision claims indications that, by their
5
very nature ‑‑ for example, fear indicies,
6
that sort of claim ‑‑ could that be based on
7
historical control, or would we need a
8
concurrent control? We need
feedback on
9
these types of concerns.
10 Then
of course, we want your
11
thoughts on the generalizability of data and
12
how the data could be used in a package
13
insert, for example, where it looks as if
14
our sponsors may study a very small subset
15
of people with Type 1 diabetes.
So your
16
thought perceptions are greatly appreciated
17
in that respect. I think that's
my last
18
slide. That's it. Thank you for your
19
attention.
20 There are lots of questions here
21
and FDA certainly cannot answer them all.
22
But we hopefully can address some of the
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1
questions related to clinical development of
2
islet products. Thanks.
3 DR.
RAO: We had no requests for
4
any comment from the public. Is
there
5
anybody who'd like to make a comment?
In
6
that case, I propose we adjourn for lunch
7
and then take up the discussion of the
8
questions after that.
9 (Whereupon, at 11:02 a.m., a
10 luncheon recess was taken.)
11 *
* * * *
12
13
14
15
16
17
18
19
20
21
22
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1 A F T E R N O O N
S E S S I O N
2 (12:10 p.m.)
3 DR. RAO:
We'll begin the final
4
part of this meeting. This will
be the time
5
to see if we can address some of the issues
6
specifically regarding the clinical data
7
part of the issues that FDA raised.
8 In terms of starting the
9 discussion,
what I'm going to try and do is
10
ask Dr. Sherwin to make a couple of comments
11
on issues, and just following up on diabetes
12
and what kind of lead‑outs he feels one
13
needs in cases of patients who have had some
14
kind of transplant. Maybe we'll
use that as
15
a starting point to look at things.
16 DR. SHERWIN:
Well, these are
17
unprepared remarks. Just to begin,
there
18
are two types of diabetes. One's
an
19
autoimmune disease that destroys the beta
20
cells. There's another kind of
diabetes
21
that affects the majority of people that is
22
due to beta cell failure in the face of
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1
insulin resistance.
2 We're really talking about
3
treatment of the former, where there's
4
specific beta cell loss. But the
5
complications of diabetes are not that
6
different, at least the long‑term
7
complications, which take many years to
8
develop. They involve the small
vessels
9
that principally involve ‑‑ from a clinical
10
perspective, although they involve all the
11
vessels in the body, the retina, and kidney,
12
and consequently, one can ultimately see
13
blindness in about 30 percent of patients,
14
ultimately legal blindness.
15 About 30 percent of people develop
16
kidney failure with Type 1 diabetes, and
17
neuropathic complications occur.
All these
18
complications tend to develop over an
19
extended period of time. Most
20 complications, the retinal and renal
21
complications, really start to occur after
22
the first decade and really are into the
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1
second decade. Consequently, the
slow
2
development of those kinds of complications
3
mean long‑term studies. So
that's a
4
difficult thing to deal with.
5 The other complication that leads
6
to death in most people with diabetes is
7
actually cardiovascular disease.
That's
8
even true for patients with Type 1 diabetes
9
as well as Type 2. There's a
much higher
10
rate of heart attack and stroke.
And
11
clearly, women are disproportionally
12
affected because they lose their protection,
13
as a woman, from cardiovascular disease. Of
14
course, that also develops very gradually,
15
and making assessments of impact on that is
16
not an easy thing and requires long‑term
17
studies such as the DCCT.
18 There are then these short‑term
19
complications. The major one
that one deals
20
with in this setting of islet
21
transplantation today is the problem of
22 hypoglycemia in
patients with Type 1
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1 diabetes. I should
point out that there are
2
more patients with Type 2 diabetes who are
3
on insulin than Type 1.
Nevertheless, the
4
complication of severe hypoglycemia is much
5
more common in Type 1 patients.
The reason
6
for that is that those patients are not
7
insulin‑resistant, number one, or generally
8
not. Number two, they develop
9
counter‑regulatory defects that increase
10 their
susceptibility.
11 So as soon as a patient with
12
Type 1 loses their beta cell function, their
13
alpha cell function is lost as well.
14
Consequently, they have no glucagon response
15
to hypoglycemia, and that's a very
16
consistent finding in patients that do not
17
have beta cell function.
18 The other thing that happens to
19
these patients is, as they become more
20
susceptible to hypoglycemia and as we try to
21
treat them more aggressively today, they
22
develop loss of their other key
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1
counter‑regulatory hormone, epinephrine.
2 This adrenal medullary defect is
3
due to hypoglycemia itself, and perhaps due
4
to the disease itself, which people haven't
5
emphasized as much, but there is a loss of
6
adrenal medullary function that combines
7
with the lose of glucagon and the inability
8
of the beta cell to regulate itself and
9
reduce its own insulin secretion, so
10
hypoglycemia becomes a problem.
11 Now, the major reason we encounter
12
this is because our methods of
delivery of
13
insulin are unphysiologic, as I'm sure you
14
well know. So that we try in
good practice
15
to simulate physiology as best we can by
16
delivering insulin subcutaneously.
And
17
there are a number of different systems that
18
have evolved to try to deliver insulin
19
physiologically, and the problem we face
20
clinically is that we don't have a feedback
21 control system,
so we rely on the patient's
22
compliance with frequent monitoring of
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1
glucose, but it's impossible to get as many
2
readings as one would like to function to
3
like a beta cell.
4 A beta cell has its own sensor and
5
can continually adjust its secretory rate,
6
something we cannot do by insulin delivery.
7
Consequently, even though we deliver insulin
8
more physiologically and more effectively,
9 we often don't
overcome the problem of
10
hypoglycemia. This has been the
major
11
impediment to our ability to effectively
12
treat diabetes.
13 We do know that treatment matters.
14 Clearly, the DCCT study,
which was a
15
beautiful study that was conducted by NIH,
16
clearly demonstrated benefits in terms of
17
the classical complications of diabetes. I
18
think the UKPDS data and the EDICTS
19
follow‑up studies from the DCCT provide
20
soft, but some evidence I think that
21
cardiovascular disease can be improved by
22
controlling glucose.
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1 The other thing that is
2
interesting from the EDICTS study was that
3
in those patients that were aggressively
4
treated for the 6‑1/2 years, once they got
5
off that kind of regimen where they weren't
6
followed as closely and their glucose levels
7
rose to the levels seen in the control
8
group, the benefits seemed to persist for an
9
extended period of time.
10 So there was some memory effect or
11
some benefit, even from that intervention
12
over a six‑ or seven‑year period, which
13
seemed to lead to some benefit.
14 So from a clinical perspective,
15
most patients can be treated effectively I
16
think with the regimens we have today.
17
Between insulin pumps, and long‑acting and
18
short‑acting insulins that have been
19
recombinant insulins. I think
the majority
20
of patients do reasonably well.
I think we
21
can have a significant impact on their care.
22 Now whether an islet transplant
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1
would be a more effective way of treating
2
these complications is up for grabs I think
3
at this point. I'm not sure.
4
Theoretically, I think the control is
5
better, but what the downside is in terms of
6
the drugs that are used with the islet graft
7
are really up in the air. So
from the
8
standpoint of long‑term complications, I
9
don't think we know which approach would be
10
a better approach in the long run.
11 Really, that will require a
12
long‑term clinical trial, head‑to‑head
13
perhaps, to really look at this
issue if
14
islet transplantation really became
15
available to a large group of people.
I
16
think what we're talking about today,
17
however, is a specific problem; namely,
18
severe hypoglycemia, hypoglycemia
19
unawareness.
20 That problem is in many cases
21
hyatragenic (?) and probably could be dealt
22
with by seeing specialists who are perhaps
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1
expert in this area. Some of
these patients
2
probably would benefit from more
3
physiological insulin delivery systems, and
4
perhaps a lot of their serious problems ‑‑
5
they'd still have hypoglycemia, but the
6
serious problems might be diminished by
7
better medical care.
8 There are some patients who even
9
in the best care don't do well.
It is, from
10
a psychological perspective, knowing
11
patients who suffer from that problem, it
12
has a tremendous impact on their ability to
13
function normally. Or for
children, surely,
14
for parents to deal with the problems.
So I
15
think there are a subgroup of patients that
16
theoretically could benefit from this.
17 I think that looking at whether
18
you could actually document and clearly
19
demonstrate superiority of this approach, I
20
believe it could occur. It could
occur in a
21
relatively short time from the perspective
22
of hypoglycemia. Then the
problem is if the
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1
primary indication is hypoglycemia, how long
2
would you need to look at this to really
3
resolve that question? It wouldn't take as
4
long as the chronic complications,
5
obviously, because these are acute events.
6 The problem is detecting them and
7
really documenting that indeed you're
8
dealing with hypoglycemia, because many
9
patients experience symptoms which they
10
attribute to hypoglycemia and may even feel
11
better after eating, but that doesn't always
12
mean that they have hypoglycemia.
13 Then there are a lot of patients
14
who are unaware of hypoglycemia.
And I
15
should point out that these events that do
16
occur frequently in these patients, the
17
long‑term consequences of that over one's
18
lifetime are not clearly established.
It's
19
clear that for young children who have
20
hypoglycemia, I think, before the age of
21
five or six, and I have pediatricians here
22
to back me up one way or another ‑‑ clearly
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1
there in the developing brain, episodes of
2
hypoglycemia are serious, and will have an
3
impact on long‑term function cognitively.
4 As far as adults, it's not clear.
5
The studies from the DCCT over a period
6
of 6‑1/2 years didn't show any differences
7
between those people who had severe
8
hypoglycemia and those that did not.
But
9
these were young people, young adults, and
10
we have no idea when they reach middle age,
11
and now they will with our therapies, how
12
they will function; whether they'll be
13
premature, senescence, things like that, we
14
have no clue about.
15 So I think the story about what
16
the impact in adults of hypoglycemia is a
17
question that remains unanswered.
So the
18
problem then becomes if this clinical trial
19
is going to deal with hypoglycemia, it's a
20
new ballgame. It's difficult,
because A1C
21
is not enough. A1C is very
important,
22
because if you're not achieving hopefully a
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1
normal A1C, for example, if you're given an
2
islet transplant and you don't normalize
3
A1C, you'll reduce hypoglycemia because you
4
have a higher glucose. A1C
becomes a
5
problem. It's a very important
one from the
6
standpoint of long‑term benefit, clearly,
7
for patients. But if the
indication becomes
8
hypoglycemia, it becomes not the whole story
9
by any means.
10 Then the question is how does one
11
define hypoglycemia. How do you
design a
12
clinical trial that will adequately
13
determine it? If you have high‑risk
14
patients, you need to do a power analysis
15
obviously, and I haven't even begun to do
16
that in my head. But I suspect
that if you
17
had patients that had two events at least
18
per year, that it wouldn't take too long to
19
sort out, because it'll be a striking
20
difference in the incidence. So
that would
21
be one criteria that one could use.
22 There are criteria that people
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1
have developed for hypoglycemia; going to
2
the emergency room, needing IV glucose,
3
needing glucagon, et cetera;
hopefully with
4
a documented glucose as well.
5 DR. SALOMON:
Can I just ask you a
6
question as long as you're on that line.
7
It's not two episodes a year, it's two
8
episodes a month more typically in these
9
patients, isn't it?
10 DR. SHERWIN:
Well, severe
11
hypoglycemia that requires help, emergency
12
room?
13 DR.
SALOMON: You didn't add the
14
emergency room thing in there. I
don't know
15
enough to say that they end up in the
16
emergency room. But patients I
had ‑‑
17 DR. SHERWIN:
I thought the
18
criteria is ‑‑
19 DR. SALOMON:
Who have been on
20
that close to the line had at least one to
21
two episodes a month.
22 DR. SHERWIN:
Oh, sure they have
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more than that.
2 DR. SALOMON:
At least one of
3
those episodes a month, they end up with the
4
paramedics in their bedrooms, but I don't
5
about whether they actually end up in the
6
ER.
7 DR. SHERWIN:
I don't know. Maybe
8
I'm wrong. I thought your
criteria was at
9
least two events a year.
10 DR. HERING:
I think this is
11
correct. This is two events a
year. I
12
think I wanted to emphasize one point.
13
Patients make a serious effort and measure
14
glucose levels every two hours, including
15
during the night, in order to avoid
16
hypoglycemia. So I think really
the
17
lifestyle is clearly affected. I
think that
18
is how they can avoid more episodes of
19
severe hypoglycemia.
20 I think you have to understand
21
this as well and take this into
22
consideration. That is why I
think
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documenting absence of symptom perception,
2
neurogenic symptom perception, I think that
3
is one way of looking at this.
Or in the
4
setting of a clinical trial, I would ask a
5
question whether there is an epinephrine
6
response to developing hypoglycemia.
If
7
this response is lost in addition to the
8
glucagon response, which is lost in 100
9
percent of all people with 1 diabetes
10
within 5 or 10 years, this will help
11
identify this subgroup that let us
12
basically ‑‑ not in a position to develop
13
any symptoms, any warning symptoms anymore.
14
That would define this, and whether they
15
have episodes of severe hypoglycemia
16
requiring assistance or not should not
17
really be the only criterion that is of
18
importance.
19 DR. SHERWIN:
Well, I think you're
20
right in part. You could set up
criteria of
21
epinephrine response that was less than 20
22
percent or 10 percent of normal.
But most
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1
people that we treat with insulin pumps have
2
suppressed epinephrine responses. They have
3
no glucagon and still, they don't end up in
4
emergency rooms. They do
okay. I mean,
5
they don't do perfectly. They
may do better
6
with a transplant. I accept
that. But
7
that's another issue.
8 Getting back to the point. One
9
possibility is to clearly document
10
hypoglycemia and severe as the easiest way
11
to do it. The other is to think
about, in a
12
trial which I never heard of doing really
13
for FDA would be using sensors as a way of
14
really picking up. Even though
there are
15
deficiencies in all these glucose sensing
16
devices, although they're approved, they're
17
not perfect. You'll false‑positives,
18
false‑negatives. But if
you have a good
19
comparator, you should be able to
20
distinguish easily between the two, I think.
21 That might be very helpful as well
22
in terms of trying to sort out what's going
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on. I'll stop. I took too long.
2 DR. RAO: Let
me try and see if
3
I've summarized some of the points that
4
you've made and trying to keep a little bit
5
more general in terms of the issues.
The
6
issue at least I thought I was trying to
7
address in this case was, you've decided on
8
some criteria, you've selected a set of
9
patients, and you've decided that you're
10
going to use islets for transplant.
11 DR. SHERWIN:
Yes.
12 DR. RAO: Now
we're going to
13
follow these patients after they've been
14
transplanted over a certain time period. We
15
want to ask ourselves, well, they were
16
diabetics before, so there's a certain set
17
of tests that we were going to follow
18 routinely that's
sort of standard of care
19
that you would do. Those would
be things
20
that you might have to follow.
21 As you rightly pointed out, there
22
are very specific tests that you need to
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consider, and perhaps one of the things that
2
was not considered was looking at
3
cardiovascular abnormalities that might
4
occur in a long‑term patient.
5 Over and above what would be
6
standard, perhaps there would additional
7
specific tests that one would want to
8
consider in any person who's had islet
9
transplant. One obvious thing
that came to
10
mind in my mind was how do you monitor the
11
immune suppressed state? Should
one be
12
monitoring that because that's an important
13
criteria in terms of success versus failure?
14 Should that be a criteria that the
15
committee might feel that makes sense or is
16
important? Is the measure for
hypoglycemia
17
that is recommended here as a measure that
18
was a readout, should there be a glucose
19
tolerance test each time? Or is
it that you
20
need to look at epinephrine or glucagon?
21 What is the sense in the community
22
as to what would be a reasonable way to
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measure that there has been, and how long
2
should one follow it up on, or frequency in
3
some sense?
4 DR. SHERWIN:
Well, if you want to
5
look at recovery of counter‑regulation, the
6
best way to do that is to standardize the
7
stimulus, because it becomes a little
8
harder. But that can't be done
in many
9
places, so that creates a potential problem,
10
I suspect.
11 The key point to me is your
12
primary indication has to be hypoglycemia
13
for this kind of a study. So
those are
14
secondary issues. The secondary
issue is do
15
you restore epinephrine response?
The best
16
way to do that would be to what we call a
17
hypoglycemic clamp for maybe an hour, and
18
lower glucose to a specific level.
So you
19
standardize the stimulus before and
20
sequentially, and look at the epinephrine
21
response.
22 You're not
going to restore the
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1
glucagon response, but hopefully you could
2
restore the epinephrine response.
It
3
wouldn't take very long to show that.
You
4
could probably do it in a month and know
5
whether you've made significant progress.
6
Surely by three months, I would suspect
7
you'd be able to know pretty well what's
8
going on in terms of that, from the
9
perceptive of an islet graft.
10 DR. RAO: Do
you have a comment on
11
that?
12 DR. HARLAN:
I do. I agree
13
largely with what Dr. Sherwin said, as far
14
as inclusion criteria and an immediate who
15
should be studied. But I think
we have to
16
keep in mind that it's not just insulin and
17
hypoglycemia, but all these patients need
18
treatment with immunosuppressive therapies
19
which have significant toxicity and problems
20
associated with them. So I
really think
21
that the endpoint should be quality of life
22
measures and complication measures on an
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intention to treat basis.
Because it's a
2
very complex equation to integrate all those
3
various things.
4 DR. RAO: Is
there a standard
5
quality of life measure that the community
6
agrees on? For example, there
was this fear
7
index was something that was followed up.
8 Is that a
reasonable measure, since as was
9
pointed out earlier, hypoglycemic response
10
is the criteria we're using to select
11
patients, for example?
12 DR. HARLAN:
I believe it's
13
insufficient, because it doesn't take into
14
account what can be fairly significant
15
toxicity associated with current
16
immunosuppresives. But it points
out how
17
difficult this study would be, because as
18
Dr. Ricordi has pointed out and Dr. Hering,
19
there is no standard of care
20
immunosuppression. This is a
constantly
21
evolving business. So we start
out
22
comparing two things at the
beginning. At
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the end of the study, the
things that you're
2
comparing are irrelevant. It
makes it
3
difficult.
4 DR. RAO: Dr.
Viner.
5 DR. VINER: I
think Dr. Sherwin
6
raised another interesting point, and that
7
was the entry criteria for these patients
8
and the use of other improved metabolic
9
approaches, or more physiological
10
approaches, including insulin pumps.
I'm
11
wondering if the data that we have to date
12
approaches or addresses that issue.
13 In particular, how much better are
14
these patients doing in terms of their
15
hypoglycemia controls compared to those
16
patients that would be put on an insulin
17
pump? And should there be some
kind of
18
randomized trial that includes those two
19
different approaches?
20 DR. RAO: Hold your thought until
21
we get a response on that.
22 DR. LEVITSKY:
I think that to
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look at quality of life without a randomized
2
trial becomes impossible. I
mean, you just
3
can't do that. You can look at
objective
4
measures like episodes of hypoglycemia, if
5
you can document them, or hemoglobin A1C, or
6
glucose excursion.
7 But once you are dealing with
8
something where the Hawthorne Effect becomes
9
very important, you can not look at that.
10
These people all want their quality of life
11
to improve and will improve even if their
12
renal disease is developing. So
you can't
13
use those measures in this unless you do a
14
controlled trial.
15 DR. RAO: One
should not consider
16
a generalized quality of life measure,
17
because it won't have good predictive value
18
as a follow‑up. But
specific measurement
19
quantifiable measures would.
20 DR. LEVITSKY:
I'm not sure you
21
could use any without a controlled trial. I
22
would have to talk to someone who did those
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sorts of things for a living.
But my
2
experience with them is that they are very
3
subtle and hard to interpret and you have to
4
have a controlled group. You
can't just
5
input a change and then look at what the
6
person says about the change.
7 DR. RAO: Dr.
O'Fallon.
8 DR. O'FALLON:
Well, certainly,
9
the conversation which I thought was
10
restricted to what kinds of measurements we
11
would be interested in has gone pretty far
12
afield. We need to do a
randomized clinical
13
trial. Whether we use quality of
life
14
measurements or not is kind of beside the
15
point. Certainly there's a lot
of research
16
going on in the quality of life arena right
17
now. I don't know if any that is
specific
18
to people with diabetes, but I can imagine
19
that it wouldn't be hard to work
on some of
20
them.
21 DR. SILVERSTEIN:
There are. They
22
use the DCCT, too.
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1 DR. O'FALLON:
I just said I don't
2
know. So if there are existing
scales,
3
maybe they could be modified to take into
4
account some of the things that are going to
5
have to be hoped for as our endpoints in a
6
study of this point. But we
certainly need
7
to decide on what those endpoints are and
8
what kind of measurements we're going to
9
look at before we start deciding about
10
whether a randomized clinical trial is even
11
a possibility here.
12 DR. SILVERSTEIN:
This is also
13
just addressing quality of life.
We've done
14
studies on quality of life in children.
15
There are some validated standardized
16
questionnaires, and I don't think we need to
17
decide on which ones to use at this
18
particular time. But we did use
the
19
children as their own controls.
I
20
understand what Dr. Levitsky is saying about
21
wanting to have improved quality of life,
22
but there are some objective things.
Days
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of work missed, you know, things like that
2
that affect day‑to‑day functioning that can
3
be assessed, I think.
4 DR. RAO: I
think the FDA is going
5
to try and remind us that we want to really
6
discuss the specific outcomes measures as
7
listed here in terms of follow‑up. Go
8
ahead.
9 MR. DAPOLITO:
Actually, that's
10
exactly right. To try to keep
this a little
11
bit focused here, we're talking about
12
endpoints. There were several
items within
13
Dr. Sherwin's comments that were very
14
useful. One point I want to be
sure I have
15
clarity on, if I understand correctly, the
16
clinical meaningfulness of asymptomatic
17
hypoglycemia in adults is unclear.
That's a
18
very important regulatory status there.
Did
19
I understand that correctly?
20 DR. SHERWIN:
In terms of
21
cognition. In terms of risk,
there is a
22
greater risk. Because what
happens is that
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patients for example may have a glucose
2
of 50 and be functioning and seem fine and
3
not recognize as anything as going on.
But
4
a small change all of a sudden can throw
5
them from functioning into totally
6
non‑functioning. It's sort
of like in a
7
healthy individual without diabetes, they
8
have a lot of room as they begin to drop to
9
develop symptoms and other cues that allow
10
them to take protective action quickly;
11
whereas, these patients, the window becomes
12
so narrow between function and falling
13
apart, that there is a risk form that
14
perceptive.
15 So the risk of unawareness is
16
severe hypoglycemia, and then perhaps an
17
auto accident or something like that.
In
18
terms of whether these changes in glucose
19
that are lower than normal that they're
20
unaware of, is that impacting on how they're
21
going to function when they're 55
22
cognitively, that's what I was saying that
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we don't know about.
2 DR. RAO: Did
you want to
3
continue?
4 DR. SHERWIN:
No, no.
5 DR. RAO: Dr.
Shapiro, did you
6 have something to
add?
7 DR. SHAPIRO:
No, I was only going
8
to comment very briefly on the quality of
9
life instruments currently being used in
10
islet transplantation. Dr. Jeffrey
Johnson
11
from our health economics unit has a panel
12
of six different tests, including
13
immunosuppressive quality of life scores;
14
health utility index; cost utility indices;
15
that are being tested in fact across the
16
board at the collaborative islet transplant
17
registry, across the ten centers network
18
trial and at their own site.
That data is
19
being generated currently.
20 DR. RAO: Go
ahead.
21 MR. DAPOLITO:
Hi, again to talk
22
about the asymptomatic hypoglycemia in adult
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issue. For example, if we came
to you say a
2
year or so from now with a couple of pivotal
3
studies that show the sponsor profoundly
4
impacts the outcome of asymptomatic
5
hypoglycemia as detected by sensors; there's
6
no clinical correlate whatsoever in these
7
data. It's asymptomatic
hypoglycemia. How
8
would you view those data?
9 DR. SHERWIN:
Tough. I would say
10
it's not good, because my intuition tells me
11
that. That's why I emphasized
before
12
events. Because clearly events
are events,
13
they're serious. During the
course of the
14
DCCT, in the intensively treated patients
15
who were optimally treated, the best
16
possible care, the rate of severe
17 hypoglycemia that
required help from someone
18
or emergency room visits went up threefold.
19
So in the best of circumstances, as we
20
improve the treatment, we had a threefold
21
increase in these serious events.
22 So it indicates we have better
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treatments, we can lower glucose, we can
2
have an impact on the chronic complications.
3
There is a subgroup of people, maybe
4
overemphasized in number; I suspect that may
5 be true. But there are clearly are a
6
subgroup of people who really are in
7
trouble.
8 MR. DAPOLITO:
Again, may I
9
follow‑up on that? I find
myself wondering
10
are we talking about a
surrogate? Any
11
outcome that doesn't have a clinical
12
manifestation might be viewed as a surrogate
13
for a clinical outcome. Meaning,
the
14
patient knows no difference here.
If we
15
have this data and we come to you, the
16
question will be is this a surrogate?
17
Again, making this determination has
18
regulatory implications. I want
to be sure
19
we have clear understanding of your
20
thinking.
21 DR. SHERWIN:
My thinking would be
22
that if I saw that, I would think that the
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therapy that didn't create that was a
2
superior therapy. That's my
judgment.
3
That's clinical medicine. It's a
judgment
4
call on that. I'm not sure that
all the
5
facts are in. I know that those
people will
6
have a higher likelihood of having some
7
serious event at some point. It
might be in
8
a car somewhere. They'll be at
risk. Their
9
risk will go up. That's for
sure. So I
10
would say it's not a good thing.
11 If you didn't see it in one
12
therapy and you did see it in the other, you
13
would say it's more efficacious.
But then
14
you have to balance of course what David was
15
saying is obviously the risk.
We're just
16
focusing on efficacy right now.
There are
17
obviously potential risks.
18 So I don't know how to judge the
19
whole story, but if I am just focused on
20
that one question, is a lower glucose bad,
21
below normal, I would say yes, because I
22
think the risks are higher as a result.
But
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then it's not as bad as if you have events.
2
Because events mean a lot more, and
3
therefore, I can accept more toxicity, more
4
risk from the other side. That's
the way I
5
look at it.
6 DR. RAO: So
if one is measuring
7
events already, is there any specific
8
additional monitoring that's in your mind
9
absolutely critical, for example, or in
10
anybody's mind, absolutely critical?
11 DR. SHERWIN:
I think you want to
12
get a better picture. These are
secondary.
13
I think the primary, in my own view, would
14 be the events. The
other issues are looking
15
at continuous monitoring; getting a sense of
16
how much subtle hypoglycemia; whether you're
17
losing your epinephrine response; what's the
18
effect on cognition in general.
All these
19
other issues become parts of secondary
20
endpoints that you'd like to think about
21
when you're addressing risk of hypoglycemia.
22
I've said enough.
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1 DR. RAO:
Let's look at the first
2 question in a little bit.
3 DR. HERING:
I would like to make
4
the following comment. I think a
defined
5
use could be restoration of u‑glycemia,
6
which is difficult if not impossible to
7
achieve in a small subgroup of patients.
8
Dr. Sherwin quoted the DCCT study that the
9
risk of hypoglycemia increased three‑ to
10
fourfold. We have to understand
that those
11
patients with a history of hypoglycemia were
12
excluded from participation in this study.
13 So the true risk is possibly
14
higher than just a three‑ to fourfold
15
increase in severe hypoglycemia.
So I think
16
there's a group of patients that cannot
17
experience the benefit of u‑glycemia,
18
because hypoglycemia is the single most
19
limiting factor in terms of delivering
20
intensive insulin therapy. So
those
21
patients have no really opportunity to have
22
u‑glycemia restored unless transplantation
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1
is performed. This is a small
subgroup.
2 I think if you now want to monitor
3
outcomes, I think the incidences of
4
hypoglycemia can be monitored. I
think I
5
would not necessarily only look at severe
6
hypoglycemia, which is a life‑threatening
7
event every single time it occurs, I think
8
one could measure the episodes
of events
9
with glucose levels below 54 or 50 mg/dL
10
without any associated warning symptoms.
11 I think one could do this over a
12
period of time, for example, using a
13
continuous glucose monitoring system over a
14
three‑day period every month and see what is
15
the incidence of hypoglycemia that is not
16
noticed by patients. Because
very single
17 hypoglycemia,
whether you have symptoms or
18
not that are relatively severe will continue
19
to change the threshold to the point that
20
your risk of severe hypoglycemia increases.
21
Hypoglycemia begets hypoglycemia.
I think
22
it's a vicious cycle.
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1 The second outcome measure should
2
be the hypoglycemia fear survey, because
3
this is another instrument that has been
4
used already. This had turned
out to be the
5 most responsive
quality of life, if you
6
wish, instrument. It was used in
islet
7
transplant patients, and I think this would
8
indicate whether quality of life is improved
9
in this group of patients as based on the
10
hypoglycemia fear survey instrument.
11 DR. RAO: I
want to try and go
12
back to the first question and look at what
13
is considered a good outcome. So
you've
14
transplanted cells, and you heard that one
15
criteria that's been used is to look at
16
insulin independence at a period of one
17
year. Is that a good measure or
is too
18
rigorous? Should reduction in
insulin usage
19
be a criteria, or should it always be this
20
criteria? Should it be for four
years?
21
Should it be for one year?
Should it be for
22
ten years? Is there a consensus,
opinion,
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1
suggestions?
2 DR.
LEVITSKY: I think that
3
insulin independence should be the gold
4
standard; insulin independence without
5
hypoglycemia. The problem is
that you can't
6
have insulin independence in an individual
7
who's hypoglycemic over time.
But I would I
8
guess at this point caution against the use
9
the presently available commercial devices
10
to continuously measure blood sugar over
11
three, because they keep redoing their
12
computer algorithms to deal with normal
13
blood sugars.
14 If many normals use them right
15
now, they end up finding out they're
16
hypoglycemic a good deal of the
night.
17
They're actually not. It's a
problem with
18
the computer algorithms. So I
think that it
19
could really upset the data that you were
20
trying to collect if you use the present
21
equipment.
22 DR. RAO: Dr.
Harlan.
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1 DR. HARLAN:
The question I'd like
2
to raise in regards to using insulin
3
independence, on the one hand, it appears
4
like a very clear endpoint, and it is.
But
5
the question I wish to raise about it is
6
that, as Dr. Shapiro presented the data
7
today, that was defined as not having a
8
fasting blood sugar above 140 more
9
than three days a week, or not having
10
a two‑hour post‑prandial above 180 I
11
think three times a week.
12 But those are not normal blood
13
sugars. We don't know if that
level of
14
glycemia control is going to yield the
15
long‑term safety that we are looking for.
16
It looks black and white, but it's not black
17
and white. I would much happier
if it was
18
insulin independence with normal glycemia,
19
using currently defined criteria.
20 DR. SHERWIN:
I think that was a
21
very fair statement, by the way.
I forgot
22
to comment on that yesterday.
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1 DR. SILVERSTEIN:
I think that
2
insulin independence is a gold standard.
3
But I would also accept basically a
4
honeymoon definition, where people would now
5
have the ability to maintain normal glycemia
6
with low doses of insulin as being a
7
success. The only time when you
can really
8
manage diabetes easily is during the
9
honeymoon when they have still some
10
endogenous insulin. Even if they
require
11
some exogenous.
12 MR. DAPOLITO:
Could we get some
13
feedback also on, again, the insulin
14
independence as an endpoint.
Correct me in
15
my thinking if I'm misunderstanding.
16
There's an understanding that the
17
achievement of u‑glycemia is a good thing
18
based on certain data that suggests it's a
19
good thing in people who are not taking
20
immunosuppressives.
21 Are we
comfortable generalizing
22
the data from people who are not receiving
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1
immunosuppressives, such that u‑glycemia,
2
conceptually a surrogate, we are very
3
confident that u‑glycemia in this secondary
4
group of patients is the same as u‑glycemia
5
in the patients who are not receiving
6
immunosuppressives.
7 Because when we say insulin
8
independence is the gold standard, perhaps
9
it's the gold standard among the average
10
somewhat complicated diabetic patient.
But
11
does that implication carry over to a
12
patient population that now is receiving
13
multiple concomitant medications that may
14
impact their long‑term
outcomes above and
15
beyond simply the glycemic control?
16 DR. EGGERMAN:
I just wanted to
17
expand a little bit on what was said there.
18
Insulin independence is still a surrogate
19
until proven otherwise, particularly in this
20
patient population. If you could
have
21
definitive clinical outcome that can be
22
utilized as an endpoint, I think there's
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1
significant strength in that in that you
2
will achieve something that is more
3
definitive and wait for the experts to
4
answer Dwaine's questions.
5 But I think that when you have to
6
choose between surrogates versus definitive
7
clinical endpoints, there's a real strength
8
in the clinical endpoints until you get
9
enough data to know if those surrogates are
10
actually translating into clinical benefit.
11 DR. RAO: Before you respond, let
12
me make sure I get this clear.
One would
13
suggest that in addition to insulin
14
independence, quality of life measures would
15
be very important because they would be more
16
direct clinical endpoints.
There's no other
17
surrogate substitute for insulin
18
independence.
19 DR. EGGERMAN:
Right. To evaluate
20
it, you have to look at all the clinical
21
possible outcomes that occur using that
22
surrogate endpoint, and that would take a
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1
significant amount of time to determine.
2
Certainly previous trials have required
3
many, many patients to ascertain that over a
4 long period of
time.
5 DR. RAO: Dr.
Shapiro.
6 DR. SHAPIRO:
I was just going to
7
comment further on whether our goals should
8
be restoration of complete, perfect glucose
9
control or not. That would be a
wonderful
10
goal if we could achieve it. But
11
realistically, we're taking patients who are
12
on intensive insulin therapy or optimal
13
insulin therapy, who have unacceptable
14
glucose control to a point where these
15
patients are now off insulin and have
16
acceptable glucose control, and more
17
importantly, have normal hemoglobin A1C. I
18 think that's a
realistic practical goal for
19
us to achieve right now.
20 There is data from the University
21
of Milan that shows quite clearly now, in a
22
large cohort of islet transplant patients,
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1
approximately 50 patients that have been
2
followed for 10 years with ongoing c‑peptide
3
secretion that have islet and kidney
4
transplants. In those patients
that have
5
ongoing islet function, their mortality
6 rates and their
survival and their kidney
7
grafts have improved.
8 DR. RAO: Dr.
Salomon.
9 DR. SALOMON:
A little bit of this
10
reminds me of Sam Dash during the Watergate
11
hearings when we kept referring to the fact
12
that he was just a little lawyer from the
13
backwoods area.
14 SPEAKER: It
was Sam Ervin.
15 DR. SALOMON:
It was Sam Ervin.
16
Anyway, I'm corrected. The
feeling is the
17
same here. I feel like I'm just
the little
18
general practitioner from Southern
19
California. Number one, you have
a patient,
20
I have these patients, who are ending up
21
with the paramedics in their bedrooms a
22
couple times a year, if not a couple times a
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1
month. Then a year later, they
haven't had
2
a single episode. We're like
going well,
3
now we need to be more objective and maybe
4
they need to go ‑‑ I think Dr. Sherwin was
5
very patient. Put them in a GCRC
metabolic
6
unit and do a glucose clamp and measure
7
their epinephrine and glucagons.
I mean, am
8
I missing something here?
9 I think the patients would say
10
thank you very much. Then
there's the whole
11
lot of very serious issues that I think we
12
could discuss about what was the trade‑off
13
on the immunosuppression, and then we need
14
to wait 5 or 10 years and do a couple
15
thousand patients and look at whether their
16
retinopathy and the progression of their
17 renal disease
changed. I'm all for that.
18 If you guys were regulating kidney
19
transplantation that way, then you'd put us
20
out of business. I've got
thousands of
21
patients who bless me every time they come
22
to the clinic about the wonderful lives they
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1
have now with a creatinine clearance
2
of 40 mL per minute. Everyone
here who
3
hopefully doesn't have renal disease has got
4
a clearance of 100 mLs per minute.
But now
5
we're having this conversation about how,
6
well, maybe we need totally normal glucose
7
control. Again, show me a
diabetic who's
8
not sticking themselves with a needle and
9
tell me they are going to be
upset a year
10
later.
11 I don't know why we're making
12
something relatively simple so complicated
13
under the rubric of an objective outcome
14
principal.
15 SPEAKER: I'm
Krista Nuratha (?)
16
from the NIH, and I'm just a little
17
practitioner in that sense, and you make my
18
comment almost superfluous, because I think
19
it's a question of how closely
do we look.
20
If we just look at blood sugars during the
21
day measured by these transplanted patients,
22
we see nice blood sugars. If
look closer,
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1
we all agree that we do not see a normal
2
first phase insulin release after a
3
challenge. We do not see normal
immediate
4
post‑prandial blood sugars.
We see all
5
kinds of abnormalities, but that may not be
6
the goal.
7 The goal may be that the patient
8
has now very nice blood sugars during the
9
day overall and you don't necessarily need
10
to look at the fine points. But
there's
11
just one danger in that we think that maybe
12
the definition of insulin independence may
13
lead some people who care for these patients
14
to not institute a little bit of insulin
15
therapy that they would just require to
16
normalize or improve their blood sugars,
17
because the outcome is insulin independence.
18 So if now our very successful
19
patients are on a little bit of insulin,
20
they don't count as full successes anymore.
21
That shouldn't be the case.
That's why I
22
like very much your comparison to the
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1
honeymoon phase. These are
successful
2
patients. They are easily
managed, no
3
hypoglycemia, little bit of insulin.
That's
4
success.
5 But we need to look at the other
6
side, and therefore create something that is
7
a global picture. If somebody
needs to
8
build in a toilet in the car because they
9
have more or less normal blood
sugars, but
10
have to go to the bathroom 15 times a day
11
for a prolonged period of time, that
12
minimizes again the success.
13 So in the end, you need something
14
that puts several criteria, and therefore,
15
probably something like quality of life that
16
would take that into account would very much
17
help to kind of give us some objective
18
outcomes measures. So it must be
a puzzle.
19
I agree fully that the closer we look, the
20
more abnormalities we find, and that may not
21
be the best way to judge islet
22
transplantation outcome.
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1 DR. RAO:
Please identify
2
yourself.
3 SPEAKER: I'm
Kim Ritter. (?) I'm
4
a patient at NIH. I had
transplant
5
almost 2‑1/2 years ago. As
the doctor over
6
there mentioned, I was one of those patients
7 that had the lows
at least twice a week.
8
Okay, I didn't go to the paramedics, or I
9
didn't go the hospital because I refused,
10
because they take away your insurance and
11
all sorts of other reasons. But
you can't
12
believe the difference this makes.
13 I have a life.
I don't have to
14
have a babysitter when my husband goes away.
15
I can watch my children. My
three‑year‑old,
16
as she was at the time years ago, learned
17
how to feed me raisins because she couldn't
18
open the refrigerator yet. I'm
not on
19
insulin right now and I may be on low dose
20
shortly, but my sugars this morning
21
were 114. There's nothing you
can say to
22
replace the difference in not having a low.
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1
I could function very normally at a 40 blood
2
sugar. If I wasn't paying
extremely good
3
attention and I didn't check my sugars, you
4
know, 5 to 10 times a day, I wouldn't catch
5
the 40 to the 30 or the 20, where I passed
6
out and had no recollection of anything.
7
It's a difference that you can't judge.
8 The islet transplant; yes, there
9
are problems with the rejection drugs.
I
10
can't deny that. I've had the
nausea. I've
11
had mouth sores. I've had a lot
of the
12
complications, but they're nothing compared
13
to the lows. You have a
life. You can't
14
cross that. It's a big
difference.
15 DR. RAO: I
guess this really
16
re‑emphasizes the point that quality of life
17
scores of some fashion are important in
18
terms of considering follow‑up and those
19
issues that are there. Go ahead.
20 SPEAKER:
Hello, I'm Ellen Birdie
21
again. I would just like to
summarize
22
exactly what you had to say and the way that
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1
both Kim and I feel. Throughout
the past 28
2
months since my transplant, people have
3
often asked me, how do you feel?
How do you
4
feel now that you don't have diabetes, now
5
that you've had an islet transplant?
6 I always say, you know, I think
7
it's much more effective to show you rather
8
than to just tell you. My shirt
says "kiss
9
my islets." These are
pictures of islets on
10
my shirt.
11 DR. RAO:
Thank you. I'm going to
12
try and summarize this a little bit, because
13
there are several other things we'll also
14
discuss as well, and then Dr. Ricordi, if
15
you feel you need to make a comment on that,
16
then we'll go with that.
17 DR. RICORDI:
Very briefly, to
18
emphasize the fact that insulin independence
19
has been in a way imposed on the islet field
20
by pancreas transplant results, because we
21
have to compare our results with those of
22
pancreas transplants. But the
data that
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1
Shapiro is referring of the Milan trial
2
following up patients for 10 years,
3
successful islet transplant versus an
4
unsuccessful with a kidney transplant, with
5
difference of patient survival or death
6
from 90 percent survival to 45 patient
7
survival at 10 years.
8 These were in all patients that
9
require insulin, small doses. So
this is to
10
re‑emphasize that I wouldn't underestimate
11
whether it is better to give like six units
12
of insulin of single injection with an islet
13
transplant, single dose, versus trying to
14
achieve this complete insulin independence
15
to continue to measure our results with
16
pancreas transplantation.
17 But there is clearly a metabolic
18
effect and a beneficial effect if you
19
normalize hemoglobin A1C, even if you have
20
to take a single injection a day of insulin.
21 DR. RAO: Go
ahead.
22 MR. DAPOLITO:
I just want to try
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1
to be clear on what I may be hearing.
It
2
sounds of if a number of folks have opinions
3
that the primary endpoint should be
4 something with
tangible clinical benefit;
5
something that patients know, experience, if
6
I understand correctly, as opposed to a
7
primary endpoint which may be a hypothetical
8
endpoint.
9
Meaning, for example, u‑glycemia,
10
in the absence of any symptomatic correlate.
11
Is that the correct perception?
Because I
12
don't want to walk away thinking ‑‑
13 DR. RAO: I
was going to ‑‑
14 DR. SALOMON:
You were on it, but
15
keep going. U‑glycemia
without an insulin
16
injection is really tangible for a diabetic.
17 MR. DAPOLITO:
Okay.
18 DR. RAO: Is that to say it's not
19
a substitute.
20 DR. SALOMON:
If they have to be
21
on total perineal nutrition to get it, that
22
doesn't work for me.
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1 MR. DAPOLITO:
But we don't
2
need ‑‑
3 DR. SALOMON:
I'm just saying
4
there's a way to do this. We can
be
5
practical.
6 MR. DAPOLITO:
I want to be sure.
7
The avoidance of exogenous insulin with
8
u‑glycemia will be viewed as a sufficient
9
primary implant. Thoughts?
10 DR. SILVERSTEIN:
You can use some
11
insulin.
12 SPEAKER: How
are you going to
13 define u‑glycemia?
14 DR. SILVERSTEIN:
Yes, I think
15
that they can have some insulin, and the
16
question is ‑‑
17 SPEAKER: Dr.
Silverstein, use
18
your microphone please.
19 DR. SILVERSTEIN:
I'm sorry. I
20
think that you need to allow these patients
21
to have some insulin injection and still be
22
considered a success. The real
question
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1
then is how do you define u‑glycemia?
2
Hemoglobin A1C less than 6.5 percent with
3
low glycemic excursion seems reasonable to
4
me. I don't know how ‑‑
5 DR. RAO: I
think we are repeating
6
ourselves to some extent, and so what I am
7
going to try and do is exercise some
8
executive authority here and try and
9
summarize and then see if there was any
10
really dramatic way I've missed a summary or
11
if I've left out something.
12 So what seems to me pretty clear
13
from the conversation here has been that you
14
need to follow‑up and you need to follow
15
them up quite a long period of time, given
16
that these are diabetics who would have
17
lifetime follow‑up in some fashion. There's
18
a standard follow‑up that people have used
19
for diabetics, and that seems to be a
20
reasonable way to follow them up.
21 There are certain specialized
22
things that you need to worry about in
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1
patients who've got islet transplants, and
2
part of that seems to be to worry about the
3
immune suppressive regimen that's been
4 there, and to
use as an outcome measure that
5
you need both outcome measures which is
6
quantifiable in some sense achieving insulin
7
independence, which is loosely defined in
8
that you don't have to a normal glycemic or
9
u‑glycemic curve in response to a glucose
10
challenge; and that one can use surrogate
11
measures such as glucosylated hemoglobin and
12
serum c‑peptide as measures of what your
13
glycemic state is.
14 But in addition to this, quality
15
of life measures are going to be quite
16
important as part of the endpoint in terms
17
of looking at any of these cases.
Is there
18
any additional really specific test that
19
seems to have been missed, or a huge gap in
20
terms of what one would consider follow‑up
21
which is not there?
22 DR.
SALOMON: Yes, I think the
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1
other one that came up in Dr. Shapiro's
2
discussions, and I think the
3
endocrinologists have done a good job with
4
things like MAGE, which is the mean aptitude
5
of glucose excursion; James had come up with
6
an alternative, which I think if he could
7
justify that, would be fine for a clinical
8
trial.
9 I defer to my endocrinology
10
colleagues if they want a different test.
11
But they have some objective tests that are
12
useful in further defining what's going on.
13 DR. SHERWIN:
Obviously, the other
14
thing that you're going need to look at,
15
even though we assume
everything will be
16
alright, is microobrevenarious (?).
You may
17
even want retinal photographs.
One of the
18
things that we observe when we put people on
19
insulin pumps was an acute deterioration in
20
their retinopathy, and then it went away,
21
and then things improved.
22 The assumption would be that you
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1
might see a similar phenomenon here or you
2
might not. But I do think that's
relevant.
3 Whether
one should look at ‑‑ if
4
you're really going to do a trial, I mean,
5
it depends on the magnitude and the money
6
and so on ‑‑ is to think about some of the
7
markers of cardiovascular disease, you know,
8
see reaction to protein, things like this.
9
Just to keep a feeling for what these
10
regimens might be doing from that
11
perspective, islet six, et cetera.
12 So I'd think about the
13
complications, but my focus still is on the
14
primary promise; this not a big subgroup of
15
people, but there are real subgroup of
16
people that I think therapy can have big
17
impact, and we have to prove it to the
18
world. I think that's one of the
issues.
19 You want to do a good study, I
20
think, that really tells you unequivocally
21 that this approach is superior to the best
22
medical approach that we can come with.
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1
That won't take too long.
2 DR. RAO:
Brief?
3 DR. HARLAN:
It will be brief. I
4
has sensing maybe a developing groundswell
5 that it shouldn't
be insulin independence,
6
but it should be u‑glycemia which is the
7
goal, rather than insulin independence.
I
8
say it for two reasons. One is,
it's not
9
proved. I accept your point that
we don't
10
know that glycemia is as important to the
11
immunosuppressed patient as it is in others,
12
although the great preponderance of data is
13
that anytime it's been looked, at it's
14
glycemia, glycemia, glycemia, that regulates
15
endpoint.
16 So I think from a practical
17
standpoint, since we really are interested
18
in patient long‑term outcome, if we can
19
achieve that easily ‑‑ and I agree with
20
Dr. Ricordi perfectly, and I think patients
21
would agree with it ‑‑ if you can give them
22
an islet transplant and a single shot of
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1
insulin a day and they've got normal blood
2
sugars, that's a fantastic
success and
3
shouldn't be defined as anything less than
4
that.
5 Then the practical issue is that
6
we want these islets to survive as long as
7
possible once we transplant them.
There's
8
also considerable, not proof, but
9
considerable data that high blood sugars in
10
and of itself decreases the survival of
11
those islets. So if we choose anything
less
12
than normal glycemia, it's bad for two
13
reasons, I think. One, bad for
the patient,
14
and two, bad for the islets.
15 I was sensing that people were
16
starting to agree on this. I'd
rather it be
17
u‑glycemia than insulin independence.
18 DR. RAO:
Point taken. Does the
19
FDA feel that we've covered this question
20
adequately?
21 MR.
DAPOLITO: I think it's good
22
to get clarity. If I understand
correctly,
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1
on 1A, the take‑home message is that the
2
avoidance or the minimal use of insulin with
3
u‑glycemia is a reasonable primary endpoint
4
per se. There likely will be
symptomatic
5
correlates with that type of endpoint, but
6
the interpretability of that endpoint is not
7
contingent upon symptomatic correlates;
8
meaning, that endpoint of avoidance or
9 minimal use of
insulin with u‑glycemia in
10
and of itself is a clinically meaningful
11
endpoint. Is that correct?
12 DR. SILVERSTEIN:
Could I ask a
13
question? We're talking a lot
about
14
hypoglycemia, but one of the indications for
15
islet transplants was also metabolic
16
instability, with I believe two or more
17
episodes of DKA in a year. We
haven't
18
addressed that at all. But I
think that
19
that is a reasonable inclusion criteria,
20
assuming that the person has been compliant
21
and has received optimal insulin therapy
22
before hand.
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1 To that end, I would think that we
2
should use not only episodes of
3
hypoglycemia, but number of episodes of DKA
4
as an endpoint to be monitored.
5 DR. RAO:
What's there as part of
6
the monitoring and the readout and what has
7
been followed. But it's an
important point.
8
Something to keep in mind.
9 I'd like to go on and try and get
10
some discussion. We can come
back to it if
11
we have time, if there's any burning
12
question left. But let's
consider the
13
section question as well. I'm
going to read
14
this out, because I want and try and make
15
sure that we get this all clear to people,
16
including myself.
17 It says "regarding the overall
18
clinical development program for responses
19
allogenic islets, please discuss the
20
importance and the meaningfulness of the
21
following types of clinical data with
22
respect to the ability to form a
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1
risk/benefit assessment of the product."
2 I read this to mean that you use
3
this, and you now want to predict what is
4
the risk of using this, and in some set of
5
tests or in some sort of criteria, what is
6
the benefit? For me, this was a
little bit
7
hard, because from all the data that we
8
heard, even though it's preliminary, there
9
didn't seem to be any risk.
10 I know I'm stating this too
11
boldly, mainly for effect, but that is true,
12
right? There was no adverse
response to
13
report. There were no
deaths. There's no
14
infection criteria to report.
15 DR. LEVITSKY:
The risk of
16
immunosuppression with renal disease though
17
is still ‑‑
18 DR. RAO:
Yes. Exactly.
19 DR. SHAPIRO:
Just to clarify. We
20
didn't say there was no risk. We
said that
21
that was acceptable, and that there were no
22
deaths or life‑threatening events. It's not
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1
the same as saying this is risk‑free.
2 DR. RAO: It
certainly helped
3
start the conversation, didn't it?
Go
4
ahead, Dr. Silverstein.
5 DR. SILVERSTEIN:
One of the
6
issues we don't really know is what the
7 long‑term
affects, or even how long the
8
lipid elevations will remain after you begin
9
therapy. I want to just agree
with
10
Dr. Sherwin that I believe that some measure
11
of cardiovascular outcome should be
12
included. Somebody mentioned
that they were
13
already doing some intimal chorodid (?)
14
thickening studies. That's a
hard one to
15
reproduce. Maybe even brachial
artery or
16
radial artery tonometry might be easier and
17
more reproducible, but something like that
18
might be of use.
19 DR. RAO: Do
you have a comment?
20 SPEAKER: One
of the major risks
21
for me ever present is infection.
Not that
22
I get more infections, but if I get an
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1
infection, it is major in a minute.
It just
2
blows up. So that is a constant
risk on
3
immunosuppressives.
4 DR. HARLAN:
I just want to
5
mention some of the risks that we have seen
6
in our six patients. We've seen
anemia in
7
five of the six; thrombelsidapenia in four
8
of the six; neutropenia requiring GCFS
9
treatment in two; peripheral edema; profound
10
fatigue in a couple. Renal
insufficiency in
11
one requiring discontinuation of the agents.
12
Severe diarrhea in a couple.
Mouth ulcers
13
in the five of the six. Arthralgias,
14
fatigue. Two of patients have
been here to
15
tell you it's a great thing. But
it is a ‑‑
16 DR. RAO: We
should say whether
17
these are short‑term ‑‑ early versus late.
18 DR. HARLAN:
They can be late.
19
One of our patients who was
20
insulin‑independent for 19 months developed
21
a Rapamyacin‑induced numimytis, which is a
22
known complication of the agent
that didn't
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1
respond to decreasing the
doses, and
2
eventually for her, she said it's been
3
wonderful being off insulin for 18 months,
4
but I've had enough.
5 So there are problems associated
6 with it. I feel like I'm frequently the one
7
saying the downside of this, but you've
8
already heard from two of our patients that
9
have experienced the miracle of it, too.
10
It's not free. That's for sure.
11 DR. HERING:
I think it is
12
important to emphasize that, like it was
13
said before, that islet transplants should
14
be done in centers that have expertise with
15 the management of
immunosuppression. You
16
may want to point out how many patients have
17
you immunosuppressed before you enrolled
18
your first patient into this one clinical
19
trial.
20 I think
this is perhaps part of
21
the equation, and I want to make this point
22
because this is an expertise that is
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1
required, and it is not to say that if you
2
have this expertise, you can prevent
3
complications, but it will clearly add to
4
the safety of the patient care if this
5
expertise is available.
6 DR. RAO:
Maybe I can ask you this
7
question. Since immune
suppression is
8
life‑long, it means the follow‑up in terms
9
of the risk that one has to worry about is
10
life‑long in case of this patient? Is that
11
what would the consensus perhaps in terms of
12
the complications associated with immune
13
suppression?
14 DR. HERING:
I agree completely.
15
We have no understanding of the risk of
16
immunosuppressive protocols that we use at
17
this point in time. Immunosuppressive
18
therapy has undergone major changes.
We
19
assume and believe, that the risk/benefit
20
profile has improved, but I agree with you.
21
The long‑term implications are completely
22 unknown, have
not been studied. That is why
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it is more than reasonable to follow
2
patients long‑terms.
3 DR. RAO: Dr.
Sherwin.
4 DR. SHERWIN:
I may be wrong,
5
because it's not my area. But my
impression
6
is that there's accelerated arthrosclerosis
7
in patients who received transplants in
8
general, not this kind. So from
my
9
perspective, that's my big fear.
And I
10
don't know why that is. I don't
know if
11
anybody has any ‑‑
12 DR. SALOMON:
I think it's correct
13
what Dr. Sherwin says. If you
look at
14
liver, kidney, and heart transplants ‑‑
15
hearts maybe not quite fair because there's
16
more going on there ‑‑ but if you look at
17
liver and kidney transplants, pancreas
18
transplants, there's certainly an increased
19
incidence of ischemic cardiovascular and
20
peripheral cardiovascular disease.
21 The mechanisms are something that
22
we're intensively aware of right now in the
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1
transplant field. Because to be
honest with
2
you, as our success is now routinely getting
3 out at 10, 12, 15 years, the focus in the
4
field has appropriately turned to the fact
5
that the major cause of a kidney transplant
6
failing, after chronic rejection, is
7
basically the patient dying of an ischemic
8
cardiac event with a functioning kidney.
9
That's been a real wake‑up call over the
10
last 5 or 10 years in our field.
11 Issues.
Hypertension's been
12
extremely poorly controlled. We
probably
13
have not been anywhere near aggressive
14
enough in lifestyle changes, dietary
15
changes, exercise, and functionality.
We're
16
experiencing the transplant population in
17
intense microcosms of what's happening in
18
the whole society in general.
Because of
19
the other risk factors present in this
20
group, it's amplified manyfold in the
21
transplant population.
22 So without going on a lot further
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than that, I think that's an area that is
2
part of transplantation and
3
immunosuppression. It's
absolutely a part
4
of this discussion today. It's
something
5
that we need to do better, and
we're trying
6
really hard at it.
7 DR. HARLAN:
Yes, in response to
8
Dr. Hering's question, I'll start with a
9
general response and then a specific one.
10 The general one is, as I
alluded earlier
11
today to this recent paper in The New
12
England Journal that looked at the incidents
13
of renal insufficiency in the transplant
14
population. It's a significant
proportion,
15
anywhere from 7 to 21 percent of patients
16
that get a non‑kidney transplant that end up
17
with renal insufficiency.
18 We know that the number one
19
predictor of mortality of patients with
20
diabetes is if they develop kidney
21
insufficiency. Number one.
22 Number two is we have an analysis
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1
that looks nationwide in this country
2
from 1995 to the present date to what the
3
impact on survival is of a patient that gets
4
a pancreas graft if they've got normal
5
kidney function, and it's not good.
6 Those patients do less well than
7
similar patients that don't get the
8
transplant. If you look at the
one endpoint
9
that everybody in this room would agree
10
upon, and that's whether the patient is
11
alive or dead; that most of that mortality
12
does occur in the immediate post‑transplant
13
period, but the risk of death never gets
14
better in the transplant group.
That's
15
cause for concern. I think
that's due to
16
the immunosuppressive protocol.
17 Then the last point is that it's
18
true that I never had much experience with
19
immunosuppressive therapy before we
20
transplanted our six patients, but we're a
21 member of a team
that has three experienced
22
transplant surgeons, and all of our
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immunosuppressive dose adjustments were made
2
with advice and consent from them, and that
3
our transplant unit success at the NIH has
4
been 100 percent graft survival at one year.
5
So I think that our experience is really not
6
different than what anybody else sees.
7 DR. ALLAM:
Clarification on two
8
points, actually. One is, if you
had 50
9
percent of your islet cell patients over a
10
long period of time develop renal
11
insufficiency, would that preclude you doing
12
islet cell transplants, even if you had
13
like, say, 25 to 50 percent of the patients
14
who needed a kidney transplant in 20 years,
15
would that preclude the islet cell
16
transplant?
17 The other issue I wanted to
18
address too is, you make it sound like you
19
don't have any adverse events.
So he was
20
saying he has anemia, thrombelsidapenia in
21
some of his patients. Do you not
see that
22
at all in your patients?
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1 DR. SHAPIRO:
I did outline in my
2
presentation, and for the sake of time, I
3
didn't have a chance to go through every
4
single line item and report complications.
5
I highlighted the major points.
The
6
bleeding risk in 14 percent of patients.
7
Anemia we've seen in about 10 to 15 percent
8
of patients. Mouth ulcerations
about 85
9
percent of patients. An acute
transient
10
event that resolves over time.
11 Patients
requiring statin therapy
12
in 44 percent of patients.
Peripheral edema
13
in about 10 percent of patients.
The MRI
14
changes in the liver that I mentioned to
15
you, with steatosis in about 22 percent of
16
patients. Left side ‑‑
17 DR. ALLAM:
Wouldn't consider
18
those a risk, though.
19 DR. SHAPIRO:
Say again.
20 DR. ALLAM:
Those would not be
21
strictly considered a risk.
They'd just be
22
construed ‑‑
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1 DR. SHAPIRO:
You're asking about
2
adverse events. These are a
summary of
3
adverse events that are reasonably
4
frequently encountered in islet transplanted
5
patients. They may not be life‑threatening,
6
but they're adverse events. So I
certainly
7
wouldn't want you to go away with the
8
impression that there are no adverse events
9
in an islet patient.
10 DR. HERING:
Yes, I think we
11
clearly see complications like this was
12
presented here. But I think you
have to see
13
the big picture. We also understand
that
14
patients have not completely nominal
15
function if you use very sophisticated
16
tests.
17 But I think you have to really
18
balance the risk and the benefits, and if I
19
listen to patients like today, I see there
20
could be substantial benefit.
And you have
21
to balance this. I think this is
what will
22
be important and needs to be studied.
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1 I think many years ago, in a major
2
pancreas transplant program as part of a
3
quality of life study, patients were asked
4
what is more difficult or more challenging
5
for you, to manage diabetes or to manage
6
immunosuppression? 95 percent of
the
7
patients said managing diabetes is more
8
difficult.
9 Then patients who lost their
10
pancreas transplant function and had
11
undergone major surgery were asked, would
12
you recommend this treatment to your best
13
friend or to your family member?
The vast
14
majority said yes, I would recommend this
15
treatment to my very best friend, even
16
though I rejected or lost my transplant.
17 I think we have to keep this in
18
context. We are all aware of the
problems
19
of immmunosuppression. That is
why all our
20
research, experimental and clinical, is on
21
immunosuppression and on improving
22
immunosuppression. We are
clearly aware,
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but we also see benefits that are associated
2
with the treatment that is delivered.
We
3
understand this needs to be studied and
4
documented.
5 DR. ALLAM:
The hypothetical. If
6
islet cell patients at 10 years down the
7
line require a kidney transplant, let's
8
say 25 percent of them, you're considering
9
doing islet cell transplants and you're a
10
kidney transplanter, would you advise your
11
patients ‑‑ I mean, how would you deal with
12
this?
13 DR. SALOMON:
Well, the problem
14
with judging the incidence of kidney failure
15
in a diabetic population is the starting
16
setpoint of how much damage has been done to
17
the kidney before you do the islet
18
transplant. The way things are
going right
19
now, a lot of these patients, really all of
20
those patients, have had diabetes for a long
21
time.
22 The mean time of onset of kidney
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disease after the initial diagnosis of
2
diabetes is 17 years. It occurs
in about 30
3
percent of diabetic patients.
Most of these
4
patients who are getting islet transplants
5
right now are 17, 20 years plus
6
post‑transplant. Because
of the populations
7
that we're looking at. You know,
people
8
who've had years of difficult to control
9
diabetes, or years of these hypoglycemic
10
events. There may be
exceptions. Do you
11
know, Bernhard or James, what the mean age
12
onset after ‑‑
13 DR. RAO:
Yes, 26 years.
14 DR. SALOMON:
So just as a reality
15
check to what I'm telling you.
At that
16
point, if you had a kidney biopsy on every
17
one of these patients ‑‑ and that's not a
18
crazy concept by the way ‑‑ you would find
19
in essentially 30 percent of them
20
significant changes already. So
once you
21
had a calcineurin inhibitor regimen into it
22
and then you follow it out 10 years, it's
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just a question of how many of those
2
patients without the calcineurin inhibitors
3
would have ended up with renal disease, and
4
that has to be figured in.
That's not such
5
an easy one to answer.
6 But the fact is, I think, I agree
7
with what Bernhard said as well.
This is a
8
moving target, and that immunosuppression is
9
consistently now changing. We've
been given
10
this whole bunch of really potent new drugs
11
over the last five years. We're
really now
12
getting much better at using them.
The idea
13 of using calcineurin‑free
immunosuppression
14
is something that I think is going to become
15
a reality in many programs over the next
16
five years.
17 I was telling at lunch, we have an
18
experience now that just got finished two
19
years out, 60 patients, 30 on a calcineurin
20
inhibitor regimen and 30 without kidney
21
transplants: Their mean
creatinines are 1.8
22
m/dL in the calcineurin group and 1.0
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milligrams, I mean totally normal, in the
2
Rapamyacin group at two years.
3 These are things that can be
4
accomplished, so I think that's kind of
5
putting it into context, if you will.
6 DR.
HERING: I think the opposite
7
is also true. Clearly, I agree
with you
8
that you see problems, and 10 to 25 percent
9
may have required a kidney transplant, while
10
very high dose calcineurin inhibitor therapy
11
was used. Some patients seem to
have a
12
genetic predisposition, even in the context
13
of low dose of therapy.
14 But there is another documented
15 subgroup of
patients who showed, based on
16
kidney biopsy, evidence of diabetic
17
nephropathy of the time of pancreas
18
transplantation. Patients were
biopsied 5
19
and 10 years later ‑‑ and this was published
20
in 1998 in The New England Journal of
21
Medicine. All diabetes‑related
changes
22
basically had resolved.
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1 So I think you see both pictures.
2
I think that's why you need to select your
3
recipients very carefully and try to
4
minimize risks.
5 DR. SHERWIN:
I think that's a ‑‑
6 DR. SALOMON:
That's a really good
7
point. I just wanted to say that
in my
8
discussion, that was omitted, and I'm glad
9
Bernhard brought it up, and that is true. I
10
think the appropriate response here is that
11
this a good discussion now of risk and
12
benefit, and this is what has to constitute
13
the informed consent for these patients.
14 DR. SHERWIN:
But I would bet that
15
renal disease would probably be better as a
16
result of this therapy, on balance.
That
17
would be my guess. The only one
that I
18
worry about is the cardiovascular side, to
19
be honest.
20 DR. RAO: So
let's try and see
21
from what we've heard in terms of risk.
The
22
sense seems to me from listening to everyone
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1
is that the predominant risk is the immune
2
suppressive therapy that the patients
3
undergo. It's a moving target,
but you
4
really have to monitor, just like you would
5
in any immune‑suppressed patient.
The
6
things that you worry about are the kidney,
7
the liver, the heart, and those will need to
8
be monitored.
9 Before we move on to the other
10
sort of aspects or subheadings
in this
11
section, is there any other additional risk
12
from islets specifically that one needs to
13
monitor or one thinks may be important in
14
terms of looking at this?
15 DR. RICORDI:
Yes. To me, the
16
major risk in this procedure is an
17
inexperienced team performing it.
I think
18
there will be direct proportionality of the
19
severity and the number of side effects, the
20
rate of failure. And I'm not
pointing out
21
any one specific one problem.
But it is
22
very dangerous to generalize, if you have an
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experience with a few patients; if you see
2
very high incidents of complication or side
3
effects, then you should critically
4
reevaluate what they're doing, compare the
5
results with those of others and prepare to
6
move to the next step.
7 In pancreas transplantation, which
8
is not regulated by FDA, a center that I
9
will not name had decided to enter into the
10
field, and they had three out of their first
11
four patients died following pancreas‑alone
12
transplantation. The suggestion
to that
13
group was to stop. There was no
FDA
14
imposing.
15 That is something that comes from
16
your community, the hospital. So
it is
17
really something that shouldn't be
18
underestimated. In the case of
islets,
19
maybe less dramatically, but that is a risk
20
there should be considered. So
the issue's
21
not can be done, because it has been shown
22
that it can be done. It is not
should be
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done, because I think has been demonstrated
2
that it should be done. The real
issue is
3
who should do it at this stage.
4 DR. LEVITSKY:
Dr. Ricordi, you
5
just gave me the opening I was waiting for.
6
We were sitting at lunch today talking about
7
the fact that none of us had asked a very
8
important question, which is that we were
9 shown 10 centers in
the larger study and 3
10
of them did superbly and some of the others
11
didn't so well at all. We never
found out
12
whether it was an islet problem or some
13
other problem. Are there data on
the
14
quality of the islets at the different
15
centers?
16 DR. SHAPIRO:
That question was
17
asked. There is some data on the
quality of
18
the islets. There's also some
data on the
19
immunosuppressive levels in the patients
20
that were maintained or weren't maintained.
21
In four of six cases, in fact, where there
22
was early rejection events.
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1 So I think cumulatively, there is
2 data to suggest
reason for graft failure at
3
those sites was islet‑related in some cases,
4
graft‑related in others,
5
immunosuppressive‑related in others.
6
Ongoing analysis is going to outline that in
7
a little bit more detail.
8 DR. RAO: I
think it's not really
9
relevant to the kind of question we're
10
trying to answer right now. So
I'll wait on
11
that.
12 DR.
O'NEILL: One of the risks
13
that haven't really been discussed but were
14
presented by Dr. Shapiro were the risks
15
involved with the transplant procedure
16
itself, with bleeds, thrombosis, and
17
bleeding. I think that's
something
18
certainly the panel should discuss.
19 DR. EGGERMAN:
One other issue
20
that was discussed yesterday I didn't hear
21
you mention were related to the
possible
22
sensitization if you have multiple donors
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that are supplying islets for an islet
2
recipient, for subsequent transplantation.
3 DR. RAO: Dr.
Sherwin, do you have
4
anything to add?
5 DR.
SHERWIN: The islets are put
6
in the liver. So one issue, even
though the
7
data so far don't support it, is steatosis,
8
possibility of nash, (?) even though it
9
seems unlikely. The other
question I would
10
have is when islets are put in the liver
11
does the insulin escape the liver?
Is there
12
peripheral hyperensonemia (?) as a result or
13
not? If that has implications
perhaps in
14
terms of cardiovascular disease.
15 DR. SHAPIRO:
Maybe I can answer
16
the issue first about the concern about
17
nonalcoholic steathohepatitis, and is this
18
going to be a risk in the 22 percent of
19
patients we've identified that have
20
steatosis on MRI. I don't think
we have
21
long‑term data in our patients today.
22 I think we as a group regard the
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MRI findings as being benign and expected in
2
islet patients, which in our feeling is that
3
these are unlikely to have long‑term
4
sequelae. The reason in addition
to that
5
that we feel this way is that islet
6
autografted patients have similar findings,
7
and some of those patients are followed up
8
beyond 18 years and do not have nash.
So
9
our feeling is that that is unlikely.
10 Your second question: Is insulin
11
spilled from the islets into the systemic
12
circulation, whether or not it's embolized
13
to the liver and re‑vascularizes through the
14
pancreatic arterial system. The
answer is
15
probably yes. Exactly how much
insulin then
16
follows through the portal circulation and
17
is how much is delivered systemically, I
18
don't think we know for sure.
19 I think very detailed clamp
20
studies and hepatic vein instant output
21
monitoring might be required to define that
22
in more detail. I'm not
personally aware of
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data that really defines that today.
2 DR. RAO: I
want and try and move
3 on to the next few questions as well,
4
because those are really quite important in
5
terms of issues for what happens with any
6
kind of study.
7 DR. SALOMON:
Mahendra, do you
8 want to answer one
last question here? That
9
is, do we mean it should be three years,
10
five years?
11 DR. RAO: I
tried to get a summary
12
on that, and it seemed that the biggest
13
complication was immune suppression, and for
14
that you'd have to have long‑term, but that
15
there was no pre‑submission data that you
16
could collect because the data was
17
short‑term for almost all the patients that
18
were there.
19 DR. SALOMON:
Certainly for
20
immunosuppressive side effects, two to three
21
years would be good for a large number of
22
them. Not all of them of course,
but almost
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all the serious infectious complications
2
occur in the first year. Most
often, things
3
like PTLD occur in the first, though I don't
4
think that's really a big risk here
5
actually. Hypertension, cardiovascular,
6
risk factor increases.
7 So the only thing that would
8
really require more than two years follow‑up
9
to answer those questions would be actual
10
measurements in changes in, let's say, I
11
like the idea of the retinal pictures and
12
measurements of vascular function; several
13
were mentioned. That would take
5 to 10
14
years probably.
15 MS.
HARVEY: Can I just make a
16
comment on that? I know it's not
easy, but
17
I come back to what is it that the FDA is
18
going to be giving approval on for the BLA
19
that we're talking about? This a
very
20
important aspect for the patients, the
21
overall risk/benefit. But should
we really
22
be studying the long‑term implications of
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the immunosuppressant therapy as part of the
2
approval of the islet cells and their
3
effectiveness? I don't know the
answer, but
4
I just raise it as a question around.
5
Should we really be looking at the
6
immunosuppression piece of that or not?
7 DR. SALOMON:
Just so my comments
8
are clear, I was responding to a factual
9
question. You know, how long do
you have to
10
follow it? That's the answer, as
best I can
11
say, based on my experience. I
wasn't
12 trying to imply that you'd hold up a BLA
13
approval for 5 to 10 years while you finish
14
this, no.
15 DR. RAO: Go
ahead.
16 DR. DAPOLITO:
Just a comment, and
17
again getting to what Dr. Lawton was talking
18
about. It gets back to the
choice of the
19
benefit outcome, the primary endpoint in
20
these studies. It sounds as if
what I'm
21
hearing is that the panelist is comfortable
22
accepting clinical data that from the basis
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from a risk/benefit analysis that does not
2
include long‑term follow‑up data, such that
3
the committee, depending on how persuasive
4
the benefit is, would accept the risk that
5
there is a potentially substantial mortality
6
disadvantage in the long‑term associated
7
with the product, if I'm understanding
8
correctly. Am I wrong?
9 MS. MEYERS:
It sounds to me like
10
it's not the product, it's the
11
immunosuppressive agents that are used.
12
That's were the risk is.
13 MR. DAPOLITO:
Again, it gets back
14
to that we don't operate in a vacuum.
As
15
with all concomitant therapies, you look at
16
the entire package.
17 DR. RAO:
Let's move on to the
18
next aspect, because I think it will
19
illustrate some of these things more and it
20
will help.
21 DR. RICORDI:
Can you just keep in
22
mind also that we do also islet after kidney
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in patients that are already taking
2
immunosuppression, in which we don't think
3
they interfere with the selection.
In that
4
case, there is no added risk of the islet
5
procedure. So we'd like to if
possible
6
suggest that we keep separate, and what is
7
the risk associated to the product, and it's
8
a figure set to the risk of
9
immunosuppression that is in constant
10
evolution, hopefully in the right direction.
11 DR. RAO:
Yes, I think here, all
12
we're trying to look at was what are the
13
kinds of monitoring things in terms of
14
assessing risk and benefits. To
me, this
15
was really an important question and I think
16
it's something to really consider,
17
historically controlled clinical data.
How
18
does one compare, and how specifically the
19
appropriateness of the use of historical
20
controls in the whole development, and
21
whether data from studies that have no
22
concurrent controls would be sufficient to
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1
provide substantial evidence of
2
effectiveness of the product.
3 Spots of this issue were raised
4
where people said, well, should we be
5
implanting insulin pumps in any kind of
6
study, or you know, is that the concurrent
7
control? Or can we can just look
at the
8
historical controls since the endpoints are
9
so clear‑cut in terms of looking at insulin
10
independence. We know what
happens with the
11
patients in terms of if they are labile and
12
that subgroup has clear predicable outcome,
13
can we use historically controls.
14 Maybe just some sense from people,
15
in a yes and no fashion, so that we can then
16
have a discussion on it.
17 DR. SILVERSTEIN:
Could I just
18
bring up one that you haven't mentioned,
19
which is having the patient serve as his or
20
her own control. We could
actually, in this
21
scenario, fulfill Cox Postulates, because
22
you have them before, you have them during,
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1
and in a certain proportion of them, they'll
2
fail and go back to the way they were
3
before.
4 DR. RAO:
That's an important
5
point.
6 DR. HERING:
Yes, I would like to
7
echo this point. I think that
the point
8
that needs to be made in this context is
9
that islet transplants are considered
10
predominately if not exclusively in patients
11
in whom other treatment options have
12 consistently
failed to ameliorate the
13
situation.
14 So you cannot possibly compare to
15
insulin pump treatment. That is
why it
16
might be difficult to randomize patients,
17 because the control
arm has failed to
18
deliver.
19 DR. RAO:
These are really
20
important points. I'd like to
bring up
21
peoples' opinions on them. Dr.
Salomon.
22 DR.
SALOMON: Yes, I was just
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going to say I agree completely that a
2
randomization protocol would be hard to
3
follow, with these hypoglycemic unawareness
4
patients, for example. I think
you would
5
have ethical problems, but I defer to my
6
colleague, Jim Childress, for that.
7 But in contrast, there is a group
8
that was mentioned by Camillo that I
9
personally favor, and that is the
10
islet/kidney combination, because there,
11
we're going to immunosuppress them for the
12
kidney transplant anyway. In
those
13
patients, actually, you could number one,
14
have a control group, because there's plenty
15
of patients who are going to get kidney
16
transplants that could be compared in the
17
same center with similar immunosuppressive
18
regimens.
19 But I would say, just to finish,
20
that historical controls, to say that we
21
support those I think would contradict
22
everything we've been saying.
Because I
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can't tell you five minutes ago that, you
2
know, we're evolving our experience and our
3
skills using these immunosuppressive drugs
4
and then tell you right now that I think
5
historical controls are fine.
6 DR. RAO:
There was an important
7
idea here, right, and we heard a little bit
8
more about, is that the patient has already
9
failed therapy. You follow them,
so you
10
have pre‑ and then you have post‑, and then
11
you have a follow‑up which is mandated, and
12
could a patient in that sense serve as their
13
own control so that you wouldn't really need
14
to ‑‑ or would that be sufficient in
15
peoples' minds?
16 DR. O'FALLON:
Well, I'm going to
17 have to say no.
18 DR. SHERWIN:
No. No, yeah.
19
Yeah. First of all, historical
controls I
20
would not accept. Number two,
what Janet
21
described as a reasonable approach, it
22 depends on how
definitive you want the
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1 answer. I'm a little concerned about the
2
history before patients going in.
I mean,
3
the problem you face is that the level of
4
care that's delivered to the patient has a
5
lot to do with the outcome.
Ideally, what
6
you'd like to do is compare head‑to‑head in
7
some way; either note change in therapy in a
8
group of patients that were defined.
9 I mean, the problem is defining
10
the population to start with, and then in
11
that population demonstrate a difference
12
Ideally, you would like to compare it in
13
part to the best therapy available, and
14
ideally, you'd like to compare it with pump
15
therapy and show it's better, and that would
16
be a very useful piece of information, and
17
it would really put islet transplantation on
18
a map definitively, and it wouldn't have the
19
diabetologists arguing that we have a better
20
therapy.
21 On the other hand, I think it
22
depends on finances, a lot of other issues.
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I think if you have good historical data
2
before and after, it's reasonable.
It's not
3
the best. The best is head‑to‑head,
do it
4
like a regular clinical trial just like you
5
would do a drug.
6 DR. RAO: Go
ahead.
7 DR. LEVITSKY:
I agree with that.
8
I would just add one thing, which is, you
9
could have in your control group a crossover
10
option if they met certain stopping rules.
11
Like they had x‑many life threatening
12
hypoglycemic events.
13 DR. SHERWIN:
Absolutely.
14 DR. LEVITSKY:
So that you could
15
keep everybody safe, and it could be a
16
6‑month or a 12‑month time frame so that you
17
weren't ‑‑
18 DR. SHERWIN:
Yes. I would
19
totally agree with that. I mean,
in fact,
20
that would be one way of inducing people to
21
be randomized, is they would have the
22
option, depending on the data, to be first
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1
in line.
2 MS. HARVEY:
One of the issues
3
with all of this discussion, as always the
4
case with controls, is the ethical issues
5
for the patients, with the treatment versus
6
the standard of care, which we've heard is
7
not good enough at the moment.
8 The one issue I wanted to raise
9
is, from the discussions from around this
10
source material, it seems like over the last
11
couple of days everything we've heard is
12
there's not enough pancreases to go to the
13
patients available. So why would
we not use
14
the excess patients who are getting standard
15
of care without the islet transplantation as
16
a control group?
17 DR. O'FALLON:
That was exactly
18
what I was going to say. We've
been told
19
there's a waiting list. All
you'd probably
20
have to do is set up a monitoring system so
21
that you were following the people on the
22
waiting list to the same extent that you
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1
were following the people that were getting
2
the transplant. That's not
perfect, but ‑‑
3 DR. SALOMON:
No. The problem
4
with waiting lists; if we talk about a year
5
follow‑up maybe, you're pushing it on the
6
waiting list, but that's possible.
But you
7
really are asking for three‑ to five‑year
8
follow‑up eventually, then your design's
9
flawed from the very beginning, because
10
nobody's going to be on your waiting list
11
for five years. There's too much
going on
12
in that patient to ‑‑
13 DR. SHERWIN:
Right. If your
14
indication is severe hypoglycemia, if that's
15
the defined beginning group that you're
16
looking at, then you don't
need that. I
17
think if you focus in on that complication,
18
we're talking about no more than two and
19
maybe one year.
20 DR. SALOMON:
But the problem is,
21 I remind you
how it would look then. So we
22
start the trial together, and five years go
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1
by. We get up at a major meeting
event of
2
endocrinologists and conclude that it's
3
fantastic, based on the fact that the
4
patients were really different over a
5
six‑month period compared our patients in
6
five. Then someone like Abbey
says but the
7
immunosuppression was a major risk factor,
8
and you immunosuppressed all your patients
9
for five years. Where's your
control group
10
for that?
11 DR. ALLAM:
Those are two
12
different questions. So you're
really
13
asking for two different control groups.
14
You're asking for a control group on risk
15
and a control group on efficacy; right?
16 DR. RAO: Dr.
Shapiro?
17 DR. SHAPIRO:
Just a point of
18
clarification. Are you asking or
suggesting
19
for a randomized comparison of patients on
20
pump therapy versus an islet transplant? Or
21
are you proposing, as we've doing so far,
22
taking on patients that have failed on pump
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1
therapy and giving them an islet transplant?
2 DR. SHERWIN:
I have to think
3
about that. It depends on how
they failed,
4
why they ‑‑ I mean, I don't 100 percent
5
know. Assuming that they failed
and then
6
you could document a lead‑in period well
7
enough, perhaps that would be a reasonable
8
approach. I mean, I won't argue
that. I
9
just worry when I hear that they couldn't be
10
managed, and therefore, they need this
11
therapy. I'd like to define a
group that
12
has a serious problem, randomize them to one
13
therapy that I think is the best, compare it
14
to the other and show a difference.
I'd
15 like them all starting out
at the same part.
16
That's the best way to do it.
17 DR. RAO: So
can we make a
18
statement here then? I mean, it
seems to me
19
a very clear‑cut, absolute consensus here
20
was that historical controls are not
21
adequate, and that seems very clear.
There
22
was some idea that one needed a comparison,
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1
and it's not clear what that comparison is
2
and we're not really making an absolute
3 suggestion on a
comparison. But clearly
4
there has to be some kind of comparison, and
5
it should be on a reasonable time point.
6 Since the criteria for inclusion
7
is hypoglycemia in this case as having, you
8
know, uncontrollable hypoglycemic episodes,
9
then perhaps you could have a short‑term
10
read‑out in terms of looking at that in any
11
kind of comparison, which would be done.
12
There would have to be of course discussions
13
on what kind and whether it could be
14
particularly accurate, and whether there
15
would be crossover issues, et cetera.
But
16
that would be something that
would be ‑‑
17
would that ‑‑
18 DR. SALOMON:
I'd say the clear
19
point that I think Dr. Allam made was there
20
could be efficacy controls and side effect
21 controls, and that
we should deal with those
22
separately. The other point I
think, just
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to add what you just said, is that depending
2
on the trial design, the controls could be
3
different. As I said, a control
for the
4
kidney/islets is really rather reasonable to
5
ask for since there are going to be many
6
patients getting kidney transplants that
7
with diabetes that won't get islets in the
8
same center, or certainly in an adjacent
9
center with an equivalent immunosuppressive
10
protocol. So that would be a
much easier
11
group. So I think you'll adjust
your
12
controls and the application to the trial
13
design.
14 DR. RAO: I
think that seems like
15
a pretty fair consensus. Since
we have some
16
time, there are two important questions.
17
I'm not sure we're going to get to all of
18
this here, but it's the third part of the
19
question. There are two
parts. I'm going
20
to try and see if we can slide through the
21
last part and see whether we can get some
22
kind of general consensus.
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1 "Additionally, please discuss
2
those baseline characteristics that you
3
regard as important for a sponsor to
4
consider in the clinical development of the
5
product." To me, this seems
like inclusion
6
criteria, how do you decide what kind of
7
patients you're going to include.
We heard
8
presented here that there was a very
9
clear‑cut and narrow definition of patients
10
that were going to be considered in this
11
case, and these were these severely
12
hypoglycemic, who've had more than two
13
episodes of hypoglycemia and had tried
14
conventional therapy and failed it in some
15
definite criteria.
16 Is there specific inclusion or
17
exclusion criteria, based on what you've
18
heard so far in terms of age, extent, or
19
nature of diabetic complications, which are
20
absolute exclusionary or
inclusionary, or
21
things that have not been considered that
22
one would want to?
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1 DR. SHERWIN:
I don't know. To
2
try to resolve that one question, I would
3
think people with other complications,
4 cardiovascular
disease, for example. If
5
someone had angina, I would be a little
6
concerned about enrolling them in a trial
7
like this. It would be mainly I
think the
8
severity of complications. I
don't have
9
enough experience compared to the ‑‑
10 DR. RAO:
What about pre‑existing
11
kidney failure or something? Is
that ‑‑
12 DR. SHERWIN:
You know, kidney
13 disease in and
of itself can alter the rate
14
of hypoglycemia. So if you had a
control
15
group, you'd have to standardize it.
If I
16
had my way, I would avoid that, but I don't.
17
Personally, as a scientist, I'd like to keep
18
it as clean as I could. But the
surgeons
19
might have a totally different perspective,
20
and they have more experience in this area.
21 DR. VINER: I
wonder if there
22
might be some way of including the
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1
population of patients where immunotherapy
2
might be considered a benefit as opposed to
3
a risk. That group of patients
may be
4
patients like rheumatoid arthritics that
5
also have diabetes, where
there's a
6
coexistence of autoimmune disorder, and they
7
have therapeutic benefits from the ongoing
8
immunotherapy. I wonder if
there's been a
9
selection of patients so far to date, and if
10
that's been considered.
11 DR. LEVITSKY:
In order to obtain
12
a group that you want to study that will
13
have an immediately accessible endpoint, you
14
need a very small, well‑defined group of
15
patients who have ‑‑ in this case, we've
16
selected very severe hypoglycemia as the
17
endpoint. If we were also to
look for
18
people with severe hypoglycemia and
19
rheumatoid arthritis, we would have to cast
20
a rather wide net. I don't think
you could
21
do that. I think that won't be ‑‑
22 DR. RAO: Go
ahead, Dr. Harlan.
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1 DR. HARLAN:
We are approaching
2
this question along this line exactly.
I
3
have a couple provisoes, and I promised
4
James Shapiro I'd make a statement that I
5
want to make after I make this specific
6
comment that will get to this.
7 But the general
comment is that
8
testing immunosuppressives in a population
9
that absolutely needs them, to us, is a
10
patient with Type 1 diabetes and kidney
11
failure that needs a kidney transplant.
The
12
way you randomize it is that some of the
13
patients get islets and some of them don't.
14
They all get immunosuppressed.
They all
15
benefit from the kidney transplant.
No
16
question. That's well‑established
in the
17
literature.
18 They all need immunosuppression,
19
and now you can ask the specific question,
20
do the islets make a difference.
21 DR. SHERWIN:
David, is the
22
immunosuppression identical?
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1 DR. HARLAN:
Yes, we have that ‑‑
2 DR. SHERWIN:
Do we know the
3
outcomes per renal disease?
4 DR. HARLAN:
Yes.
5 DR.
SHERWIN: Okay.
6 DR. HARLAN:
I think that's a nice
7
small study; getting enough patients to do
8
is tough. And that addresses one
point. I
9
know I've been saying a lot of, cautionary,
10
is the way I'd word them. Other
people
11
would say negative statements about islet
12
transplant.
13 But I absolutely, as evidenced by
14
these two people sitting here, believe in
15
this as a field that needs to be
16
investigated and perfected. We
are going to
17
proceed with this. I hope my
cautionary
18
comments haven't been viewed as too
19 negative.
20 The other statement I'll make is
21
that when I say things here, I have to say
22
it, especially because I'm wearing the
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1
uniform today, I want it to be known that
2
I'm speaking with an investigator with a
3 passion for this cause, just like many
4
people in this room, but I'm not professing
5
or any official NIDDK or NIH policy.
6 The third point I wish to make is,
7
I wish these three people and anybody else
8
doing research in this field all the credit
9
in the world for getting a field that all
10
the experts predicted would never be here
11
for 20 years to this point. I
hope my
12 negative or
cautionary comments haven't been
13
viewed other than being very laudatory and
14
respectful for all that they've done.
15 DR. LEVITSKY:
You selected an
16
excellent population for study, but from the
17
point of view of immunosuppression, what are
18
you going to use as your endpoints for
19
success in terms of the diabetes component?
20 DR. HARLAN:
Maybe I can just
21
discuss this with you privately.
22 DR. RAO: To
me, it seems then
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1
that it's clear the way the selection of
2
baseline characteristics is nearly defined
3
by very narrow specific population that has
4
been laid out in a reasonable way, and that
5
that's reasonable and that there shouldn't
6
be any additional specific criteria.
7 It didn't seem that ‑‑ even apart
8
for the obvious, right? In terms
of obvious
9
complications ‑‑ that for immunosuppression
10
which would be a no‑no or something else
11
that would there, and there's no way to make
12
it broader or more inclusionary, given the
13 waiting list and
the shortage of material
14
and what's existing, so that the criteria as
15
laid out seems to be reasonable in my
16
opinion.
17 I want to try and spend a little
18 of time here,
because this is, I think,
19
going to be contentions and a little bit
20
difficult to be able to say this with any
21
definiteness. Let's say that you
have a
22
small trial or you have a small study, and
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1
you have two arms and it's well‑controlled,
2
and you use hypoglycemic episodes as a
3
clinical outcome that you can measure.
4 Can you generalize from this to
5
then say well, you know, here's this case.
6 Here, we have islets, they
secrete insulin.
7
We know that you can correct an insulin lack
8
by this. Can we generalize it to
treatment
9
of other diabetics who need insulin?
Again,
10
I'm making it broader than perhaps one would
11
want, but it's a useful way to start
12
thinking of this and say, can we generalize
13
from this? If not, would adding
additional
14
parameters to study allow us to generalize
15
from such a study?
16 DR. SHERWIN:
Well, I don't think
17
you can generalize from the short, small
18
trial. You can maybe generalize
with
19
respect to this specific question you
20
address if the study is done well.
21 DR. RAO:
Safety.
22 DR. SHERWIN:
But the key
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question, you know, in terms of looking at
2
the big picture will be safety for all
3
people with diabetes. Most
people with
4
diabetes can be treated reasonably well, and
5
we can reduce their complication rate
6
significantly with the current standard of
7
care. But it's not perfect.
8 So then you
have to say well, one
9
is not perfect and there are problems.
What
10
are the problems on the other side to assess
11
risk/benefit ratio? The decision
about how
12
far you can expand the group really requires
13
long‑term trials and information that will
14
require five, maybe even seven years to sort
15
out.
16 But I do think that if you show
17
benefitting the most severe patients with
18
hypoglycemia, that the net will expand a
19
little bit beyond that very narrow group,
20
because a lot of people have lots of
21
problems, maybe not quite as bad.
And you
22
would begin to increase your net a little
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1
bit. But I don't think you'd
want to say
2
that you're ready for prime time for all
3
people with diabetes. I think we
would need
4
to have more information. That's
going to
5
take more time, I think.
6 DR. RAO: Dr.
Levitsky, do you ‑‑
7 DR. LEVITSKY:
No.
8 DR. RICORDI:
I just hope that
9
this discussion is not going towards an
10 indication that we
should do another five
11
years of randomized trials. This
is an
12
important issue. These studies
may be done
13
and hopefully should be done.
I'm not sure
14
who would pay for such a large trial.
But
15
in pancreas transplantation, for example, or
16
even in kidney transplantation, you have
17
procedures that have never been evaluated
18
prospectively; the kidney versus dialysis,
19
or kidney/pancreas transplantation versus
20
kidney alone.
21 Now there are insurance
22
reimbursable, and so that it would be like a
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death sentence to impose to the islet field
2
that you have to show it through randomized
3
trials in the next five years before you can
4
support immunosuppression for the patient
5
that may benefit now. Even if in
a reduced
6
cohort.
7 DR. SALOMON:
I think that as I
8
said yesterday, when were talking about the
9
product, the same kind of concept is
10
applicable here. It's the
biology of
11
diabetes in this case, just as yesterday it
12
was the biology that defined the
13
functionality of an islet prep.
14 So in this case, my thinking is
15
that if we look at the data that we have now
16
and maybe refine it over the next few months
17
to fill in the some of the gaps that have
18
come out of these very good discussions
19
today, and demonstrate that the biology of
20
these diabetic patients is really
21
significantly and positively impacted upon
22
by successful islet transplant, that to me
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ought to carry a lot of weight.
2 We should be careful. Even though
3
I agree with the concept, if someone asked
4
me the same question you asked Dr. Sherwin,
5
you know, could you generalize from this one
6
little group? His answer is
correct.
7
You've got to be careful. I
mean, you know,
8
the other group is a diabetic patient with
9 kidney failure.
10 So I totally agree with his
11
comment. At the same time, I
certainly
12
would be very careful not to go the other
13
direction, and that is to ignore the
14
tremendous impact on restoring
the biology
15
of glucose homeostasis in a diabetic patient
16
for 20, 25 years, who suffered with it, and
17
narrow down things and put another five‑year
18
barrier in front of this field.
That would
19
be a real shame.
20 DR. RAO: I
think that was very
21
clear from Dr. Sherwin's comments.
22 DR. SHERWIN:
And that's surely
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not what I would want to do.
2 DR. SALOMON: I totally agree.
3
This was not directed to you.
4 DR. SHERWIN:
It's somewhere in
5
between. We want to expand but
not
6
indiscriminately.
7 DR. RAO: I
think at this point in
8
time, it's not say this is a moot point, but
9
the tissue is not available to expand.
I
10
think the immunosuppressive treatment is not
11
safe enough to expand. It seems
to me it's
12 almost a very
appropriate setting. So you
13
have a treatment that is available because
14
of donor tissue where it would only
15
deliver 1,000 or 2,000 times a year.
16 There is a patient group that may
17
not be much larger at this point in time
18
that are really in need of treatment that is
19
different from the most sophisticated
20
insulin delivery systems. So I
think it
21 kind of is
almost a perfect match.
22 DR. O'FALLON:
That just saves us
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from having to make a difficult decision,
2
because the fact of the matter is we've
3
defined or we expect to see defined a very
4
small group. If it's expanded
more than
5
just that little bit that you're talking
6
about, we might get into the situation where
7
the therapy is no more effective than what
8
is actually going on now without the
9 transplant.
10 We certainly don't have enough
11
tissue and enough pancreata to do this.
It
12
certainly seems that a very carefully and
13
well‑designed study in this small
14 population's
going to terribly important,
15
and they should collect as much information
16
as they possibly can about the biology of
17
what's going on.
18 DR. SALOMON:
I just want to make
19
sure that the transcript's clear, at least
20
from my contribution to it. 30
percent of
21
patients with endstage renal disease in the
22
United States have Type 1 diabetes.
That
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number's shifting around a little bit, which
2 is only because the
Type 2 diabetics now are
3
contributing more, so they're knocking out
4
some of our Type 1s. Let's say
25 percent
5
are Type 1 diabetics. From my
point of view
6
at least, you don't want to do anything to
7
prevent those patients who are getting
8
kidney transplants and fully
9
immunosuppressed with state‑of‑the‑art
10
immunosuppression; you don't want to do
11
anything to create now another barrier that
12
would prevent them from getting an islet
13
transplant.
14 DR. RAO:
Would you like to make a
15
comment?
16 MR. DAPOLITO:
Dr. Rao, so
17
often ‑‑ the Lead Advisory Committee's a
18
little unclear of the message. I
want to be
19
sure on something that Dr. Ricordi actually
20
commented on. It goes back about
to the
21 discussion about
five minutes ago regarding
22
historical controls.
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1 Now, I scratched these notes, and
2
this is what I was hoping to get feedback
3
on. I probably misinterpreted
this, but I
4
want clarity. If I understand
correctly,
5
the consensus is that historically
6
controlled clinical data present major
7
challenges with respect to data
8
interpretability and are probably
9
insufficient with respect to definitively
10
accessing risk and benefit; meaning
11
conceptually, if a sponsor comes to us with
12
what they regard as efficacy data, but those
13
are not randomized control clinical data, in
14 general, our bias should
be that those type
15
data present problems.
16 Could you enlighten me if I'm
17
misinterpreting?
18 DR. RAO: I
don't think that that
19
was what was the implication of that
20
statement. Not completely. That isn't the
21
way I understood it.
22 DR. O'FALLON:
I think we have to
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worry about the interpretation of the word
2
"historical."
3 MR. RAO: Yes.
4 DR. O'FALLON:
"Historical" means
5
something that already took place before the
6
study that we're talking about.
We all
7
talked about several different kinds of
8 concurrent
activities that would fall short
9
of the purest textbook definition of a
10
randomized control trial, but at least we
11
were all encouraging each other to expect
12
that there was a possibility that this
13
concurred information could be used.
14 If you used the word "historical"
15
correctly as things that took place back in
16
time somewhere, then that's what we said.
17 We don't want to use that,
but it has to be
18
randomized goals.
19 DR. SALOMON:
But there was
20
another principle that was in your slides.
21
That was this word "persuasive." I really
22
like that. I think that the
first onus is
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that whatever the sponsor presents to you is
2
persuasive. On the front page of
the USA
3
Today that I managed to glance at as I
4
walked out my hotel room was that a new
5
cancer drug was having significant effects
6
in breast cancer.
7 My response as I was walking out
8
to the door was excellent.
That's a super
9
good way ‑‑ you know, much better than the
10 headlines in California
recently, by the
11
way. My response there is
nobody's going to
12
hold up the use of that drug for the next
13
five years while they determine the
14
long‑term risks of using it.
15 So I think that "persuasive" is
16
the word you have to remember. I
mean, as
17
far as I'm concerned, if you cure diabetes
18
in terms of the biology; if you restore
19
u‑glycemia to a group of patients who've had
20
diabetes for 25 years, that's persuasive,
21
and I think you need to put that first, and
22
then everything else comes after that.
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1 DR. RAO:
That's what I was trying
2
to say when I said not precisely, that no
3
historic controls could be used.
Go ahead.
4 SPEAKER: I
hope we're not totally
5
rejecting historical controls. I
think
6
there are certain historic controls that I
7
think everybody would accept.
And one
8
doesn't want to give the message that you
9
would not accept it.
10 For instance, if a year after
11
transplant, a patient who started out with
12
Type 1 diabetes is now c‑peptide positive, I
13
think we would all accept based on
14
historical controls that that did not happen
15
by chance, that was a result of the
16 treatment, right? We
would all accept that,
17
I think.
18 Similarly, we know a lot of
19
information from the DCCT trial, which is
20
also historical controls. We
know roughly
21
that if you have a certain hemoglobin A1C
22
level, you will roughly have a certain
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incidence of severe hypoglycemia.
2 Now let's say after a transplant,
3
the patient has a hemoglobin A1C of 5 and no
4
severe hypoglycemia, I think we would
5
accept, based on historical controls, that
6
that didn't happen randomly, that that was a
7
result of the treatment, even though without
8
a controlled comparison.
9 So we then
ask well, what if
10
Dr. Ricordi comes up with 100 consecutive
11
patients who start out with a hemoglobin A1C
12
of 10 and are poorly controlled; they're in
13
the hospital all the time; and then a year
14
later, they're c‑peptide positive; they have
15
a hemoglobin A1C of 5; and they have no
16
hypoglycemia, would we really say well, we
17
need controls; we can't approve that.
18 I think we have to be careful
19
about the comparisons of renal failure in
20
renal transplants versus dialysis.
I mean,
21
there's certain things that I think we
22
should accept and not be, you know, overly
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rigorous at this stage and really cut off
2
what may be a very important field.
3 DR. SALOMON:
Bob, I think that
4
the point there gets back to a principle we
5
articulated earlier, and that is that there
6 can be controls
of efficacy, in which case
7
you made a nice argument for historical
8
controls in that particular experimental
9
design for efficacy would be very useful.
10
Yet those same controls would not be useful
11
for risk.
12 DR. ALLAM:
Maybe I'm off‑base
13
here, but I guess the way I'm looking at it
14
is if you want to allow these types of these
15
clinical procedures to go forward, yes.
16
Historical data would probably be okay in
17
some cases. Now, if you're
talking about a
18
BLA, I don't have that familiarity with
19
licensing a biological product. But it may
20
raise the bar in terms of what kind of
21
controls you need. Because that ‑‑
22 MR. DAPOLITO:
We do consider
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historical controls in some cases as
2
sufficient. Again, it gets back
to the
3
persuasiveness of the data and how the
4
control data set is established.
5 DR. RAO:
Kathy.
6 DR. HIGH:
Just to add to that
7
point, I think for example the recombinant
8
proteins that are used to treat hemophilia,
9
patients were allowed to, in a run‑in
10
period, essentially be their own controls
11
for the licensing, for example, recombinant
12
factor nine.
13 DR.
SILVERSTEIN: I would think
14
that if part of the protocol was to put
15
these patients on the state‑of‑the‑art, best
16
therapy, for instance, the pump, and then
17
compare how they do on transplant versus the
18
pump, that would take care of Bob's problems
19
with having the patient as their own
20
control.
21 DR. SHERWIN:
I think that's a
22
reasonable approach. I mean,
it's not the
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perfect, but it is good enough given what I
2
expect to be the outcome. My
guess is it's
3
going to be a very obvious effect.
Based on
4
that assumption, I would say using the
5
patient as their own control probably will
6
be adequate.
7 If it wasn't for that feeling,
8
then I would argue strongly the other way.
9
But I think that using historical controls
10
always raises issues in the scientific
11
community. This is such a
controversial
12
therapy still that I just feel that having
13
solid data in the long run will be good for
14
these guys. I would like to see
the field
15
move forward.
16 I don't think that doing a trial
17
where people then can raise all sorts of
18
issues will be in the best interest of their
19
efforts.
20 DR. RAO: Dr.
Ricordi.
21 DR. RICORDI:
I just wanted to
22
echo that I'm perfectly in agreement with
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what you mentioned regarding that there are
2
some historical controls and other
3
historical controls. Of course,
if you will
4
compare with insulin therapy at the
5
beginning of the '30s to now would
6
inappropriate.
7 But we have spent
8
collectively $280 million taxpayer money to
9
do the DCCT trial and would be a pity for
10
you to now say well, this cannot be used any
11
longer to judge what the benefit ‑‑ even in
12
the risk in development of complications,
13
because there are now algorithms that have
14
been developed based on that huge trial that
15
can point out how the risk decreased for a
16
varying degree percent point of hemoglobin
17
A1C that you can decrease and you can deduct
18
like cost of treatment, quality
of life,
19
risk of progression of complication.
There
20
is huge volume of data coming out from these
21
very expensive and extensive trials.
22 DR. RAO: I mean,
I think
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Dr. Salomon really summarizes when he said
2
persuasive evidence. If you have
two arms
3
of a trial, one can't be a historical set of
4
controls if you have two arms of a trial.
5
But certainly, you know, when you're
6
comparing or you've looked at failed
7
patients and then you're following them and
8
you look at recovery, then that's certainly
9
not the same as saying it's a historical
10
control. And that was not what
the
11
intention was when the committee pointed
12
this out in terms of looking at historical
13
controls.
14 If that's true, then we really
15
have surprisingly come to some sort of
16
consensus in a lot of this. I'm
going to
17
try and see if I can summarize question
18
three and see whether we have to reopen it
19
as well. It's a small number of
patients
20 which are a pretty defined population. In
21
that small number of patients, whichever,
22
pretty defined population, we don't think
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that you can really generalize to a large
2
extent to the rest of the diabetic
3
population.
4
Maybe a small extent
based on the
5
fact that there are other hypoglycemic
6
patients or that people who have kidney and
7
pancreas islet transplants, maybe you can
8
generalize to hypoglycemic patients, but not
9
broader than that. There aren't
any
10
specific tests that one could add to try and
11
generalize it.
12 Thank you everyone for your time.
13
I declare the meeting closed.
14 (Whereupon, at approximately
15 2:16 p.m., the MEETING was
16 adjourned.)
17 *
* * * *
18
19
20
21
22
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