DEPARTMENT OF HEALTH
AND HUMAN SERVICES
FOOD AND DRUG
ADMINISTRATION
This transcript has
not been edited or corrected, but appears as received from the commercial
transcribing service. Accordingly the
Food and Drug Administration makes no representation as to its accuracy.
79th Meeting of:
BLOOD PRODUCTS
ADVISORY
COMMITTEE
March 18, 2004
Holiday Inn
2 Montgomery
Village Avenue
Gaithersburg, Maryland
Reported By:
CASET Associates
10201 Lee Highway, Suite
160
Fairfax, Virginia 22030
(703) 352-0091
TABLE OF CONTENTS
Page
Welcome, State of Conflict of Interest, Announcements 1
Open Committee
Discussion
Clinical Trials
for Licensing hepatitis B Immune Globulin Intravenous as Treatment to Prevent
HBV Liver Disease Following Liver Transplantation in HBV+ Recipients.
- Introduction and Background - Basil Golding, MD 6
- Presentation - Anna S. Lok, MD 11
Open Public Hearing 74
Open Committee
Discussion (Continued)
- FDA Current Thinking and Questions for Committee 99
- Committee
Discussion and Recommendations
Committee Updates:
- Current thinking on Variances to Address the 136
Specificity of Ortho HBsAg 3.0 Assays
- Gerardo Kaplan, PhD
- Summary of meeting of PHS Advisory Committee on 155
Blood Safety Availability - Jerry Holmberg,
MD
- Summary of Meeting of Transmissible Spongiform 163
Encephalopathies Advisory Committee Meeting
- David Asher, MC
- Current Thinking on Draft Guidance for Nucleic Acid 173
Testing for HIV and HCV: Testing, Product
Disposition
and Donor Deferral and Re-entry - Paul Mied,
PhD
- Current thinking on Final Guidance for Use of Nucleic 191
Aid Testing on Pooled and Individual Samples
from Donors
of Whole Blood and Blood Components to
Adequately and
Appropriately Reduce the Risk of
Transmission of HIV-1 and HCV -
Pradip Akolkar, PhD, Judy Ciaraldi, BS, MT
Open Committee
Discussion:
Supplemental
Testing for Human Immune Deficiency Virus
and Hepatitis C
Virus.
- Introduction and Background, Robin Biswas, MD 203
Indira Hewlett, PhD
- Performance of HIV and HCV Supplemental Assays
- Wendi Kuhnert, PhD 208
- Dale J. Hu, MD, MPH 224
- Susan Stramer, PhD 231
- Michael Busch, MD, PhD 255
Open Public Hearing 282
Open Committee Discussion 287
- Questions for the Committee
- Committee Discussion and Recommendations
COMMITTEE
MEMBERS:
KENRAD NELSON,
MD, Chair. Johns Hopkins
University, School of Hygiene and Public Health, Baltimore, Maryland
LINDA SMALLWOOD,
PhD, Executive Secretary.
CBER, FDA
PERLINE K.
MUCKELVENE, Committee Management Specialist. Scientific Advisors and Consultants Staff, CBER, FDA
JAMES R. ALLEN,
MD, MPH, American Social
Health Association, Research Triangle Park, North Carolina
CHARLOTTE
CUNNINGHAM-RUNDLES, MD, PhD, Mount
Sinai Medical Center, New York, New York
KENNETH DAVIS, JR,
MD, University of Cincinnati
Medical Center, Cincinnati, Ohio
DONNA M. DI
MICHELE, MD, Weill Medical
College and Graduate School of Medical Sciences, Cornell University, NY, New
York
SAMUEL DOPPELT,
MD, The Cambridge Hospital,
Cambridge, MA
JONATHAN GOLDSMITH,
MD, Immune Deficiency
Foundation, Towson, Maryland
HARVEY KLEIN, MD,
Magnuson Clinical Center,
NIH, Bethesda MD
SUMAN LAAL, PhD, New York University School of Medicine, NYC
JUDY LEW, MD, University of Florida, Gainesville, Florida
NON-VOTING INDUSTRY
REPRESENTATIVE.
MICHAEL STRONG,
PhD, BCLD, Puget Sound Blood
Ctr, Seattle WA
TEMPORARY VOTING
MEMBERS:
MARY CHAMBERLAND,
MD, MPH. NCID, CDC, Atlanta,
Georgia
LIANA HARVATH,
PhD, NHLBI, NIH, Bethesda,
Maryland
BLAINE F.
HOLLINGER, MD, Baylor
College of Medicine, Houston, Texas
JAY HOOFNAGLE,
MD, NIDDK, NIH, Bethesda,
Maryland
KATHARINE
KNOWLES, Health Information
Network, Seattle, WA
T. JAKE LIANG,
MD, NIDDK, NIH, Bethesda,
Maryland
JEANNE V. LINDEN,
MD, MPH, New York State
Department of Health, Albany, New York
DANIEL MC GEE,
PhD, Florida State
University, Tallahassee FL
KEITH C. QUIROLO,
MD, Children's Hospital and
Research Center at Oakland, Oakland, California
GEORGE B. SCHREIBER, ScD, Westat, Rockville, Maryland
DONNA S.
WHITTAKER, PhD, Lt. Colonel,
United States Army, Brooke Army Medical Service, Fort Sam Houston, Texas
P
R O C E E D I N G S (8:00 a.m.)
Agenda Item:
Welcome, Statement of Conflict of Interest, Announcements.
DR. SMALLWOOD: Good morning, and welcome to the 79th meeting of the Blood
Products Advisory Committee. I am Linda Smallwood, the executive secretary.
At this time, I will read the conflict of
interest statement regarding this meeting.
This announcement is part of the public record for the Blood Products
Advisory Committee meeting on March 18 and 19, 2004.
Pursuant to the authority granted under the
committee charter, the director of FDA's Center for Biologics Evaluation and
Research has appointed the following individuals as temporary voting members:
Drs. Mary Chamberland, Liana Harvath, Jay
Hoofnagle, Blaine Hollinger, Jake Liang, Jeanne Linden, Daniel McGee, Keith
Quirolo, George Shreiber, Donna Whittaker, and Ms. Katherine Knowles.
Based on the agenda, it has been determined
that there are no specific products being considered for approval at this
meeting.
The committee participants have been screened
for their financial interests. To
determine if any conflicts of interest existed, the agency reviewed the agenda
and all relevant financial interests reported by the leading participants.
The Food and Drug Administration has prepared
general matters waivers for the special government employees participating in
this meeting who required a waiver under Title XVIII, United States Code 208.
Because general topics impact on so many
entities, it is not prudent to recite all potential conflicts of interest at
they apply to each member.
FDA acknowledges that there may be potential
conflicts of interest but, because of the general nature of the discussions
before the committee, these potential conflicts are mitigated.
We would like to note for the record that
Dr. Michael Strong is participating in this meeting as the non-voting
industry representative, acting on behalf of the regulated industry.
Dr. Strong's appointment is not subject to
Title XVIII United States Code 208. He
is employed by Puget Sound Blood Center and, thus, has a financial interest in
his employer. He is also a researcher
for two firms that could be affected by the committee discussions.
In addition, in the interests of fairness,
FDA is disclosing that his employer, Puget Sound Blood Center, has associations
with regional hospitals and medical centers.
With regard to FDA's invited guests, the
agency has determined that the services of these guests are essential.
These are interests that are being made
public to allow meeting participants to objectively evaluate any presentations
and/or comments made by the guests.
For the discussions of topic one, related to
clinical trials for licensing hepatitis B immune globulin as a treatment to
prevent hepatitis B virus liver disease, Dr. Anna Lok is employed by the
University of Michigan Medical Center.
She is a researcher with the National
Institute of Diabetes and Digestive and Kidney Diseases, that collaborates with
NABI.
She also consults with, and is a scientific
advisor for two firms that could be affected by the committee discussions.
For the discussion of topic two, on the
effectiveness of supplemental testing, methodologies for human immune
deficiency virus, and hepatitis C virus, Dr. Susan Stramer is employed by
the American Red Cross, National Reference Laboratory of Infectious Disease.
She is a researcher, a scientific advisor,
and has financial interests in firms that could be affected by the discussions.
Dr. Wendi Kuhnert is employed by the CDC in
Atlanta, Georgia.
Dr. Michael Busch is employed by the Blood
Center of the Pacific. He is a
scientific advisor for firms that could be affected by the discussions. He also receives speaker and consulting fees
and is a principal investigator on contracts and grants with firms that could
be affected.
Dr. Dale Hu is employed by the CDC in
Atlanta.
For the discussions on topic three, on the
review of data supporting FDA's current thinking on product standards, quality
assurance, and submission requirements for platelets pheresis, Dr. German
Leparc is employed by the Florida Blood Services.
In addition, there may be speakers making
industry presentations and speakers giving committee updates on regulated
industry and other outside organizations.
These speakers have financial interests
associated with their employer and with other regulated firms. They were not screened for these conflicts
of interest.
FDA participants are aware of the need to
exclude themselves from the discussions involving specific products or firms
for which they have not been screened for conflicts of interest. Their exclusion will be noted for the public
record.
With respect to all other meeting
participants, we ask, in the interests of fairness, that you state your name,
affiliation, and address any current or previous financial involvement with any
firm whose products you wish to comment upon.
Waivers are available by written request under the freedom of
information act.
At this time, I would like to ask if any of
our participants, our committee members, or our invited consultants, if there
are any additional declarations that would need to be made.
Hearing none, I would move forward. I would
like to introduce to you the members of the Blood Products Advisory
Committee. I will call their names as
they appear on the roster and, when I call your name, would you please raise
your hand.
Chairman, Dr. Kenrad Nelson, Dr. James Allen, Dr. Kenneth Davis, Dr.
Samuel Doppelt, Dr. Harvey Klein, Dr. Suman Laal, Dr. Michael Strong.
We have with us several temporary voting
members: Dr. Mary Chamberland, Dr. Leanna Harvath, Dr. Jay Hoofnagle, Ms.
Katherine Knowles, Dr. Jake Liang, Dr. Jeanne Linden, Dr. Daniel McGee, Dr.
Keith Quirolo, Dr. George Schreiber, and Dr. Donna Whittaker. Did I omit anyone?
I would just like to bring to your attention
that out on the table there is a flyer announcing a forthcoming workshop on
radiolabeled platelets for assessment of in vivo viability of platelet
products.
This will take place on May 3, 2004, at the
Lister Hill Auditorium, and you may pick one up on the table outside.
With regard to the meeting, again, as always,
we have a very full agenda. We have
identified the topics and the expected times for those.
We will try as best we can, and probably even
better, to keep everyone on time. So, we would ask that you would adhere to
your time frames, and the committee chair will also help to see that this
happens.
At this time, I will turn the proceedings of
this meeting over to the chairman, Dr. Kenrad Nelson.
DR. NELSON:
Thank you, Dr. Smallwood.. The first topic for today is clinical trials
of licensing of hepatitis B immune globulin IV, the treatment for patients
receiving liver transplants. Dr. Basil
Golding from FDA.
Agenda Item:
Open Committee Discussion.
Clinical Trials for Licensing Hepatitis B Immune Globulin Intravenous as
Treatment to Prevent HBV Liver Disease Following Liver Transplantation in HBV+
Recipients. Introduction and
Background.
DR. GOLDING:
Good morning. Before I give my
brief presentation, I would just like to thank Dr. Anna Lok and the two other
experts who are here, Dr. Jake Liang and Dr. Jay Hoofnagle, for joining us for
this session.
Their expertise is highly valued, and I think
they will make a big difference in helping us come to the right decisions
regarding these questions, in particular Dr. Anna Lok, who is going to provide
a background to the subject.
My job, really, is to give you an idea of
what the regulatory issues are, and to indicate up front what questions are
going to be asked of the committee so that, during the actual presentation, you
will be able to have the questions at the back of your mind and you will be
able to put them in better focus.
Hopefully, that will make the process a lot easier.
So, what we are talking about are clinical
trials for hepatitis B immune globulin intravenous and, in particular, it is in
the post-transplant situations.
In terms of background, we are talking about
hepatitis B virus, which is a major cause of both acute and chronic liver
disease worldwide.
Occasionally, infection with this virus will
cause a fulminating hepatitis, or it could go on to chronic liver disease,
cirrhosis and end in liver failure. The
liver failure would then be treated by liver transplantation.
Orthotopic liver transplantation, or OLT,
often results in failure due to recurrent HBV infection of the new liver.
It is believed, by the people in the field,
that the rate of recurrent liver infection by HPV can be significantly reduced
by treatment with high dose hepatitis B immune globulin given intravenously,
either alone, or in combination with an antiviral drug.
So, hepatitis B immune globulin is a product
that is for intramuscular use. It is licensed for post-exposure to hepatitis B
virus. It could be sexual exposure,
needle stick, accidental transfusion, mucosal splash. It is given as prophylaxis.
It is also given for infants born to
hepatitis B surface antigen positive mothers, and it is used off label,
intravenously and intramuscularly to prevent recurrence following OLT.
The current standard of care for OLT in HBV
patients involves use of both HBIGIV and an antiviral drug. The FDA has not
approved either the HBIGIV alone, or in combination with the antiviral drugs.
So, trials with either modality alone may be
difficult to do prospectively because of ethical and feasibility concerns.
So, the questions that we are going to ask to
the committee, this is the first question:
In clinical trials to show efficacy for HBIGIV treatment, can hepatitis
B surface antigen seronegativity be used as the primary end points of clinical
outcome, indicating prevention of recurrent HBV disease in the transplanted
liver?
The second question: Is a single arm study for safety and
efficacy during the maintenance period -- that is, avoiding the perioperative
period -- following OLT sufficient for licensure?
The study would compare either HBIGIV with an
historic control of no treatment for 12 months, or HBIGIV plus lamivudine --
one of the antivirals, or another antiviral -- for 24 months with an historical
control of lamivudine or appropriate antiviral alone.
The reason for the difference in time is that
the breakthrough cases to the antivirals usually take at least a year to become
apparent. That is why you need a longer
follow up in this kind of trial.
The third question: What PK or pharmacokinetic studies are required for licensure:
A. To test quality of immune globulin in
normal volunteers intramuscularly or intravenously, depending on available
comparators.
So, if there is a licensed product out there
that is given IM, you would probably want to use that product and compare your
new product to the previous product using the IM route, or you could, if you
had a comparative that had been licensed for IV use, you could compare it by
doing a PK study comparing your new product to the old product by that route.
B. To
collect data that can be used to establish the frequency and level of dosing by
studying the target population. That
is, PK data in HBs Antigen-positive OLT recipients during the maintenance
period following transplant.
These PK studies would probably be different
from those, because very low levels of hepatitis B surface antigens in these
patients could conceivably change the PK profiles.
You would want to know what kind of PK
profiles you are actually getting in the target population to try to decide on
the dosage regimens.
C. Lastly, to determine whether trough levels
are useful in titrating the HBIGIV dose in individual patients.
The idea is that individuals, normal or
infected, would have different metabolic rates of immune globulin, and it may
be useful to individualize this based on some PK parameter in a particular
patients, and trough levels may be a way of doing this.
So, this concludes my presentation, and I
will now hand it over to Dr. Anna Lok.
Agenda Item:
Presentation - Anna S. Lok, MD.
DR. LOK:
Thank you very much for inviting me here. I hope that, in the next hour
or so, I will be able to provide an overview on a very complex subject that is
rapidly evolving.
First of all, I am going to talk a little bit
about the history of liver transplantation for hepatitis B with historically
poor results.
Then, the evolution of prophylaxis for
recurring hepatitis B post-liver transplantation, showing you how far we have
come in the last 10 to 15 years.
Then, what is considered to be standard of
care right now, so that hopefully this would help the panel make the necessary
decisions.
As many of you know, historically, in the
absence of any prophylactic therapy, liver transplantation for hepatitis B
results in a very high reinfection rate, approximately 80 percent when defined
as reappearance of hepatitis B surface antigen.
In those patients with recurrent infection,
they tend to have extremely high levels of virus replication, they are Antigen
positive, with very high HBV DNA levels.
In a setting of immunosuppression, these
patients progress very rapidly, with severe hepatitis, and oftentimes
progressing to cirrhosis and liver failure within the next year or two.
This therefore results in a very high
mortality, a 50 percent mortality, within one or two years
post-transplantation.
Because of the initial poor results, medicare
did not approve payment for transplantation for hepatitis B until only a few
years ago.
We have come a long way. This is largely led by the European
investigators showing that the use of hepatitis B immune globulin dramatically
changes the outcome of these patients.
Hepatitis B immune globulin in this setting
is believed to work largely by neutralizing circulating virus. This tends to be given at a time when the
patients are still in the operating room, when the damaged liver is removed,
and before the new liver is anastomosed, in the so-called anhepatic phase.
The idea is the IV infusion would mop up
unneutralized circulating virus that is preventing infection of the newly grafted
liver.
However, the early European studies have
shown that, if we give HBIG only for a short period of time -- days or a couple
of months -- what it does is only delays, and does not prevent, re-infection.
Long-term infusion, on the other hand,
decreases HBV recurrence, and also is associated with improved survival.
So, this is some data from European studies
of more than 300 patients transplanted from hepatitis B. As you can see, in the
left panel, the risk of recurrence is in the region of 75 to 80 percent, if
there is no prophylaxis, or if HBIG is only given for a short period of time.
In contrast, if HBIG is given for at least
six months, there is a dramatic reduction in the recurrence rate, down to about
30, 35 percent.
This is associated with improvement of
long-term survival such that, at a five-year time point, you get about a 75
percent survival compared to only about 45 percent survival.
Note also that, in the absence of
prophylaxis, most of the recurrence actually occurs within the first six months
and that, even in the absence of prophylaxis, there are very few cases of
recurrence after the first two years.
As I mentioned, we have really come a long
way. We started in the mid-1980s, late
1980s, using short-term HBIG.
When we realized that this only delayed, but
did not prevent, infection, people started using HBIG long term. Until very
recently, most of us would plan on suing HBIG indefinitely.
With the availability of new antiviral
agents, lamivudine, people started exploring the efficacy of antiviral agents
alone, starting before the patients get transplanted, and continuing
post-transplant.
As we have heard, the problem with lamivudine
is that the virus can select for resistant mutation. Therefore, the efficacy may be lost.
When we realized the problems with lamivudine
and drug resistance, everybody started combining lamivudine and HBIG, because
they work through different mechanisms and may have additive or synergistic
effect.
As we started using combination therapy, we
also started asking ourselves the question, with the use of antivirals, do we
still need to use HBIG forever, and do we need to use such high doses. So, some investigators started exploring a
combination, but using tapering doses of HBIG.
By 2000, by the late 1990s, when we began to
see more and more problems with lamivudine resistance, and with the
availability of new antiviral agents that are effective against lamivudine
resistant virus, we are beginning to see that sometimes patients receive triple
therapy.
They may have been started on lamivudine
initially, developed resistance to lamivudine either before or after transplant
and, therefore, got put on an additional antiviral agent that combat the
lamivudine resistant mutants, and again, HBIG is frequently used, at least
initially post-transplant.
Since the approval of adefovir, various
investigators are also exploring the use of adefovir as a first line antiviral
agent, and we really don't have much data on adefovir when used de novo.
This is really complex, as you can see. We are dealing with a moving target, which
makes design of studies very difficult, and which also makes interpretation of
data somewhat complicated.
Because of all these improvements, we have
seen dramatic improvement in survival. This is data from the European
transplant registry, taking into account all the patients transplanted from
January 1988 to December 2001.
As you can see, even though patients
transplanted in the late 1980s, early 1990s, were included in this slide,
patients transplanted for hepatitis B actually have better survival compared to
patients transplanted for hepatitis C at a 10-year time point.
That is because we really don't have the
equivalent of HBIG and effective antivirals for hepatitis C, and the 10-year
survival is in the region of 70 percent.
If we confine this data to only patients
transplanted from the mid-1990s onward, the survival is actually much better.
So, let me talk about each of these
prophylaxes individually, and focusing mostly on HBIG. As mentioned, from the
late 1980s to the late 1990s, most centers would use HBIG monotherapy.
This is, again, the European data from the
early 1990s, the initial slide that I show you, showing that, although HBIG is very
effective at reducing recurrence rate overall, there are different populations
of patients within the hepatitis B patients.
Hepatitis B is an extremely heterogeneous
disease, and the lowest of recurrence actually occurs in the patients
transplanted for fulminant hepatitis, as well as patients who have HBC
co-infection.
If you look, however, at the patients of
hepatitis B cirrhosis, the pink line here, and the yellow line here, the
patients who have hepatitis B positive cirrhosis and who are either DNA positive
or D antigen positive, still had a very high rate of recurrence, despite the
use of long-term HBIG. This actually
has 60 to about 85 percent recurrence rate in the highest risk groups.
These European studies tell us a few things.
HBIG is effective in reducing recurrence and in improving survival.
Within the whole big basket of hepatitis B
patients, the outcome varies, depending on several factors, patients with very
high levels of hepatitis B virus replication prior to transplant, those who are
antigen positive, those who are HBV DNA positive.
I note that HBV DNA positive, in the 1990s,
really means HBV DNA detection, using hybridization assays, with detection
limit of 100,000 or 1,000,000 copies per ml.
We also know that the indication for liver
transplant is an important factor. Patients transplanted for cirrhosis tend to
have a higher rate of recurrence, compared to those with fulminant hepatitis.
That is because we think that patients with
fulminant hepatitis usually have very aggressive immune response and, by the
time they present to us, frequently HBV DNA is no longer detectable. So, these patients tend to have low levels
of virus.
We also know that patients co-infected with
hepatitis D or delta tend to have a lower rate of recurrence, and that is
because delta suppresses hepatitis B virus replication.
So, one key message that we have learned is
that, the higher the level of virus replication, the more likely recurrence is
going to occur.
This is actually an update from the European
data. This is from one single center in
France, D. D. Samuel's group, where they specifically looked at patients
transplanted for cirrhosis only.
So, now they have excluded the patients with
delta co-infection and the patients with fulminant hepatitis, and 81 patients
received IV HBIG monotherapy, and the aim of maintaining anti-SB titer of more
than 100 iu per liter.
As we can see, the DNA positive patients had
a very high rate of recurrence, compared to the DNA negative patients, about 90
percent compared to 35 percent, and the DNA detection is a much better
predictor compared to e antigen.
As you can see, even in the e antigen
negative patients, if they are DNA positive before transplantation, the
recurrence rate is still very high.
Note again that most of the recurrence
occurred within the first year, with a small increase in the second year.
How do we use HBIG? This is really a complex issue.
There are, broadly, two different ways of using HBIG within the
transplant community.
Some of us use the fixed dose regimen, in
which 10,000 international units are given intravenously through an infusion
through the anhepatic phase. That is when the old liver had gone out and the
new liver hasn't been anastomosed.
We then subsequently follow by giving, again,
another 10,000 international units daily for the next seven days.
We believe that that is a time when there is
still a lot of uncirculating virus, and it is important to protect the newly
grafted liver. This is subsequently
followed with monthly doses of 10,000 international units.
The idea of using a fixed dose regimen is
really simplicity. We understand that
not all patients are alike, but given the fact that it is very difficult to
give patients a titrating dose regimen, in particular when the patients have
been discharged and they are outpatients, and they might not necessarily be
coming back to the transplant center for the HBIG dosing, it is extremely
difficult to wait for a result, and then call in to a local community hospital
a home nursing team and adjusted dose of HBIG.
Actually, there are more centers in the
United States using fixed dose regimens than a titrated dose regimen.
The titrated dose regimen appears to be more
sensible, though, although no one really has published data on how to titrate a
dose in the era where we have antiviral agents.
So, most of the data really comes from the
pre-lamivudine, pre-adefovir era. The
Europeans have decided that they would use a trough anti-HBs titer of 100 iu
per liter.
Studies at the University of Virginia have
shown that this may not be sufficient, particularly during the early
post-transplant period, and they advocate that a trough titer of more than 500
is necessary is necessary during the first week, and a trough titer of more
than 250 is necessary actually from day eight to day 90. After day 90, 100 might be sufficient.
As I have mentioned, there is a subtle issue
in whether we use a fixed dose or a titrating dose. Titrating dose is probably more logical, although logistically
more difficult.
As I will show you, fixed doses have some
problems because of marked inter- as well as intra-patient variability in the
anti-HBs titer, and the half life of the HB.
There are a number of factors that contribute
to variability. First of all, as we
would anticipate, the concentration of circulating HBs antigen -- perhaps this
is more important than the virion, because we know that the HBV makes a lot
more HBs antigen than it does the virion.
Certainly, during the first few days
post-transplant, there is still a lot of circulating virus and a lot of
circulating HBs antigen, and we expect that over time that would decline. This obviously would affect the half life.
In particular, during the perioperative, or
immediate post-operative period, this also can be affected by transfusion of
blood products, as well as also drains that we put into the patient's body to
drain out abdominal fluid.
For those of you who don't deal with
transplantation, you might see patients in whom you only had one or two units
of blood product transfusion, or you could have a disastrous situation when a
patient had 50 to 60 units of whole blood, in addition to plasma and platelets
and also some other products.
As I have mentioned, the half life of HB is
variable depending on the time in post-transplant. It is important that we really study the pharmacokinetics in the
setting of the target population, as Basil had mentioned.
If you look at half life of HB in a normal
subject, this is how long it is going to last.
If you look in the post-transplant setting, the first few days
post-transplant, the half life is extremely short, because there is still a lot
of uncirculating virus, whenever HB infusion might be going out in the
abdominal drain and being diluted out by all the blood products and bleeding.
As the patients progress further along
post-transplant, the half life becomes longer, but even after three months
post-transplant, the half life is still shorter than in a normal subject.
There is also some difference in a half life
between an e antigen positive patient, which is shorter, and an e antigen
negative patient.
I am sure if the data had been available on
HBV DNA positive versus negative, we would see an even bigger difference in the
half life.
I have also mentioned about the variability
of anti-HBs titer. This is data from a
UC San Francisco study, where they plot out 20 patients.
This really shows you how much the anti-SB
titer can vary with a fixed dose regimen.
So, 10,000 units can give you a trough titer that is almost undetectable,
to a trough titer that is more than 2,000 iu per liter, and these vertical
lines represent a spread for each individual patient.
There are also patients that you are never
able to maintain a very good titer, despite the fact that you give them the same
doses, and these few patients out here actually turn out to be patients who
subsequent develop re-infection.
This is actually a very useful tell tale
sign. Generally speaking, when a
patient is beginning to have signs of re-infection, we notice that we are not
able to maintain the titer.
As a result of all these studies, the U.S.
centers tend to say, well, we looked at the European data, they told us to use
HBIG. They are not getting the best
results, maybe because they are not using enough HBIG.
So, U.S. centers tend to use more HBIG and,
as I mentioned, most of use a fixed dose regiment. With the fixed dose regimen that I mentioned, most of the
patients are able to maintain trough titer of more than 500.
We do see a lower infection rate overall of
about 20 percent, compared to an overall re-infection rate of 35 percent in the
European studies.
The difference might be, in fact, even bigger
because, in the European centers they tend to have more patients with delta
infection, whereas delta infection is far less common in the United States.
So, let me summarize the use of high dose IV
HBIG monotherapy. Using the dose regimens that most U.S. centers use, up until
the mid to late 1990s, before antivirals became popular, using HBIG monotherapy,
we were able to decrease recurrent hepatitis B to about 20 percent and improve
survival to about 90 percent at two years.
So, an improvement from 50 percent survival
to 90 percent survival is really a major improvement, and that was really the
reason why medicare decided to reimburse transplantation for hepatitis B.
This comes at a huge price, because HBIG is
very expensive. I can never really quite figure out how much it costs, because
no one will tell you how much things cost.
We only know how much we charge outpatients or their insurance. Therefore, every medical center reports a
different figure.
With the doses that we use in the first year,
if we take into account HBIG plus the cost of IV infusion, please all this
monitoring that go into it, the charges in general would exceed $100,000.
In subsequent years when we give monthly
doses, it would be in the region of about $50,000. You can see that, if you plan on lifelong, indefinite therapy,
this is going to break the bank of most people.
We also show that HBIG monotherapy, while it
has a significant benefit overall, it has limited efficacy in cirrhotic
patients, who are antigen or DNA positive.
If you use HBIG only therapy, long-term
treatment is needed. Despite all this, we do have failures, and some of the
failures are related to S escape mutants.
These are mutations in the HBV S protein,
which reduces bonding to the anti-HBs and, therefore, these patients can still
get reinfected.
So, what are the reasons for failure? There are several reasons. One is inadequate neutralization, because
the patients have too much virus in the circulation prior to transplant, and
you are just not giving them enough HBIG.
These patients tend to develop recurrence
very early, most times within the first two or three months, and certainly
within the first six months, post transplant.
As I mentioned, sometimes, with long-term
usage of HBIG, you get selection of S escape mutants. These patients tend to develop recurrence a little later, because
you need to give HBIG for long enough to select for those resistant mutations.
There are also instances when the patients
are non-compliant, if they don't come back, they forget to show up for the HBIG
dosing. They can certainly develop
recurrence.
What about these S escape mutants? These are mutations that cluster around the
'a' determinant, which is the immunodominant epitope of the S protein. The most common mutation is a glycine to
arginine substitution, which reduces binding to the antibody.
These mutants are detected in some patients,
not everyone, because in some of them the failure is really due to inadequate
dosing.
So, the mutant S is detected in some patients
who develop recurrence, even though they keep coming back, and you know, you
document, that they have received the HBIG therapy.
We have found that these mutants are more
common in the early days, in a study using monoclonal anti-HB, not
surprisingly, compared to HBIG, which is a polyclonal antibody.
As I have mentioned, mutations tend to occur
with longer duration of therapy.
Earlier on, we had a study which showed that these mutations can be
reversed when HBIG is stopped.
Let me now move on to antivirals. As I have mentioned, one important lesson
that we have learned from the use of HBIG is that high levels of HBV
replication is the most important factor in determining whether the patient
developed recurrence or not.
So, it made sense to put the patient on an
antiviral agent that would suppress the level of virus prior to the patient
going forward to transplant.
So, we have currently two FDA approved
antiviral agents. One is lamivudine or
adefovir, and the other is adefovir dipivoxil, or hepsera.
These agents inhibit HBV replication by
competing with cCTP and, in the case of adefovir, dATP. Now, for incorporation into hepatitis B
virus DNA, they are orally administered antiviral agents that have been
approved by FDA for treatment of chronic hepatitis B, and adefovir is also
effective both in vitro and in vitro against lamivudine hepatitis B virus.
So, let's just compare these two antiviral
agents. They are administered
orally. They both are very effective in
suppressive HBV DNA, decreasing serum HBV DNA levels by about three to four
log.
In the treatment of immunocompetent patients
with chronic hepatitis B who are e antigen positive, one year of lamivudine
results in HBe antigen seroconversion in about 15 to 18 percent of patients.
Adefovir, in the dosage approved by the FDA
of 10 milligrams daily, results in an e antigen seroconversion rate of 12
percent after one year.
Lamivudine has really negligible side
effects. It is extremely well tolerated.
Adefovir, on the other hand, has been shown to be nephrotoxic at high doses,
and when used for long durations of time.
So, there are really some potential concerns
in a setting of patients with decompensated cirrhosis, who are already very
prone to develop renal problems because of the side effects of diuretics and
the potential for hepatorenal syndrome in a post-transplant setting, where they
are concomitantly receiving other nephrotoxic medications, such as cyclosporins
or tetralimers.
The problem with lamivudine, though, is that
there are big issues with drug resistance, 15 to 25 percent in year one and,
with continued therapy, up to 70 percent in year five.
With adefovir dipivoxil, the 10 milligram
dose, we have not seen drug resistance at the end of year one, but drug
resistance begins to emerge later on and, at year two, it has been reported in
the region of two to three percent.
Well, have these drugs been used in patients
with decompensated cirrhosis and recurrent hepatitis B post-transplant?
The answer is yes although, in the case of
adefovir, the data is really mostly on patients who have developed lamivudine
resistance, and adefovir was added as a sort of salvage therapy.
Well, let me now then share some of the data
on lamivudine monotherapy. As I have
mentioned, initially when lamivudine became available, everyone was very
optimistic. This is a wonder drug, it
rapidly reduces the level of virus and maybe lamivudine alone is going to take
care of the job and, boy, wouldn't life be easy. One pill a day and it is a lot cheaper.
Well, this, as I mentioned, is orally
administered, negligible side effects, and effective in reducing the viral
level.
You say, so what. Well, the suppression of viral level is not just a cosmetic
effect. In fact, it does reduce, in both biochemical as well as clinical
improvement of liver disease.
We, as well as many other centers, have
observed that this improvement might allow us to delay the need for transplant
and, in some patients, actually take them off the transplant waiting list, because
they are doing so well, they don't need the transplant any more.
So, we do see improvement in survival, and we
certainly see that, in some patients, this results in reduced risk of
recurrence after transplantation, because the patients go to the operating room
with less virus in their circulation.
So, let me share with you one study. This is one of the early studies from a
Canadian group, where they looked at 35 patients with decompensated cirrhosis.
They were put on lamivudine therapy. These
were patients who were all about to die.
Quite naturally, some of these patients don't make it.
So, early on, during the first six months,
five patients die from liver failure, and seven patients went ahead and had
liver transplant, because they needed it.
Of the 23 patients who actually toughed it
out and were on treatment for at least six months, 22 out of these 23 patients
had improvement based on decrease in the Chow Turcott Peer(?) score.
For those of you who are not familiar with
this, this is actually a scoring system which includes two clinical variables,
a situs, encephalopathy, and three laboratory variables -- albumen, bilirubin
and perfromen time.
So, this is actually a measure of clinical,
as well as biochemical, improvement.
One of these patients then went on to transplant.
These 22 patients have been followed for more
than a year, and 20 patients were still alive. Three of them had resistant
mutants, but there were two late deaths, one with spontaneous bacterial
peritonitis, and one with hepatocellular carcinoma.
So, this is one of those studies that show
that we can bring about clinical improvement. We can reduce the need for
transplantation, but some of these patients who are extremely sick might not
have a chance to benefit from the treatment.
This is another study. It is a retrospective analysis of 133
patients with decompensated cirrhosis put in lamivudine therapy.
You can see that, overall, the survival was
very impressive. These were patients
who were looking like they were on death's door at a time when they were
started on treatment and yet, at a three year time point, they still had 75
percent survival.
In fact, if you look carefully, the patients
split into two groups. There were some
patients who died very rapidly, within the first six months, and then there is
a group that went on and did extremely well.
These were the patients who were very, very
sick at the time of presentation. They had higher bilirubin levels. They already had some impairment in renal function
and more of these patients were HBV DNA positive.
Another issue with lamivudine in treating
patients prior to transplant is, it is not just that it takes time to work, but
we have talked about the issue of resistance.
Some of these patients have been placed on
treatment too long and they develop resistance prior to transplant. It can be a problem.
We really don't know exactly how big a
problem this is, but when you look at the case in series, you do find that they
have a higher rate of developing recurrence.
In these two European series where HBIG was
rapidly tapered post transplant, of the two patients that they followed, both
developed recurrence and here,of the three patients that they followed, three
developed recurrence.
This brings up one of the issues, that if you
identify patients with lamivudine prior to transplant, do we need a higher dose
of HBIG.
I should, however, mention that these studies
were all performed in the era before we had adefovir dipivoxil available. So, there was no other antiviral agent that
we could use as a salvage therapy in these studies.
So, lamivudine can help some patients, but
there are some limitations. As I
mentioned, there is genotypic resistance, 15, 20, 25 percent at the end of year
one, and it certainly increases with the duration of treatment.
When a patient develops resistance, there is
a risk of hepatitis flair. Liver
enzymes can go up and we can push the patients into liver failure. Now, there is also a problem of increased
risk of recurrence post-transplantation.
It does seem that, even though we improve on
the hepatic decompensation or complications of cirrhosis, the risk of
hepatocellular carcinoma persists, although it may be reduced, but this risk
does persist.
For some patients, the clinical improvement
is just way too slow. If you don't get the patients early enough, these
patients would not have a chance to benefit.
So, this is looking at the use of lamivudine
while the patients are waiting for transplants. What about continuing
lamivudine post-transplant, that you continue to suppress virus.
Even if a few virus escape and get into the
newly grafted liver, if we are able to prevent a virus from replicating and
making new virus, that would be useful.
Certainly if this approach works, it would be
far more economical, and it is a lot more convenient compared to HBIG.
However, the studies to date show that, even
though the results are pretty impressive at year one, and certainly not all
that different from HBIG monotherapy -- recurrence rate of 10 to 30 percent --
but because of issues of resistance, you get more breakthrough infection over
time.
So, recurrence rates go up to 30 or 40
percent at three years, and this is certainly not an acceptable monotherapy in
this day and age.
When patients develop resistant mutants
post-transplant, they can have rapidly progressive liver disease and die.
So, this is a slide showing several studies,
now, using lamivudine monotherapy. So,
HBIG was not given to these patients.
These patients received varying durations of
lamivudine prior to transplant, they were continued on the lamivudine post
transplant, with a single dose of HBIG.
You can see that most of these studies
involve a small number of patients, except for this study, and some of these
studies involve very short durations of follow up.
The studies with shorter rates of follow up
report better results with lower recurrence rates, where some studies with
longer duration of follow up show a recurrence rate of 35, 40 percent would be
seen, and that is why lamivudine monotherapy is no longer acceptable.
As I have mentioned, if HBIG alone, if
lamivudine alone, work, why don't we combine the two together?
Well, this is a busy slide, but all you
really need to do is focus on the blue columns. This slide really illustrates many different studies using a
combination of lamivudine and HBIG in preventing HBV recurrence after
transplant.
In all these studies, patients were put on
lamivudine for varying durations of time during transplant. Lamivudine was continued post-transplant.
HBIG was given in the operating room and
continued post-transplant. When you
look at recurrent rates, we note that you have several studies, most of them
small studies, where they reported some sero recurrence rates.
In these two studies with a higher recurrence
rate, all of the recurrence occur in patients with prior lamivudine resistance.
So, patients who did not have prior
lamivudine resistance did not develop recurrence. So, with combination therapy, we are actually able to get the
recurrence rate down to extremely low levels.
What is interesting, though, is to look at
how much HBIG is used in the era of combination therapy. This study from UCLA continued to use very
high dose HBIG, 80,000 international units during the first month and 10,000
international units for each subsequent month.
Now, this is a cheap version of the regimen.
. This is an Australia New Zealand study.
The Australian New Zealand government says, okay, for every patient you
transplant, you get a fixed sum of money and you figure out how to do it.
So, our colleagues down south decided they
would ration out the HBIG. You can see
they were using very little.
They were using 1,600 to 3,200 in the first
month and 600 to 800 units in each subsequent month, compared to 10,000 units
here. Yet, the results appear to be
very comparable.
Before you jump to the conclusion that a
sprinkle of HBIG is going to be sufficient, we have to really understand that
somehow they managed to get the patients transplanted very quickly down south,
and most of the patients had only been on lamivudine a couple of months prior
to transplantation.
So, they weren't really dealing with issues
of lamivudine resistance by and far, and that might allow them to use less
HBIG, I think.
Graft in patients survival now is similar, if
not better, than patients transplanted for other liver disease. We certainly have much better results than
transplantation for hepatitis C patients.
A big question these days is, well, if we
have lamivudine and we have adefovir and maybe next year FDA approves another
antiviral agent for hepatitis B, how much HBIG is really needed.
Can we ever discontinue HBIG and maintain the
patients on antiviral? If so, who are
the patients that we can cut out HBIG, when should we be cutting it out, and
how should we maintain the patients on long-term prophylaxis. These are questions for which we don't have
very good answers yet.
Let me share with you some attempts at
addressing those questions. This is data from the UC San Francisco group.
They used some combination therapy and they
said, gee, if we use combination therapy, all that we need to do is really give
HBIG for six months and then we can stop.
They had 26 patients, with a mean follow up
of about two years post-transplant, and two of the 26 patients developed
recurrence. We don't really have
long-term follow up data on those patients.
So, after they had two cases of recurrence
they said, well, maybe six months isn't quite enough. Let's stretch the HBIG out to 12 months.
This is some data that was reported about a
year and a half ago. They had 25 patients. Lo and behold, they had identical
results, and in fact, maybe even worse results, because the follow up here is a
little shorter.
The investigators actually tried to explain
the data because, if you give a little more HBIG, you don't get any better
results.
I think it is because of the changing
field. Now lamivudine is more widely
available. Now we have patients who
have been taking lamivudine two years, three years, before they come to
transplant. So, you are dealing with a
bigger problem of lamivudine resistance.
Those two patients who had recurrence were
patients who had lamivudine resistance prior to transplant and, of course, when
you stop the HBIG, you essentially weren't giving them any prophylaxis at all.
These two patients were in the era before we had adefovir therapy.
There are other people who are even more
courageous, and these data from a Spanish group, although they are very
selective, they tried to look at lamivudine and long-term HBIG versus much
shorter term HBIG.
In this case, what they did was, they
selected for patients who were either HBV DNA undetectable at the time of
presentation or, if they were DNA positive when they put the patients on
lamivudine, the patients actually became HBV DNA negative prior to transplant.
The patients received, again, very short
durations of lamivudine prior to transplant.
They had the transplant. They
continued the combination therapy for four weeks.
So, they had one dose in the operating room,
they had daily doses for six days, and then weekly doses during the first
month.
Then the patients were randomized to stop
HBIG right after one month, or to continue the combination therapy.
What you can see, they had 32 of these
patients who went to transplant.
Twenty-nine were randomized, 14 to lamivudine only and 15 to
combination.
At month 18 post-transplant, all the patients
remained surface antigen negative, but note that they do have three patients in
one group and one patient in another group that were HBV DNA positive by PCR
assay in the serum.
I will come back to look at HBs antigen
versus HBV DNA by PCR, and they did have some patients with lamivudine
resistance.
So, longer follow up is going to be important
to find out what happened to these patients with lamivudine resistance,
although very likely, in this day and age, these patients would have been put
on adefovir therapy.
Well, there are other ways of short cutting
on HBIG, and many of us are switching to using what FDA approved. We give it IM.
Now, of course, we can't get the same
dose. What most of us do is, we give IV
initially during the early transplant period, when we most worry about patients
and, over time, as we try to taper down the dose, we switch from IV to IM.
The switch occurs at varying time points in
different studies in difference centers, but many of us who have tried to
switch when the patients are at least one year post transplant, giving the
patients doses of 1,000 to 1,500 iu, have found that we are able to maintain a
titer of 80 to 250 iu per liter, but this is in the setting of patients
receiving concomitant antiviral therapy.
We really don't know what is going to happen
if we start using this approach immediately post transplant, and in patients
and hope they have not developed resistance to antiviral in which we did not
suspect and put a patient on an appropriate second line antiviral.
So, I talk about prevention, but we can never
really get 100 percent success. So,
what happens when we fail?
When we fail, this day and age, in 2004, we
don't wait for the patients to develop bad liver disease, cirrhosis,
re-transplant them or let them die. We treat them.
We treat them because we really have good
antivirals. I really just focus on them
here, because these days the recurrence rate is only five to 10 percent, and
this is really a small number of patients that we need to treat.
It is important to really know what
prophylaxis the patients have received prior to them developing the recurrence,
to assist us in choosing the right treatment.
These days, the treatment will be mostly
lamivudine or adefovir dipivoxil therapy for patients who have not received
lamivudine before.
This slide is actually a North American
multi-center study. We are looking at
the treatment of patients who fail, who develop recurrence, because they
received HBIG only.
So, these were patients transplanted in the
1990s. They received HBIG only. When
they developed recurrence, since they have not seen lamivudine before,
lamivudine would be an effective treatment for them. As you can see, you can get a dramatic drop in the viral level,
as well as improvement in liver enzymes.
Overall, when you look at week 24 or week 52,
there is some drop in the proportion of patients who remain e antigen positive,
as well as a drop in the proportion of patients who are HBV DNA positive when
you put them on treatment.
More important, it is not just the virus
suppression. There is also improvement in liver histology. The light blue represents the patients with
reductio in necro-inflammation, and reduction in fibrosis, when you put them on
antiviral therapy and you do a re-biopsy.
So, we can improve the clinical outcome, even
in patients with recurrence, although we obviously prefer not to have
recurrence in the first instance.
Unfortunately, with lamivudine alone, you are
going to have patients who develop resistance. In this particular study, 27
percent of the patients developed resistant mutations, and when the patients
developed resistant mutations, some of them would have clinical deterioration,
due to progression of liver disease..
So, lamivudine, as a treatment for recurrent
hepatitis B, it is safe, it does suppress the virus. It can improve liver chemistry as well as liver histology, but
the issue is with resistance. When the
patients develop resistance, things can go down south very quickly.
So, what do we do with patients with
lamivudine resistance? Fortunately, we
do have new antiviral agents with proven in vivo advocacy.
Adefovir has been FDA approved, and entevacir
is being evaluated, it is still an investigational drug at this time.
Both drugs have been shown, in clinical
trials, to suppress HBV DNA levels and result in stabilization or improvement
of liver disease.
What we are going to need to deal with in the
next five years is what would be the recurrence of hepatitis B post transplant
among patients with lamivudine resistance, if we can optimally manage
them. If we recognize the patients
early and put them on salvage therapy, would we be able to reduce recurrence.
Do the patients with lamivudine resistance
need more HBIG than patients who do not have lamivudine resistance? Again, I think this would be in the context
of whether we have a second line antiviral agent or not.
So, let me show you some adefovir data. This is really data from patients who
develop recurrent hepatitis B post transplant.
They were put on adefovir and you can see that there is a dramatic drop
in the HBV DNA level.
These were patients who initially were on
lamivudine and were recognized to have breakthrough infection, and there is a
drop in the HBV DNA level.
In this study, which is recently studied, on
adefovir therapy in pre and post transplant patients with lamivudine
resistance, this is more than 300 patients, you can see that a large proportion
of these patients have normalization of liver enzymes and a drop in HBV DNA of
about 3.5 to 5.0 log.
There is also associated improvement in the
CTP score, which I have mentioned is a combination of asitis encephalopathy,
albumen, performin time, and bilirubin.
Side effects, they were treatment related,
were considered to be uncommon, but there were issues with adefovir.
As I mentioned, it is a potentially
nephrotoxic drug, and 28 percent of the pretransplant patients had increasing
serum creatinine of more than .5 milligrams per deciliter in the
post-transplant patient.
It is, however, extremely difficult to
interpret these data, because the pretransplant patients would be compensated
cirrhosis, and asitus on diuretics and are already very prone to develop renal
insufficiency, because of the diuretic therapy, as well as progressive liver
disease and hepatorenal syndrome.
Certainly, in post transplant patients, even
in the absence of adefovir, we do see some increasing creatinine over time,
because we put the patients on ne nephrotoxic antirejection therapy,
cyclosporin and tecrikuners(?). So,
whether these increases are related to adefovir or to other issues is really
difficult to sort out.
This, again, shows the proportion of patients
with increasing creatinine over time in the pre as well as the post transplant
patient. At the one year time point, it
is in the region of 15 to 25 percent.
So, in terms of adefovir in liver transplant
patients with lamivudine resistance, it does suppress the virus level. It is
associated with clinical and biochemical improvement in liver disease, but
there are issues with nephrotoxicity.
So far, all the data that we have on adefovir
in the transplant setting has been in patients with prior lamivudine
resistance. We don't really have data
on adefovir as a single antiviral in this situation.
Let me then come to the questions the FDA
posed and see what my take would be on some of these questions. I don't have very good answers.
Some of these questions are, what should be
the primary end point, when should end point be assessed, what is the standard
of care, how should studies be designed, and what is the role of PK studies.
Well, when we think of looking at prevention
of HBV re-infection post transplant, we can think of it as occurring in
difference steps.
The first step would be when the virus
reappears. The virus re-infects the new
liver. How do we know that? Well, we can find it out by testing for HBV
DNA by PCR, or we can use a very simple, old fashioned assay, testing for
hepatitis B surface antigen.
I will explain which one I would pick. If we notice, if we follow the patients very
carefully, and we realize that the virus has reappeared, we could intervene.
In fact, that should also appear here. We could interfere before the patients
develop bad liver disease. We could intervene with antiviral therapy and stop
this cascade from happening.
Of course, if we don't intervene, the
patients would then develop recurrent hepatitis, which is manifested as
elevated ALT and histological liver disease.
Again, if we stop, and we don't intervene,
the patients can go into cirrhosis, liver failure, and they can die.
A small proportion of patients can have a
very aggressive form of liver disease called fibrosin incoistatic(?) hepatitis,
which can kill them in days to weeks.
In 2004, if we were following our patients,
we would not allow our patients to go down this path. We will be monitoring the patients and, when we notice something
bad is going, we would intervene and we would start the patients on antiviral
therapy, so that this cascade is not going to happen.
Therefore, it is no longer possible to use
clinical events as end points unless you are dealing with physicians who do not
take care of their patients.
So, we have to use reinfection, not recurring
hepatitis, not death, as clinical end points.
Now, with reinfection, I would prefer -- and I think this is the
standard of care worldwide -- that we use re-detection of HBs antigen in a
serum after one month post transplant.
The first few days, no matter what you do, if
you try to test a patient for HBs antigen on day two, it might still be
detectable because you might not have completely cleared the circulating HBs
antigen. So, typically we will give it
a month.
Why do I use HBs antigen? Because it is a readily available,
standardized test. It doesn't really
matter if the patient lives 300 miles away.
We can get a test and we know that we can get
a reliable test. Any HBs antigen test
in this country, it is a fairly meaningful result.
We know that all the patients that develop
clinically significant hepatitis, if you follow the patient, HBs antigen is
detected first, before you have clinically significant hepatitis.
In fact, sometimes we see HBs antigen become
positive, and the liver enzymes are still normal, and it is two or three months
later, when the virus has sufficiently built up, that the patient now has
elevated liver enzymes and bad liver disease.
So, a key is really monitoring the patients.
Well, why don't I pick HBV DNA assays? Well, first of all, we don't have any FDA
approved HBV DNA assay. So, we don't
have any standardized assay.
The second problem is that, because of the
lack of standardization, we don't really know what we are talking about when
people say that HBV DNA is detectable, because detection in one assay might be
undetectable using another assay.
We also know that, from PCR assays, sometimes
you pick up patients in home that are intermittently positive by PCR, and then
the next time it is undetectable.
We really don't know what it means, unless it
is persistently detectable and above a certain level, and we don't really know
exactly what level is associated with clinically significant hepatitis.
I think we should have better standardized
assays, and I think we should really address this issue in terms of what level
is associated with clinically significant hepatitis. Until we have that information, I would not recommend using this
as an end point.
Let me just illustrate to you an issue of
using DNA by PCR, and this is data from D.D. Samuel's group in France, where
they have followed a large group of patients who have been maintained on HBIG
for 10 years.
These were patients who remain HBs antigen
negative, 10 years post transplantation, 44 patients. When he tried to detect HBV DNA by PCR, using the serum liver of
PBMC, you can see that anywhere from between 30 or 40 of these patients would
be PCR positive, but only one of these patients, now, who did not have
co-infection with hepatitis C actually had clinically relevant hepatitis on
liver biopsy.
So, these are surface antigen negative with
DNA detectable by PCR, but they don't really have significant liver disease
unless they have concomitant HCV co-infection, and that is the reason why I
mentioned, I am not sure how to interpret HBV DNA detection by PCR.
When do we assess the end point? HBV recurrence can occur any time after
transplantation but, as I have shown you on several slides, most of the
recurrence occurred within the first year post transplant, 80 percent
recurrence in the first year and, by the second year post transplant, you will
have picked up more than 90 percent of the recurrence.
Now, designing a clinical study using one
year or two years would be a reasonable end point. We don't necessarily need to go all the way to 10 years.
Well, what is the standard of care? I think the standard of care in 2004, and
likely in the next couple of years, would be combination prophylaxis. Most of us would put a patient on antiviral
therapy while they are waiting for transplant with the hope of decreasing virus
load prior to transplant.
Post transplant we would use the combination
therapy. We will continue the
antiviral. We will use the HBIG.
There are several potential advantages of
using combination therapy. There is
additive or synergistic antiviral effects.
We might circumvent antiviral or HBIG resistance.
It may be that we can use a much lower dose
of HBIG or shorter duration of HBIG and, therefore, increase the cost
effectiveness.
Let me share with you some of the concepts
that we have in an NIDDK-sponsored study, of which I am the PI. Our approach is that, pre-transplant, we
will check everyone for HBV DNA.
If they have extremely low or undetectable
HBV DNA, we will monitor the patients.
We are not sure how much benefit antiviral therapy would have on these
patients.
We do know that hepatitis B is a fluctuating
disease. In the course of follow up, some of these patients, who initially had
undetectable HBV DNA might now have higher levels of HBV DNA, and if we catch
them then, we will put them back into this high DNA group, and we will put them
on antiviral therapy.
Once the patients get to transplant, we
actually categorize the patients into low risk patients and high risk patients.
The low risk patients are the patients with
very low viral level prior to transplant, and who have no evidence of
lamivudine resistance.
Our concept is to test if just a very short
perioperative course of HBIG and antiviral maintenance would be sufficient.
With the high risk patients, these are
patients who have high viral load prior to transplant, or patients with
lamivudine resistance prior to transplant.
We advocate using combination therapy during
the first year and, at the end of the first year, we are actually randomizing
the patients to either stop HBIG and be maintained on antiviral therapy only,
or to continue combination therapy, but using a much lower dose of HBIG. We are actually using the IM dose of HBIG.
I can tell you that we have had numerous
problems with this study, in terms of patient enrollment. Part of the problem is that none of the
companies that make these products are willing to support the study.
So, we get the money from the NIH but,
because we don't have study medication to give out, it is very difficult to get
participating centers to follow a protocol when you don't provide a very
expensive study medication.
So, this study is fraught with problems, and
I have been constantly threatened by the DSMB that the study will be closed, if
I don't manage to find more patients.
So, how would I envision study designs? I don't really know exactly how we can do it
properly, because this is a very complex field and it is a rapidly moving
field.
Ideally, if you are really trying to address
what good does HBIG do, you want to compare with nothing. This is impossible.
Unless we can turn the clock back to the
early 1980s, we cannot do a study where we compare with nothing. We can do a study where we compare with
historical controls, but again, I have mentioned that there are many factors.
So, if you compared with historical controls,
you need to be careful that you match for pre-transplant HBV replication
status.
The indication for transplant, because
whether you have a bunch of fulminant hepatitis patients in a study population
or very few makes a difference. You
need to match for HBV co-infection if you want to compare with historical
controls.
Well, is a study looking at HBIG only
feasible? As I mentioned in our study,
I was actually analyzing our data about two months ago at a time we had
enrolled 212 patients into the data base.
Of these 212 patients -- these are all U.S.
centers, by the way -- 40 percent of the patients were receiving antiviral
therapy at the time they were being evaluated for transplant.
The majority of these patients were put on
antiviral therapy by their local gastroenterologist, before they even came to a
transplant center.
This is one of the problems. We have no controls. Patients come on certain regimens before
they come to our door, and you cannot take the patients off therapy and do
something different.
Clearly, after we have seen a patient and
evaluated a patient, we realize that some of these patients do have very high
activity, high DNA level. We put some
of our patients on antiviral therapy.
At the time of transplant, 65 percent of our
patients are actually receiving antiviral therapy. You can imagine that there is no way that you can do a study of
HBIG alone if two thirds of your patients are already taking antiviral therapy
at the time of transplant.
So, in 2004, when 65 percent of the patients
are receiving antiviral therapy at the time of transplant, what can you do?
Well, if you want to know if HBIG has any
role, you can potentially have a study where you look at antiviral plus HBIG,
compare with historical data on antiviral only.
This, again, is not going to be easy to
analyze, because the historical data would be patients who received lamivudine
only. Patients, when we knew they had
lamivudine only, we weren't able to do anything about it.
In this day and age, we wouldn't. If we knew
that a patient had resistance, we will put them on a second antiviral agent.
So, the data analysis is going to be pretty
complicated. Again, what antiviral will we be using in 2004? Will we be using lamivudine in the study
design, or will we be using adefovir in a study design because it has less
issue of resistance but it might have more issue of renal toxicity?
So, that all complicates matters and, of
course, we don't have adefovir alone as historical data for a control.
I think this is my last slide. I have never been a big fan of PK
studies. I think they are great for
publishing papers, but they are impossible to use clinically.
I can tell you, for those of you who don't
manage these patients, we in transplant programs take care of patients who
travel up to eight hours to come and see us.
So, right after the initial post transplant
period, you cannot get your patient to drive eight hours to come back and see
you on a monthly basis. So, we rely a
lot on long-distance care.
So, trying to get a titer, draw a blood
sample, get a titer, get the result, and then adjust the next dose and, when
HBIG is not something you give subcutaneously or take by mouth, when you have
to liaise with home nursing care, local clinics, it is a nightmare which is
impossible to really implement.
So, it is great for getting information, but
it is impossible in clinical practice, but they have certain roles.
In evaluating a product, I think the most
important thing is really to show quality control. If you say you have X,Y and Z in a bottle, does it really contain
X,Y and Z in a bottle is something else.
When we look at these PK studies, we need to
take into account intra- as well as inter-patient variability. We need to take into account confounding
factors, viral load how long after transplant.
So, when you compare with previous studies,
you don't really look at data two years out versus six months out.
In the immediate post transplant period,
there are all these factors of blood products and drainage, three different
drains draining fluids from the patient's body.
I have given you an overview from my
perspective. I am not really sure that I have actually clarified the issues or
confused you.
This is certainly a very complicated topic,
for which we don't have simple answers, and I am not sure if there is time for
questions. I would be glad to take some
questions, then.
DR. NELSON:
Thank you for a very comprehensive review.
[Applause.]
DR. NELSON:
Are there questions from the committee?
DR. MC GEE:
How big is the study that you are having trouble recruiting on?
DR. LOK:
How big is the study?
DR. MC GEE:
Yes, what is the sample size.
DR. LOK:
Well, we were hoping to get about -- actually, initially we wanted to
get about 150 patients for the high risk group and 50 patients in the low risk
group.
NIDDK has already shut down my low risk
clinical trial because we are too slow in enrollment. The high risk studies are actually on life support, and it is
very hard to do these studies.
So far we have only enrolled 13 patients. We
want to get 150. It has taken us two
years to get 13 patients. Part of the
problem is, with most clinical trials, when you compare one treatment against
another treatment, you provide the study medication.
This is a study in which we don't provide
study medication. So, it is very hard
for people to stick to a protocol, if you don't give them the study
medication. Then they say, well, we
will go back and do whatever we want to do.
So, they don't follow the protocol and they don't enroll the patients.
DR. STRONG:
A question about your monitoring for surface antigen or surface
antigen. What level of sensitivity are
the DNA PCR assays that are being used now?
You mentioned that they weren't standardized, but what is their
sensitivity?
DR. LOK:
The assay that we use is the Roche Amplicor monitor assay. Its sensitivity is less than 200 copies per
ml.
DR. STRONG:
So, there are assays in the works that have more sensitivity than
that. You mentioned that the surface
antigen assays are standardized, but there are also newer assays with better
sensitivity there as well. I am
wondering about standardization for both.
DR. LOK:
That is not true. The surface
antigen assays in general are sort of more uniform than the DNA assays, because
the DNA assays, first of all, in dealing with the NIDDK funded study, we
realized that there are still a lot of centers that don't even use a PCR assay.
They use a branch DNA assay, a hybridization assay.
There you are talking about a very major
difference, two logs versus six logs
With surface antigen, I don't believe that any of these assays will vary
that much.
It is true that with PCR assays, there are
now real time PCR assays. Again, the
problem is, even with the real time PCR assays, that there is really no
standardization, and they are not as widely available in clinical practice.
There are a few commercial diagnostic
reference labs that use real time PCR assays, and they claim a certain level of
sensitivity, but no one has validated their claims. So, you don't really know what you are dealing with.
One of the problems with doing these studies,
for the NIDDK funded study, we had the samples shipped in and we ran it
centrally.
So, at least for the study, we used one
assay. It may not be the best assay,
but we used one assay so we could really figure it out.
In clinical practice, a lot of times we don't
have any choice as to what assay. The insurance companies dictate where the
patients get their blood draw. Therefore, they also dictate what assay the
patient is going to get.
DR. HOOFNAGLE: I think maybe it wasn't clear from your presentation, but I think
a very important occurrence occurred when the U.S. group started studying HBIG,
and they found that higher doses were needed for patients with higher levels of
virus.
Of course, it made sense. We all felt very
stupid that we didn't know that. That
was the reason from Samuel from Europe.
They had a very high rate of recurrence in e
antigen positive patients, and you wondered whether HBIG was working alone.
What McGrory showed was that those patients
had this very rapid disappearance of anti-HBs after infusion. By measuring the disappearance rate, he
showed that you needed more HBIG for people with e antigen and with high levels
of virus.
Of course, it makes all the biological sense,
and they were really the first ones to achieve a 90 percent prevention of
occurrence, even in people with very high levels of virus. He treated some of my patients, and these
patients today, 10 years later, are still on HBIG every month.
So, one of the generations of Anna's study
that she has been a real trouper trying to get this going, was the fact, can we
ever stop HBIG. This is very expensive.
How do we know whether we can stop it or not.
So, as you heard, this was the first use of
the word control in her presentation. There haven't been control trials.
It was an attempt to do a control trial, and
it has been plagued by the fact that we can't provide the HBIG. The patient has to pay for it.
So, there is an enormous resistance to get
into the standardized trial. It is an
attempt to try to figure out whether you can ever stop HBIG.
DR. LIANG:
Thank you for that very comprehensive review. One thing I thought maybe
you can help us with is the question of a vaccine escape mutant. Do you think
that potentially would be a problem in HBIG treatment.
I think that is a sort of important issue,
and maybe you can kind of tell us a little bit about what the risk of immune
escape, or vaccine escape mutants in a patient with HBIG treatment.
DR. LOK:
The s escape mutant appeared to be more of a problem in the HBIG
monotherapy era. Right now, when we are
dealing with combination therapy, by and far, are really patients who either
are non-compliant and they weren't taking the medicine after a while, but more
commonly it is really due to lamivudine resistance.
Unfortunately, what we have observed is that
sometimes transplant centers are not necessarily monitoring HBV DNA level often
enough, and some of these patients were not noted to be lamivudine resistant
prior to transplant.
They were put on combination therapy
initially and, when the patients were receiving a very high dose of HBIG
together with lamivudine, you get away.
After a while, as you titrate down, you find
that the patients develop recurrence.
We haven't actually systematically looked at s escape mutants in the
current studies that we are doing.
Of the patients who have developed
recurrence, I think we have about 130, 140 patients who have been transplanted,
and seven patients have developed recurrence out of 130, which still gives us a
less than 10 percent recurrence rate.
All except one had lamivudine
resistance. The one patient who did not
have lamivudine resistance actually had an extremely high viral load before
transplant and, despite me picking up the phone and calling the investigator,
please put the patient on an antiviral therapy before transplant, the patient
didn't have antiviral therapy while waiting, and developed very rapid
recurrence within two or three months post-transplant. I think that one is really insufficient therapy
post transplant.
DR. LIANG:
As you are aware, some of the lamivudine resistant mutants actually can
confer resistance to HBIG.
I just want to know your perspective in terms
of dealing with mutants that could potentially be double resistant to either
antiviral or HBIG.
DR. LOK:
You are right. Jake is really raising a complex issue. Because of the overlapping, open reading
strain, the polymerase gene and the s gene actually overlap.
When you get a resistance in the polymerase
gene, you might actually change the surface gene as well, and that might
diminish the response to HBIG.
I haven't actually gone and analyzed every
one, because we use a simple screening method to pick up the 1DD mutation.
We haven't actually sequenced all of them and,
because we haven't sequenced them, it is more difficult for us to interpret
what the changes in the s gene are.
DR. CHAMBERLAND: Thank you. I had a couple
of questions about your last few slides. When you talked about the issues
around a study design to assess efficacy of HBIG, you mentioned, in the context
of HBIG monotherapy versus historical controls, some of the issues that would
have to be addressed in terms of trying to make sure that the controls were
comparable to those folks who got monotherapy.
You mentioned some of the really important sort of clinical factors.
I wondered about also, since I think you said
that HBIG monotherapy started in the late 1980s, early 1990s, would there be
other factors that would need to be taken into consideration that have changed
over time, such as perhaps either pre or inter or post operative care or
techniques and things that would also potentially influence outcome and, hence,
contribute to the difficulty of trying to use historical controls that far
back.
DR. LOK:
Certainly, transplant is a field where we have a lot of improvement,
both in terms of anti-rejection therapy as well as the technique of
transplantation itself.
Those can influence survival of the patients,
if you use survival as the end point. However, if you use HBV markers as the
end point, I don't think they would play a major role.
DR. CHAMBERLAND: Then I wanted to ask you, I wasn't sure if I heard you correctly,
in the slide in which you looked at design issues looking at HBIG plus an
antiviral, versus antiviral alone using historical data, did I understand you
to say that those data just are not available.
Are there historical data using antivirals alone?
DR. LOK:
There is very limited data, and those limited data would be lamivudine
only. We do not have data on adefovir
only.
One of the reasons why I caution the group
here is that the historical data on lamivudine only would make lamivudine only
look bad, largely because, when the patients developed resistance, we were not
able to salvage them. So, some of these
patients rapidly go downhill.
So, in this day and age, when we are moving
forward, it depends on which antiviral we use for the combination group.
Now, if you use a different antiviral with
less problems with resistance, let's say you use HBIG plus adefovir, but you
use lamivudine only as your historical control, then you will be comparing
apples and oranges.
DR. NELSON:
You didn't mention patients co-infected with hepatitis C and B. Are these patients just not transplanted?
DR. LOK:
These patients are transplanted but, in most clinical studies, patients
who are co-infected are not included in clinical studies, or they are sort of a
very small group and they tend to be separately analyzed.
There are really tremendous problems with
analyzing those patients. In this day and age, if they are co-infected with B
and C, the problem that we deal with afterwards is really the recurrence of
hepatitis C. That is what causes the
recurrent disease and the recurrent cirrhosis.
So, they tend to be separately analyzed.
DR. KLEIN:
I hope this is not too naive a question, but I appreciate the fact that
we have no controls, but we have a lot of data, and you told us what the
standard of care is.
It seems to me that this is a safe and
effective therapy. It is the standard
of care. The question is how best to
use it and the details. Is that not the
case? I know that we are not being
asked that question.
DR. LOK:
That is the case. The standard of care is to use therapy. We can't have no therapy. The standard of care is to use combination
therapy.
The devil is in the details. The devil is
when to start antivirals. Do we start
antivirals in everyone. Which one do we
use first. Do we use them sequentially or do we pick a different one.
We know that some HBIG is going to be
necessary post transplant. I think very few of us are comfortable enough to say
that, in this day and age, antivirals are so good that you don't need even a
sprinkle of HBIG.
I think many of us are thinking that, in this
day and age, we should be thinking of tailoring to the patient. There are some patients who are going to
need more and some patients who are going to need less.
Even in the high risk patients, there is room
for gradually tapering, either in terms of cutting down on the dose or actually
stopping after the most vulnerable period, the first year or the first two
years, is over. So, the devil is in the details.
DR. HOOFNAGLE: One thing that would solve the problem is if you could immunize
the patient with hepatitis B vaccine, so that they would make their own
anti-HBs.
The difficulty is these people don't respond
to hepatitis B vaccine. The people on lamivudine alone will have no anti-HBs.
They will be s negative and anti-HBs
negative, but they will have low levels of virus in the liver or
something. That would be the perfect
group to immunize, but they usually don't respond to vaccine.
There will be advances here with the use of
new adjuvants and understanding of tol-like receptors and the innate immune
system. Eventually, that might be the
solution.
DR. KLEIN:
Do you think in the transplant setting, that the immunization is going
to work with these patients who were immunosuppressed in the transplant
process?
DR. HOOFNAGLE: They are
immunosuppressed. Most of them are on
two agents. Some you can get off
prednisone.
DR. LOK:
Actually, there are separate attempts with immunizing these patients
with varying success. There is a paper from Spain a couple of years back.
These are very highly selective patients. So,
they picked patients who had extremely low levels of virus prior to transplant.
They waited until the patients were more than
one year post transplant, and they vaccinated them, and they had fairly
successful results.
An Italian group, using the same approach,
giving more doses of vaccine, found that it doesn't work. I think this is an
unresolved issue.
There are people now who say, well, instead
of using the conventional vaccines for prophylaxis in healthy people, we should
use more potent vaccines with perhaps more potent atruvin, maybe higher doses,
maybe intradermal administration versus intramuscular administration.
We have actually approached a couple of
vaccine manufacturers, but no one is interested, because they see that the
market is way too small for them to be worth working with us.
DR. LIANG:
I think one of the problems is also not so much the immune suppressive
agent they are on because, very often, after a year or so, you can really taper
off to a minimal dose and they will do fine.
I think the issue is that most of these
patients are already non-responsive to HBV, because they were chronic infected
prior to transplant.
So, they are basically immune tolerant. So,
it would be very difficult to induce an immune response when they are already
nonresponsive to the antigens. I think
that is really the major problem.
DR. LAAL:
Is HBIG standardized based on antibody titers or neutralizing antibody
titers? Could that be one of the reasons that you have this intra-patient
variation?
DR. LOK:
You mean the labeling of the product?
DR. LAAL:
Well, the product has to be standardized in terms of, either it has so
much titer of the antibody.
Is it neutralizing titers? I mean, all antibodies that are made do not
necessarily neutralize the virus. I am
just curious.
DR. LOK:
I think this is probably a question that is best answered by the
manufacturers.
DR. HOOFNAGLE: There is no neutralizing assay.
It is just an antibody assay using surface antigen as the capture. It is a licensed assay.
DR. NELSON:
One of the manufacturers is going to testify or give a speech in a few
minutes in the open public hearing.
DR. HOOFNAGLE: The HBIG is a polyclonal antibody. It is made from donors with anti-HBs. So, the escape mutants are less a problem because it is
polyclonal.
When groups use monoclonal antibodies, that
is when you get the escape mutants, because you select. It is just a gmish. Here is our expert on anti-HBs.
DR. NU:
I am from CBER, FDA, May Ling Nu(?) speaking. We licensed intramuscular hepatitis B immune globulin.
So, every lot has to meet the
specification. Usually -- we have a
CBER standard, and also WHO currently depends on the manufacturer, because of
the PK studies and so forth, what the manufacturer has to meet, at least one
CBER standard. That is usually around 210 iu, international units, per ml, or
another manufacturer, it depends on the PK study, the specifications for
anti-HBs has to be 312 iu per ml.
I hope I have -- the anti-HBs, it is a
binding assay, it is an ELISA or radioimmuno assay. It is not a neutralizing assay, but they have been
characterized. It is a licensed kit.
DR. LIANG:
How much lot to lot variation do they see?
DR. NU:
What we have now, you have to take into consideration the potency assay
variation and also the dating period.
When we license or release the lot,
throughout the dating period, the lot has to meet that minimum specification,
which is either 210 iu per ml, or 312 iu per ml.
DR. HOOFNAGLE: Do you allow anti-HBC to be present in the HBIG? Are these people who have had natural
infection or are they all immunized?
DR. NU:
They are immunized either by plasma derived or recombinant -- well, the
manufacturer is here. Of course, these are from source plasma donors.
So, the anti-cor is not screened out. Most
likely, anti-cor is there. In fact, it
is there, because it is by plasma pheresis donors.
DR. STRONG:
I just wonder if it is really possible to have an historical control in
this setting, with the changes in immunosuppression and surgical procedures.
For example, we certainly see the dramatic
decrease in the use of blood components in this setting. Is it really possible
to have an historical control?
DR. LOK:
I am not as concerned about the blood product. I think it has some
influence and, like I said, perhaps all the evolution in the transplant field
could affect survival fairly significantly over a 10 year period of time, a 20
year period of time.
If we are measuring HBs antigen, I don't
think that that is going to be a major difference, whether you use cyclosporin
or whether you are using tecrilimers, or whether you are using serolomers. I think if there is a difference, it may be
a very trivial difference.
I think the other issues of comparing data
that we have in this country versus those in Europe, for example, can pose a
major problem.
If you look at any European series of
hepatitis B transplantations, they certainly have a lot more delta infection.
So, they should have a much lower rate of
reinfection compared to the rate that we see here, where delta infection is
extremely uncommon.
Again, if you have a series where you have a
lot of fulminant hepatitis B patients versus a series where you have mostly
cirrhotic patients, the data can be completely skewed.
Those are probably more important in
influencing the results than the changes in immunosuppression and the surgical
technique.
DR. HOOFNAGLE: One more comment, and this is theoretical, about HBIG. The
question that I had asked was, do you use donors who have recovered from
hepatitis B who have been boosted, or do you use people who have just been
vaccinated against hepatitis B?
This may be important because the vaccine is
a recombinant vaccine. So, it is one species of surface antigen, and it is the
small s, not the entire s.
The person who has recovered has been exposed
to quasi-species of hepatitis B and the whole surface antigen. There is the
theoretical issue that hepatitis B immune globulin made from vaccinees may be
somewhat like a monoclonal antibody.
That is theoretical, I know, but that is why
I think it is important to not exclude patients with anti-cor from the donor
pools, because they have the real immunity and the broad spectrum of antibody
reactivity that might be important.
We have no idea about this because there is
no system for neutralizing this. This virus doesn't grow in cell culture and
the animal models are chimpanzees and it is much too difficult to look at true
neutralization on a large scale. That
is a theoretical issue..
DR. LIANG:
I guess just a corollary to that, I guess one of the problems with
including samples from naturally recovered individuals is that there is a small
percentage of them that actually still carry low level virus.
So, I guess you would have to screen out that
unit that contains potentially a low level of virus, despite evidence of
antibodies to both cor and surface.
DR. HOOFNAGLE: That study has been done, and immune globulin made from surface
antigen positive source material is not infectious for hepatitis B. I am not
sure why, but it doesn't seem to be.
The low levels of virus are so low that they
are neutralized by the presence of antibody. So, I wouldn't worry about that
too much, just because of history. It
hasn't been infectious for hepatitis B.
DR. NELSON:
That was an issue in the early days of the hepatitis B vaccine and the
HIV issue at that time, too.
Agenda Item:
Open Public Hearing.
DR. NELSON:
Okay, I would like to open the open public hearing. There are four people who wanted to make a
presentation.
I think it is important that these be fairly
brief. Dr. Smallwood told me seven
minutes. I am supposed to read this statement from the FDA prior to the opening
of the open public hearing.
Both the Food and Drug Administration and the
public believe in a transparent process for information gathering and decision
making.
Therefore, to ensure such transparency at the
open public hearing session of the advisory committee meeting, FDA believes it
is important to understand the context of an individual's presentation.
For this reason, FDA encourages you, the
speaker, at the beginning of your written or oral statement, to advise the
committee of any financial relationship that you might have with any company or
group that is likely to be impacted by the topic.
For example, the financial information may
include the company's or group's payment of your travel, lodging or other
expenses in connection with your attendance.
Likewise, FDA encourages you, at the
beginning of your statement, to advise the committee if you do not have such
financial relationships.
However, if you choose not to address this
issue at the beginning of your statement, it will not preclude you from
speaking. So, that is a very complex
statement that I don't understand.
The first speaker is Dr. John Fung from the
University of Pittsburgh.
STATEMENT OF JOHN FUNG, MD, PhD, UNIVERSITY
OF PITTSBURGH:
DR. FUNG:
Thank you. My name is John Fung.
I am professor of surgery at the University of Pittsburgh. I have been a
liver transplant surgeon for 20 years.
I have been involved, as Dr. Lok mentioned,
in the very beginning, with some of the initial reports on adverse outcomes
associated with hepatitis B and liver transplantation.
Some of the early work with HBIG, then with
fairly poor results, because we did not appreciate the issue of dosing as well
as length of dosing.
We had been involved in some of the early
monoclonal antibody studies in hepatitis B using the OST 577 monoclonal
antibody, and also helped to identify the development of surface antigen
mutants with Dr. McMahon.
The frustration level with hepatitis B
recurrence in liver transplantation, through the 1980s, was the reason that two
attempts at liver transplantation from baboon to human were done in 1992,
because of the thought of the resistance of baboon liver to hepatitis B.
So, the data that Dr. Lok presented really
was something that, in this past decade, the decade of the 1990s, was really
what has turned around liver transplantation, and hepatitis B as an indication
for liver transplantation, as we heard.
I would like to do just for my few minutes is
just to comment on some of the points that were made. I agree entirely. I don't think there is anything that I didn't
agree with Dr. Lok.
We certainly -- I am not here to discuss the
use of hepatitis B in the pre-transplant setting, because I don't really think
there is an indication.
There have been some studies looking at the
use of monoclonal antibodies, some of the OST derivatives, for pre-transplant
hepatitis B, but that is not what I am here to talk about.
There are two different settings for
hepatitis B immune globulin in the post transplant setting. Dr. Lok talked
about using it as prophylaxis for those patients with surface antigen positive.
There is another indication, which is
something that I think is more controversial, which is potential use of this as
a prophylaxis in the use of hepatitis B cor antibody positive donors, in whom
reactivation of the latent hepatitis B from the donor organ has been reported
at approximately 50 percent into naive patients.
Again, this is not an indication that the
panel has been asked to convene on. So,
I would just like to mention a few comments about the use of hepatitis B immune
globulin for surface antigen positive patients.
Just to summarize, this was all mentioned,
again, by Dr. Lok and Dr. Hoofnagle, which is that the DNA positive patients
really represent a high risk patient.
The ones that are DNA negative, as I will
summarize our own practical use and as you already heard, are lower risk.
These patients are higher risk for
re-infection. They do have higher surface antigen titers to start with.
Therefore, they are going to require more hepatitis B immune globulin in the
perioperative period, leading to a shorter half life of the surface antibody and,
because of the use of the antiviral therapies, are more likely to develop the
YMDD mutation, as we have already heard.
So, these considerations for the DNA positive
patients, I think really make us look at this group of patients as the minimum
threshold for therapy.
In other words, since we have a very high
risk group of patients, the treatment should be tailored to provide the best
coverage for them, recognizing that the low risk patients are very easy to
convert.
The principles that we already heard, using
antiviral therapy to suppress viral replication pre-transplantation, to improve
liver function, decrease viral load.
It should be recognized that we do know
patients that are not going to benefit, in other words, those patients with
hepatomas that require early consideration for transplantation may not benefit
from a prolonged course of antiviral therapy.
Nevertheless, we do use it in many of our
patients, as Dr. Lok mentioned, and in post-transplant use to decrease extra
hepatic HBV replication.
It should be recognized that another pool of
hepatitis B exists in an extrahepatic reservoir, and may account for some of
the HBV PCR positivity in the post transplant period, as monocytes and
mononuclear cells are being released into the circulation from the extrahepatic
pool.
HUB use to neutralize circulating HBV is
critical to achieve therapeutic levels in the perioperative period in the
anhepatic and early postoperative periods.
From a practical standpoint, to summarize what
Dr. Lok mentioned, we have used suppressive titering monitor, although we
do try, by ease of administration, use a relatively fixed dosing schedule.
The combination, as she mentioned, really
does maximize protection, and this is currently the state of the art, current
standard of practice in the United States.
We have, in some cases, attempted to go to
monotherapy -- i.e., eliminate HBIG -- but this has really been limited to the
patients that are low risk -- i.e., no replicators or low replicators -- pre-transplantation,
in order to minimize the risk of re-infection.
Just an algorithm that we use, this is a
derivation of our own practice. The DNA
positive patients either will get preoperative, pre-transplant antiviral
therapy if there is enough time to wait, or skip this because of the risk of
YMDD mutations. In the DNA negative
patients, we do not use antiviral therapy.
They move to transplant using a fixed dosing
of hepatitis B immune globulin in the perioperative period, introducing
antiviral therapy as soon as they are orally able to take medication.
Then the DNA positive patients moving to
trough titers, as Tim Pruitt has done at the University of Virginia, trying to
achieve levels of 500 units per liter.
I am sorry, this should be milliunits per milliliter or units per liter,
trying to achieve levels, as I mentioned, for a total duration of 12 to 24
months IV, and then converting them to intramuscular dosing with fairly high
levels of 250 units per liter, with a combination antiviral therapy.
Then, DNA negative patients are lower
dosing. Then, as I mentioned, carefully
selecting those patients that can be taken off HBIG.
Just to summarize, we think that historical
controls can be utilized, but I do recognize what Dr. Chamberland mentioned,
that there have been some practice changes, and you can't compare survival.
Whether the ability to reduce corticosteroid
use in the current era of trocholomus(?), less rejection rates requiring less
steroids, less rejection rates requiring less steroids, we know that steroids
can aggravate HBV replication, is yet to be determined.
I don't know that. I am not entirely sure
that there isn't some role, but I think that historical controls can be used.
I do agree that surface antigen is a
reasonable end point and I think that, overall, it would be unethical and
impractical to expect a trial using HBIG to do anything else but a protocol
including HBIG. Thank you.
DR. NELSON: Thank you, Dr. Fung. Are there any questions from the panel? Okay, the next speaker is Dr. Gary
Horwith with NABI Biopharmaceuticals.
STATEMENT OF GARY HORWITH, MD, NABI
PHARMACEUTICALS.
DR. HORWITH:
While we are waiting for the first slide, let me just address a question
that was asked before regarding the hepatitis B immune globulin.
My name is Gary Horwith. I am the vice president of clinical research
and medical affairs at Nabi Biopharmaceuticals.
We manufacture one of the hepatitis B immune
globulin products. It is approved for
intramuscular use in post-exposure prophylaxis.
Our product is collected from professional
plasma donors. These donors, as has
already been mentioned, may have had natural hepatitis B infection. Others are vaccinated.
Those who are vaccinated at the present time
are vaccinated with a vaccine that was derived from the plasma material from
Merck many years ago.
So, it actually does represent a broader pool
of antigens, as opposed to the monoclonal recombinant vaccines. The immune globulin is all screened for the
presence of virus by NAT.
Dr. Lok went through a very exhaustive
summary of the data that has been generated on the use of hepatitis B immune
globulin.
I only highlight this mostly so that the
advisory committee has it on paper.
This is a summary of various studies that used either low dose hepatitis
B immune globulin or short interval therapy.
You can see that the recurrence was actually fairly high, as has already
been mentioned by Dr. Lok.
When investigators moved to a longer course
of therapy, the recurrence rate decreased substantially.
As Dr. Lok has already mentioned, when the
availability of lamivudine was the trend for monotherapy, the initial experience
indicated that the recurrence rate was actually fairly low.
The early studies, which were shorter term
duration had a lower recurrence rate but, as the experience increased, with
more data, longer duration of follow up, the recurrence rate that was seen
actually tended to increase. I will use this as the basis for the analysis that
I will show you momentarily.
Now, of course, as Dr. Lok also mentioned,
the standard of care is to use combination therapy of an antiviral, primarily
lamivudine, with hepatitis B immune globulin, which has resulted in a
substantial decrease in the recurrence rate.
So, going back to the questions that were
posed by the FDA, I tried to address this in terms of what is actually
necessary in order for the FDA, the advisory committee, that is, to make a
recommendation in terms of what should be used for an approval process for the
hepatitis B immune globulin.
Obviously, we have to have a basis for
efficacy. We have already heard that
monotherapy is no longer possible, due to the current standard of care.
So, efficacy has to be determined either
based upon some historical control information or compared to the combination
use of hepatitis B immune globulin and an antiviral, compared to the data that
is generated from lamivudine alone.
Then secondly, of course, we have to have a very nice safety profile for
the hepatitis B immune globulin.
Our own studies, which were conducted going
back to about 1997 to about 1999, includes a data base of about 153 orthotopic
liver transplant recipients.
Thirty-two of those individuals were new
transplant recipients, and 121 were what we refer to as chronic maintenance
phase patients.
These are individuals who, at the time they
entered the study, receiving the Nabi HP, they were at least three months post
transplantation.
Out of the new transplant patients, we had 32
who were evaluable. One patient was eliminated from the analysis I will show
you because the patient died within 24 hours of transplantation, due to complications
of transplantation.
We have a mean follow up for these
individuals of about 2.7 years, and you can see the range there. Of the 31 patients that are evaluable, there
is a recurrence in two patients, which gives us an efficacy rate of 78.5 percent,
based upon the recurrence rate in patients who received lamivudine monotherapy
being approximately 30 percent.
So, we are using as a basis here that
monotherapy with lamivudine results in 30 percent recurrence over the course of
one year.
That is why the efficacy here turns out to be
78.5 percent. In fact, analyzing that,
that is highly significant versus the monotherapy with lamivudine alone.
We took, in addition to the patients that
were in the expanded access program that I am showing you here, we also
included patients evaluated by Dr. Raleigh(?) Dixon at Mayo Clinic in a
prospective study. I will get to that
study momentarily. We have referred to
that as Nabi 4204.
Combining these patients, we have a mean
follow up of 1.9 years, and the recurrence rate for 60 patients in the combined
data set is three, which gives us an efficacy of 83.3 percent and, again, a
highly statistically significant p value.
Now, among the chronic maintenance phase
patients, there were 121 that were evaluable.
we have an extended follow up for 44 of those patients, which was
actually an additional data collection at the request of the FDA, bearing in
mind that these patients were initially enrolled in studies and evaluated
several years prior to the request to get additional information. We were able to retrieve information on 44.
There is a mean follow up of 3.8 years for
these individuals, and we had three recurrences out of 121 patients, giving us
an efficacy of 96.9 percent, compared to the test of zero efficacy, again, a
significant difference.
Nabi 4204, which I mentioned earlier, was an
open label studied that was conducted by Dr. Dixon. All of these were stage two or three surface antigen positive
liver transplant patients, or patients expected to go on to liver
transplantation within 12 weeks of enrollment.
Thirty patients received at least one dose of
100 milligrams of lamivudine prior to transplantation, but there was no upper
limit as to the number of doses of lamivudine they may have received prior to
transplantation.
In the first part of the study, the
individuals received 11 doses of 11,000 international units per dose. They got
two doses on the day of transplantation, as already mentioned, the first dose
usually being during the anhepatic phase.
Then they received one dose of immune
globulin daily for the next seven days, and then one dose on weeks four and
eight.
The second part of the study, which was
actually designed as a pilot to the study that Dr. Lok described earlier, these
individuals received 5,000 international units of Nabi HB intravenously every
four weeks between weeks 12 and 36.
In that study, there was a recurrence in one
out of 29 evaluable patients, giving an efficacy of 88.9 percent. Three of the 14 individuals, or 79 percent
of them, remained hepatitis e antigen positive.
What we concluded from that study, or what
Dr. Dixon and colleagues -- this was an 11 center study -- that
concomitant administration of lamivudine and Nabi HB was, indeed, safe and well
tolerated.
The adverse event profile that was observed
in the study was qualitatively quite similar to the adverse event profile that
has been seen with immunology globulin in other studies.
In the prospective trials, without regard to
relationship, there were 324 adverse events among 206 patients in the data
base, which constitutes a little over 1,300 infusions.
Eighty one percent of the adverse events were
mild or moderate and were self limited. Among those events with a frequency
greater than two percent, we have back pain, which seems to be quite a common
thread in the administration of immune globulin, no different for the individuals
who received hepatitis B immune globulin.
Nausea was reported in five percent, sepsis
occurred in three percent. This obviously is not related to the immune globulin
per se.
In our post marketing surveillance system,
based upon that, we have an estimate of about 51,000 infusions of 10,000
international units of hepatitis B immune globulin, that have been administered
since the product was approved in 1999 for post-exposure prophylaxis and
intramuscular administration.
In that data base, we have a total of 24
adverse events that have been reported, which is quite similar to the adverse
event profile that has been seen in the clinical trials.
So, in summary, Nabi HB, with or without
lamivudine, was highly effective in preventing the hepatitis B recurrence.
The efficacy is significantly greater than
that seen with lamivudine monotherapy, even assuming a recurrence rate of 30
percent.
The concomitant administration of lamivudine
and immune globulin is quite safe and well tolerated, and the adverse event
profile is really quite similar to the adverse event profile of IgG.
Now, one of the things I wanted to end with
was to address the question in terms of dosing. These are data generated by Dr. Tim Pruitt at the University of
Virginia.
This is quite consistent with what was
previously discussed today and what has been proposed by the data from Dr.
Samuel.
Dr. Pruitt looked at his hepatitis B positive
liver transplant patients over an extended period of time, and just simply
plotted the individuals with regard to their anti-HBs titer, based upon the
administration of the immune globulin.
He was able to determine that, during the
first seven days, the break point is basically at about 500 ius. The break point for those individuals
between days eight and 90 is about 200, 250, thereabouts and, beyond day 90,
the break point appears to be at about 100 ius.
You can see that there is, as was mentioned
previously by Dr. Lok -- actually, I don't have it here, but in another follow
up to this, Dr. Pruitt has looked at those who were e antigen positive, or
replicators and, of course, as Dr. Lok pointed out and Dr. Fung pointed out,
those who are replicators require much more immune globulin than those who are
not.
This is food for thought, if you will, for a
dosing recommendation. The initial
approval of hepatitis B immune globulin in Europe was for much lower doses of
immune globulin.
Recently, the EMEA, which is the advisory
group to the CPMP, the centralized agency for drug recommendations for the
European Union, has come out with a new guideline for use of hepatitis B immune
globulin in liver transplantation.
Their guideline reads as follows: Individuals should receive 10,000
international units on the date of transplantation and perioperatively.
They should receive 2,000 to 10,000
international units through day seven and then, as necessary, to maintain the
anti-HBs level at an adequate level.
That adequate level is defined as 100 to 150
IUs for DNA negative individuals, and greater than 500 ius for those who are
replicators, or DNA positive. Thank
you.
DR. NELSON:
Thank you, Dr. Horwith.
Questions?
DR. HOOFNAGLE: On that last slide, when you say DNA positive or negative, when
do you mean, before transplant DNA positive?
DR. HORWITH:
No, these are after transplantation. These are the individuals who --
the recommendation, I think, is actually based on the DNA or the replicative
status prior to transplantation.
Certainly, if an individual still had
evidence of DNA post transplantation, the recommendation is to consider them as
a replicator, obviously, and go with higher trough levels.
DR. HOOFNAGLE: I actually don't understand what you meant. Do you mean that you wanted to keep a higher
trough level in people who were DNA positive before transplant?
DR. HORWITH:
That is correct.
DR. HOOFNAGLE: The devil is in the detail again. If they are DNA positive,
negative on adefovir, is that DNA negative or is that artificial DNA negative?
DR. HORWITH:
They are not native DNA negatives, if you will, but they have been
converted to a non-replicative status, I suppose, and they are considered a
lower risk.
DR. HOOFNAGLE: Also, what test were they referring to, a PCR based test or the
old test?
DR. HORWITH:
I don't know what was the basis for the EMA recommendation. I don't know
which test they are referring to.
That final test was from the EMEA guidelines,
CPMP guideline, and I don't think there is a description in the guideline as to
which test should be used.
DR. KLEIN:
Is HBIG reimbursed in this country for this indication?
DR. HORWITH:
It is now currently reimbursed, yes.
DR. KLEIN:
So, why can't you do the trials?
Why can't they do the trials if this is being reimbursed? Will they not reimburse if it is under
study?
DR. HORWITH:
Do you not understand medicare?
If you are under medicare, you are not reimbursed for HP. You have to pay for it yourself.
DR. KLEIN:
That was the question you just asked.
DR. HORWITH:
Well, if you have a good insurance company.
DR. NELSON:
Perhaps Dr. Fung can address that.
DR. FUNG:
I think the monthly maintenance is considered as a prescription
benefit. Medicaid does not have
it. While you are in the hospital,
those are covered.
DR. HOOFNAGLE: You have the patient who has been on HBIG for years, gets
switched to medicare and can no longer at that point -- at that point has to
start paying for their HBIG. It is
devastating. Some of them quit, stop.
DR. KLEIN:
Is it likely it would be reimbursed if this were a licensed product?
DR. HORWITH:
It is reimbursed now. Most insurance companies will reimburse the HBIG
because it is a licensed product. It is
licensed, not for this indication, but for other things.
So, most insurance companies, regardless of
what the FDA has or hasn't done, will reimburse you for this. Maybe John Fung can address this.
DR. KLEIN:
:Again, trying to do the studies, if this were licensed for this
indication, would medicare reimburse and then let you look at the details?
DR. FUNG:
On the new drug prescription plan of President Bush --
DR. FUNG:
Anna, maybe you want to comment on it.
My understanding from our reimbursement people is that they do
reimburse.
Medicare does reimburse, but it is not done
because -- this is their formal policy -- they allow the intermediaries to make
their own determination. Our
intermediary allows it to be reimbursed from the medicare. Is that true in Michigan?
DR. LOK:
In general, there is no problem with reimbursement when a patient is in
the hospital. Once the patients are discharged, most insurance still don't have
a problem, but there are instances when this can be a problem, because it is
not a direct, straightforward reimbursement.
You have to go through intermediaries.
During the first initial post-transplant
period, depending on the transplant center, there is also another complicating
factor.
A lot of times insurance companies will pay a
transplant center a lump sum for the transplant. It will cover the transplant admission and for varying durations
post transplants, and that includes almost everything.
So, depending on the contract that you have
with the insurance company, if that lump sum covers a very extended period post
transplant, including medications, including readmissions and all that stuff,
then transplant centers would be in a situation where they would try to cut
back on the use of HBIG, which is an extremely expensive item.
One of the big problems with doing a clinical
trial, when you don't have the manufacturer supplying the product, is that
different transplant programs have different policies, different patients have
different insurance policies. So,
trying to standardize things makes it very difficult.
DR. LINDEN;
Can I just get clarification, though?
When you are talking about these usually are covered, do you mean if the
person's private insurance has a drug plan?
If it is medicare, at the present time, it
would not be covered, which is what Dr. Hoofnagle was saying, because at the present
time, medicare doesn't have a drug plan.
Am I understanding this correctly?
DR. HOOFNAGLE: John Fung pointed out, it varies from place to place.
DR. FUNG:
The demercs in this country have their intermediary determine that. Most of them that I know of will cover all
the inpatient costs for HBIG infusion, and in our intermediary they will cover
the outpatient infusion, or intramuscular injections.
This is the northeast. I am not sure if this is true -- I have
heard throughout the country that it isn't uniform, and I have heard of some
patients who have not been given the post transplant, outpatient coverage for
HBIG.
This is because of the off label use, based
on FDA guidelines, that they are not allowed technically to reimburse for off
label use of a medication.
DR. HOOFNAGLE: Let me also point out that, not only is it being used off label,
but in an inappropriate fashion.
The IM HBIG was being given IV. If you have
ever done this, you know it is extremely difficult. What they would do, they
would put it into a liter of D5W and run it in and give the patients morphine
and so forth, because of the systemic side effect of giving IM HBIG IV.
This was what was standard -- what was done
in the standard. You heard about McGory's data. A lot of that was using IM HBIG given IV.
So, it has been a very difficult field and
the availability of an IV product has been much needed. The Europeans have had it for some time. We
haven't had it in this country.
DR. HORWITH:
Let me just clarify that the original immune globulins were, in fact,
higher protein concentration. They were
about 16.5 percent protein, and they contained preservative.
The Nabi HB as well as the European products
that are approved for intravenous use is a five percent protein and has no
preservative.
DR. NELSON:
I would like to move on, now that we have solved all the drug
reimbursement issues. Dr. Garish Vyas
from the University of California.
STATEMENT OF GARISH VYAS, PhD, UNIVERSITY OF
CALIFORNIA.
DR. VYAS:
Good morning. My name is Garish
Vyas. I am a professor at the
University of California, San Francisco, and I am an investigator or PI of an
alternative approach to immunotherapy in post transplant patients who are
hepatitis B infected.
I have not prepared slides. Gordon Tompkins, who was a professor at
UCSF, gave a two-hour talk, and I don't intend to do that, without slides.
There are two studies that have been done,
one by our group at UCSF, to demonstrate the feasibility of making hepatitis B
immune plasma that costs less than 15 percent of that of HBIG.
Our primary motivation was, how can the cost
be reduced, particularly for patients who do not have resources to pay for
hepatitis B immune globulin.
As a blood banker -- and I am an alumnus of
this blood products advisory committee -- we considered immunizing or giving
booster to people who had been previously immunized with hepatitis B vaccine.
So, we took 100 donors, who were already
vaccinated previously, and tested their antibody titers. Those who had high antibody titers were given
one booster and then, post booster, six weeks later, they were entered into a
plasma pheresis program.
These plasma pheresis units were obtained in
500 to 600 ml, double plasma pheresis, and then aliquotted into subunits of 100
ml.
Each of the donations was standardized for
anti-HBs content by licensed assay, and labeled with the amount of antibody
content in 100 ml of this hepatitis B immune plasma.
This was an investigational new drug, permit
approved by FDA, and the committee on human research at UCSF.
We have shown that it is possible to do this
routinely to prepare such product, and everything that is done in the blood
bank is done, namely, the NAT testing and the antibody screening. These donors are certified to be suitable
for human use, like any fresh frozen plasma donors.
So, to make the long story short, I have
distributed to the committee a recent review that has been published in Clinics
in Liver Diseases, volume 7, 2003, page 537 through 550.
In one page, on 546, we have another
experience at UCSF on preparing hepatitis B immune plasma, and its clinical
trial done as phase I safety in nine patients.
So far, it has been very encouraging.
Dr. Mentha(?), in Geneva is doing -- we are
doing only anti-HBs containing plasma, that is, the donors are anti-cor
negative.
Dr. Mentha in Geneva has done studies with
hepatitis B infected, previously infected patients, who are anti-cor
antibodies, as well as anti-HBS.
As reported, a follow up period of 58 months
to show that 92 percent of the patients remain protected. With this, I would stop and let you ask any
questions that you have about hepatitis B and plasma.
DR. NELSON:
Thank you, Dr. Vyas. Questions?
DR. LINDEN: How many copies of your reprint
are there? It seems the other side of
the table got it and we didn't over here.
DR. VYAS:
My apologies. I looked at the
membership, which was nine or 10, and I brought 10 reprints. I apologize for not having brought more than
10.
DR. NELSON:
We can make copies. We will make sure everybody gets one. Any questions? Thank you. The last
person who was scheduled to speak, Dr. Forrest Dodson, director of
transplantation surgery, at Rush Hospital in Chicago. Dr. Dodson?
Okay, is there anybody else who wanted to
make any statement in the open public hearing?
Okay, so we are only 20 minutes behind. So, we can have a break and we
will reconvene at quarter of 11:00.
[Brief recess.]
Agenda Item:
Open Committee Discussion. FDA
Current Thinking and Questions for the Committee. Committee Discussion and
Recommendations.
DR. NELSON:
Dr. Golding, I wonder if you could restate the questions or tell us
really what you want us to do.
DR. GOLDING:
What I think I would like you to do is tell us how to go forward to
regulate this products. As we have
heard, we have a very complex situation and, because the field has moved quite
rapidly and we are far beyond the stage where hepatitis B immune globulin
products are used as monotherapy, we have a situation where, if these products
are submitted to the FDA, how do we approve them for safety and efficacy.
Even though this is difficult, we feel that
we need to find solutions and we need to find a path forward. I think the main
purpose, to present it to the committee, was to present them with the scope of
the problem, and to try to formulate some questions which would help us move
forward when we deal with these products at the FDA. So, I will go over the questions and see if we can get some
answers.
So, the first question, which I think is
relatively straightforward is, in clinical trials to show efficacy for HBIGIV
treatment, can HBs antigen seronegativity be used as the primary end point for clinical
outcome, indicating prevention of current HBV disease in the transplanted
liver.
DR. NELSON:
Is there discussion on this issue?
Do we need to vote?
DR. SCHREIBER: It seems, since DNA levels are important in terms of deciding
outcome, and also in terms of deciding the groups that get on the therapy with
the outcome of therapy, it would seem that, as opposed to the original write up
where it says a primary outcome, it is now the primary outcome.
I guess I would ask whether DNA measures
should also be considered as an outcome variable in any kind of clinical trial,
despite the fact that we heard that there is not standardization.
In fact, if you are going to do a trial, you
will standardize the measures and, if you are looking at outcomes, you should
be able to get a good measure.
DR. HOOFNAGLE: There are two difficulties. One is these low levels of HBV DNA
that you see in some patients of uncertain clinical significance. So, by itself, it is hard to use that as an
end point.
The people who develop surface antigen
generally will re-develop very high levels of HBV DNA. So, it is unequivocal.
The surface antigen kind of separates the men
from the boys or however you want to put it, as far as the seriousness of the
re-infection. Probably everybody gets
re-infected. What the antivirals and HBIG does is keep it suppressed.
I think you need to use surface antigen as an
end point and, in the current day, it is hard to use more than the surface
antigens, because of the therapies of hepatitis B.
DR. NELSON:
Do you want us to vote on this?
I guess that is the way it works.
Are we ready to vote? Do we just
hand vote?
DR. SMALLWOOD: The procedure for voting is by roll call. I will call your names, and you will answer
yes or no for the first question, which I will read again.
In clinical trials to show efficacy for
HBIGIV treatment, can hepatitis B surface antigen seronegativity be used as the
primary end point for clinical outcome, indicating prevention of recurrent HBV
disease in the transplanted liver. We
are ready to vote. Dr. Allen?
DR. ALLEN:
Yes.
DR. SMALLWOOD: Dr. Davis.
DR. DAVIS:
Yes.
DR. SMALLWOOD: Dr. Doppelt.
DR. DOPPELT:
Yes.
DR. SMALLWOOD: Dr. Klein.
DR. KLEIN:
Yes.
DR. SMALLWOOD: Dr. Laal.
DR. LAAL:
Yes.
DR. SMALLWOOD: Dr. Chamberland.
DR. CHAMBERLAND: Yes.
DR. SMALLWOOD: Dr. Harvath.
DR. HARVATH:
Yes.
DR. SMALLWOOD: Dr. Hoofnagle.
DR. HOOFNAGLE: Yes.
DR. SMALLWOOD: Dr. Liang.
DR. LIANG:
Yes.
DR. SMALLWOOD: Dr. Linden.
DR. LINDEN:
Yes.
DR. SMALLWOOD: Dr. McGee.
DR. MC GEE:
Yes.
DR. SMALLWOOD: Dr. Quirolo.
DR. QUIROLO:
Yes.
DR. SMALLWOOD: Dr. Schreiber.
DR. SCHREIBER: Yes.
DR. SMALLWOOD: Dr. Whittaker.
DR. WHITTAKER: Yes.
DR. SMALLWOOD: Ms. Knowles.
MS. KNOWLES:
Yes.
DR. SMALLWOOD: Dr. Nelson.
DR. NELSON:
Yes.
DR. SMALLWOOD: And our non-voting industry representative, how would you vote?
DR. STRONG:
If I were allowed, I guess I would vote yes.
DR. SMALLWOOD: The voting on question one is unanimous yes, with the non-voting
industry representative agreeing with the yes vote.
DR. NELSON:
Dr. Golding, the second question.
DR. GOLDING:
The second question is a little bit more complicated. Is a single arm study for safety and
efficacy during the maintenance period following orthotopic liver
transplantation sufficient for licensure.
The study would compare either HBIGIV with an
historic control of no treatment for 12 months, or HBIGIV plus lamivudine or
other antiviral for 24 months, with an historic control of lamivudine or
appropriate antiviral alone.
Part of the thinking here, and the reason for
the longer follow up in 2B is the observation as presented by Dr. Lok today,
that the resistance to lamivudine, at least, starts to -- you start to see
breakthrough cases starting at one year and increasing to three years, and that
you would need a longer follow up in order to be able to determine whether
there was an additive or synergistic role of the immune globulin when you had
the combination therapy.
DR. NELSON:
Any discussion about this?
DR. ALLEN:
I think, given all the information that was presented to us as
background materials, as well as the presentations and discussions today, it is
very apparent that the standard of therapy does include HBIG today.
There are still obviously some very important
unresolved questions. There is the
whole question of use of an intramuscular product, or primary use of an
intramuscular product in a different mode of administration, development of new
products and how they would be factored in and so on, a lot of very important
questions.
I guess I would prefer to see, instead of
stating a single arm study, to say that alternative study designs other than a
placebo controlled study, because I am not sure that single arm is the only
study design that would be satisfactory for this.
I will vote yes on this, but I wish it were a
little bit broader without necessarily saying that it had to be a placebo controlled
study.
DR. LIANG:
I guess the question is, is there any particular design that you would
think would be appropriate if you wanted to design another group for
comparison?
DR. ALLEN:
Study design is not really my forte.
I wouldn't want to be the restricting factor on that one. As we heard from the presentation earlier,
you might come up with an absolutely -- not you personally, but the principal
investigator might come up with an absolutely -- wonderful study design and
there would be other limitations such as the inability of patients to come in
or comply with it, as was described today, the travel factors, the factor of
people already being on certain courses of therapy prior to the enrollment in
the trial.
This is a very complex field. As I said, I will vote yes on this, but my
preference would have been to see it slightly broader.
DR. HOOFNAGLE: I agree with the question about the single arm, just maybe non
controlled. You might study two different doses, for instance, or different
regimens.
What I wondered about, what do you mean by
maintenance period? Do you mean a study
in which people are already on an unlicensed product and are switched to the
new product, or do you mean taking people from the time of transplant with a
new product?
DR. GOLDING:
The difficulty is that, when you are doing the perioperative period, a
lot of things are going on.
The actual dosage is usually a lot higher and
there are a lot of concomitant things going on besides the antivirals. There is also the immunosuppression and so
on.
What we thought, that during the maintenance
period, if the trial is done during that period, which is three months or maybe
even six months after the transfer, that you have less variability between
patients and between regimens.
What we have heard is that different centers
are using different dosages at different frequencies in the perioperative
period, but it seems like it is easier -- maybe not completely standard -- but
it is easier to expect that, during a maintenance period, there would be
agreement between the treatment centers in terms of what doses and what
frequency would be used. So, it would
be easier to set up a study during that period rather than to include the
perioperative period.
DR. DOPPELT:
I have a question. I am a little
bit confused. On group A, the HBIGIV, are these patients who would never have
been previously on an antiviral, or they had been but, at the time of
transplant, then you switched them to the HBIGIV only?
DR. GOLDING:
The idea is that these patients would not have been on antivirals. It
would have to have happened at a time when antiviral treatment was not being
used, or in a study where antiviral treatment had not been used.
This is a retrospective study. It is data that was collected some time back
before antivirals became part of the standard of care, so that you could look
at that study and compare that to a time further back when there was no
treatment, no antibody or antiviral treatment.
The numbers are that, prior to any treatment,
in this scenario, you had 70 percent recurrence in the first year and, with
HBIGIV or HBIG monotherapy, you had somewhere in the region of 30 percent
recurrence in the first year.
If you could show that your product had that
kind of effect compared to no treatment control, would that be sufficient for
licensure?
DR. LIANG:
I think Dr. Lok has correctly pointed out, really, at this stage, almost
40 percent of the patients coming to transplant are already on some kind of
antiviral therapy.
I think potentially that is a problem for the
option A, to just expect that we are going to be able to do the study with HBIG
without the patient ever having been on antiviral therapy.
DR. GOLDING:
Yes, I don't think that study is practical, feasible, ethical at this
point in time. I am saying, if data was collected previously when this study
was practical, that could be submitted to the FDA.
Does the committee think that that is
reasonable, that we can go back and say that, even though the standard of care
today is very different, could we go back in time and say, well, that showed at
that particular period of time, that that product, that immune globulin
product, was safe and effective, because it was more effective than no
treatment.
DR. NELSON:
Presumably the measurement of the end point, which we decided in vote
number one would be surface antigen, presumably that has been standard since
the early days of the liver transplant.
Now, whether the same methods were used and
whether it was done at the same time after the transplant was done, I don't
know, but I presume that it is probably comparable.
That is another argument for using surface
antigen rather than DNA, which may have varied quite a bit over time.
I would think that the end points, if we used
what we had voted on for question one, probably would be available in an
historic control that had no treatment other than -- it seems to me that since
now all of the HBIG patients, or certainly the vast majority, are getting
antivirals as well, there is no way we can not use those patients and require,
for licensure, only those that get HBIG.
DR. LIANG:
Are you also trying to answer the question of whether the use of
antivirals should be licensed for prophylaxis for transplant as well? Is that something that you are trying to
address as well, of just the HBIG.
DR. GOLDING:
Our task in the office of blood, we regulate immune globulins, plasma
derived products. The drugs are
regulated in the center for drugs.
My understanding is that these antiviral
drugs, although they are licensed, or lamivudine is licensed, it is not
licensed for the indication of OLT.
So, what we are dealing with is a complex
situation. We are not usually in the business of getting submissions where you
are using two products, neither of which is licensed, and you want to know
whether you have a safe and effective treatment.
The simple way of doing this is to license
each product on its own or its own merit, and then do a combination treatment.
We have gone far beyond that in terms of
standard of care. This is where we are now. We are going to have to deal with
that, and that is why it makes it much more complicated.
DR. LIANG:
I think that, if that is the case, it probably is not going to be
possible to conduct just HBIG alone in a study. I assume that you are going to have to look at historical
studies.
DR. GOLDINg:
Well, we are saying 2A is for retrospective analysis of data, 2B is for
prospective studies, could we conceive of studies where you are doing HBIGIV
plus an antiviral, and compare that again to historical data.
I don't think, from what I am hearing, that
anybody is going to do a study with the antiviral by itself. That is not acceptable.
Again, it would have to be a comparison to
historic controls, the combination therapy compared to the antiviral by itself.
We have seen data, and I am not sure how well
that would stand up to rigorous review, that antiviral studies on their own
have been performed, and there is data out there, but can we now go ahead and
ask a company to do -- or a sponsor to do -- a study that would have combined
therapy, and have to show in that trial that the combined therapy is better
than the antiviral alone.
DR. HOOFNAGLE: Again, we are talking about different things. What I am talking
about is two different types of studies.
One is, you have someone who has been
transplanted in the past and is on HBIG.
You do a study where you switch him to the product that you are
interested in.
In that type of study, all you can really get
is, you get the same levels of antibody.
As far as efficacy, we don't know at that point what the efficacy would
be.
The efficacy studies have to start with the
time of transplantation, as was shown by the Nabi data, where they had the
patients from the Mayo Clinic, the 37 patients or whatever, that were given
their product right up front and followed and shown to have a lot rate of
response.
That is the group from the start, from the
time of transplant forward, to either 12 months or one year, to show
efficacy. The other is just showing
equivalency of reaching antibody levels and side effects.
While that is a little bit helpful, what it
seems to me you need is someone who is started on the new HBIG or the HBIG you
are interested in at the time of transplant, and then show at 12 months that
the rate of re-infection is 10 percent or less or something like that, or the
controls were 30 percent.
DR. GOLDING:
Maybe makes sense to me. If the committee and everybody else agrees, I
think we should strike the word maintenance.
What you are saying is that you want studies from the time of the liver
transplant and throughout.
DR. HOOFNAGLE: Right, because it addresses this issue of what dose do you give
around the transplant period, which is probably the most critical dosing
period.
Thereafter, you know, you have got a stable
situation and the dose may not be as important. So, I think that, as far as
efficacy, you have to start from the transplant.
It seems to me that you can use both of those
historical controls for the patients who don't need an antiviral, who are PCR
negative. They can use HBIG alone. The
real tough group are those that are going to be on both, the Bs.
DR. GOLDING:
Did I catch or misunderstand -- did you say that if you had a patient
today who is HBV DNA negative, who is HBe antigen negative, that you would
think that it is reasonable to put that person on monotherapy during the
transplant? Could you conceive of
having a trial of that design?
DR. HOOFNAGLE: I wouldn't subject HBIG to that situation. That is a situation where you may get away
with antivirals alone, which would be cheaper and easier, like Dr. Lok showed,
in what we call her low replicative phase.
These are people who are not on antivirals,
are on nothing, and they are PCR negative at transplant. Those people can probably get away with
monotherapy using an antiviral. That is
what Anna's study was, but she couldn't enroll it much.
The problem patients are those who are HBV
DNA positive at transplant, or they are HBV DNA negative and on an antiviral
agent already. So, they are being suppressed. You don't know, if you took them
off, but that HBV DNA would come back.
That is the target population where I think
you should aim your efficacy trial. Frankly, the standard of care now includes
an antiviral agent, I think.
DR. NELSON:
I think this comparison with a control would also have to take into
account the prevalence in the control group of the other risk modifiers, such
as delta, cirrhosis, level of HBV, et cetera, et cetera.
Hopefully, those data are available on an
historical control in such a way that it could be comparable. I think probably
they are, but I am not sure.
DR. HOOFNAGLE: I am saying the study A, you are just not going to have any
patients in that group, because the transplant surgeons are not going to be
willing to do that, except for this very special group that probably doesn't
need very much anyway.
DR. GOLDING:
Right, so what I have said is that group is only a group that is viable
based on data that was collected prior to this era, and it is not a viable
design for this point in time, that we passed that point.
DR. LIANG:
So, for B, my understanding is that you were trying to ask us whether we
should endorse a study to look at the option B, the combination.
DR. GOLDING:
Correct, and the historic control there would be the antiviral itself. As was pointed out by Dr. Kenrad, there is
certain data that you would look at in the historical data to make sure that
the two groups were comparable, especially for critical things such as HBV DNA
and the D virus and so on.
DR. LIANG:
So, are any of the pharmaceutical companies making these antivirals
trying to license their antiviral for OLT use at all?
DR. GOLDING:
I don't know about that. We
would have to ask people in CDER. I don't know about that.
DR. LIANG:
I am just saying, if you plan to do the study, perhaps it would be a
good idea to get together with them and see if there is a coordinated
effort. Basically you are trying to
approve or license both drugs, if there is an effort to do that.
DR. GOLDING:
Yes, it is more complicated, but you are right. It is a good point. We should do this together with CDER,
especially if they have sponsors that are wanting to do that.
DR. LIANG:
Rather than come back later and try to address the issue again.
MS. KNOWLES:
I have a question. The question is, in the briefing materials, this
question number two states, is an open label study during the maintenance
period, and then it goes on.
Yet, in the materials we have today it has
been changed to, is a single arm study.
Can you help clarify that for me, please?
DR. GOLDING:
After the discussion I heard, I am beginning to think that our previous
form of it is a better form.
So, thanks for pointing that out. I think we should change it back to either
an open label study, rather than confining it to a single arm study.
DR. NELSON:
Are we ready to vote on this one?
AUDIENCE PARTICIPANT: At the risk of adding complexity here, part
of why this was posed as the maintenance period was also the fact that much of
the retrospective data were only generated for new products in the maintenance
period. In other words, the product was
switched.
I guess there is a question whether we should
even consider approved labeling for maintenance, independent of whether that
same product was used perioperatively.
I just want to be clear here, Jay, I
understood your comment to imply that that would not be appropriate because it
wouldn't have real clinical meaning. It
suggests that we would be striking also the idea of maintenance.
DR. HOOFNAGLE: The studies that do show that you can switch are valuable for
labeling, for instance, because you might want to say that, in the typical
patient who has been on HBIG, you can achieve a titer of 250 with this dosing
every month or something like that.
So, I think those studies are helpful, and
they are probably the preliminary studies that should be done, if a new product
comes along, try switching patients before you embark upon the critical study,
which is starting at the time of transplant.
So, I am not saying they shouldn't be done,
but I am saying that what they tell you is something a little bit different.
AUDIENCE PARTICIPANT: The question is whether one could
extrapolate from a study that showed efficacy in the maintenance phase to
approval of that product for perioperatively and maintenance use.
The argument would be that, if it has the
right pharmacokinetics, and you are going to get there in the next question,
that you would assume that, if it was equally efficacious in maintenance it
would have been a suitable product to be used perioperatively at a comparable
dose.
So, it is a little bit more complicated, and
it is not meaningless to ask the question whether we can validate these
products by studies in the maintenance period.
DR. HOOFNAGLE: Remember what Anna Lok's study now is. She is taking people a
year out on HBIG, surface antigen negative, and taking them off HBIG.
If you switch them to another HBIG, it might
be equivalent to taking them off, and you wouldn't know as far as efficacy.
You would only know that you are achieving
the same antibody titers. I am saying
that you can't really judge efficacy after you are out a year on HBIG and an
antiviral.
DR. GOLDING:
What if you switched a lot earlier than that, if the switch is occurring
at one month or two months or three months, when the incidence of recurrence is
much higher than at a year.
DR. HOOFNAGLE: I think after six months, from the UCSF data you saw, the
majority of people don't have a problem when you take them off and, the few
that did, that may occur anyway. That
is why I think it is difficult to judge completely on maintenance.
Now, when you have two or three products on
the market and someone else comes along with their products, and you have to
judge it the way you do regular immunoglobulin, you don't make them do big
efficacy trials. I think that is a
little bit down the road.
You saw from the Nabi data that studies with
30 or 40 patients are usually adequate to show significance. So, you are not asking them to do enormous
studies.
DR. LIANG:
If I understand correctly, typically, if you have a new product, you
would probably do the maintenance study first just to make sure that it still
works and, if it does, you would move ahead with doing the whole study of doing
the peritransplant area.
I agree with Jay in the sense that you don't
really need a large number to show efficacy.
I think maybe that should be the way to pursue.
DR. EPSTEIN:
What I am hearing is that there is a general sense that studies during
the maintenance period further out from one month may have value and may be
preliminary studies, but that the definitive study in question two shouldn't
say during the maintenance period.
DR. ALLEN:
Do we need the words, during the maintenance period? That doesn't preclude doing that if the
words aren't there. Does the FDA need
those words in there?
DR. GOLDING:
What you were getting from Jay Epstein is that that is an issue, because
some of the studies we are looking at only have treatment during the
maintenance period.
If we are saying that, studies during the
maintenance period are not sufficient for licensure and are only preliminary
studies, and that is what I am hearing from the hearing, then we can change the
sentence to an open arm study for -- is an open label study for safety and
efficacy following OLT sufficient for licensure, and strike out during the
maintenance period.
Unless there is a way of showing -- and it is
obviously complicated -- showing that during the maintenance period you were
really showing efficacy, and that you would have had to have started very early
after the transplant, and you would have to have enough patients to show that
during that period -- because there is a recurrent rate, a low recurrent rate,
that is occurring on antivirals, that is occurring at one year, it is higher at
three years.
I think it is still possible, but very
difficult, to show that even after the perioperative period, your product is
effective.
It is a much more difficult trial to do and
it could involve a lot more patients. I think maybe for clarity and getting
past the part of the question phase, we should change this, if everybody
agrees, to an open label study for safety and efficacy following OLT sufficient
for licensure.
DR. NELSON:
Does everybody agree with that?
DR. LIANG:
Can we vote on separate parts of the same question?
DR. NELSON:
What do you mean separate?
DR. LIANG:
Should we just vote on this question first to strike out the maintenance
period?
DR. NELSON:
Sure. Could we just have a hand vote on this? Does everybody agree with this change?
[Hands of all voting members raised in
agreement.]
DR. NELSON:
So, the change is, a single arm study for safety and efficacy following
OLT sufficient for licensure.
DR. HOOFNAGLE: I think there are two changes.
We are striking a single arm and making it an open label study.
DR. NELSON:
Oh, it is, is an open label study for safety and efficacy following OLT
sufficient for licensure. That is the
new question.
DR. LINDEN:
I think we are eliminating the peritransplant. That disappeared already and we are just keeping that out.
DR. GOLDING:
By not saying the maintenance period it implies, I think, that it is
during the entire period following transplant.
DR. LINDEN:
The wording, excluding the peritransplant period was in there before,
and that has been taken out and we are leaving that out. I was just clarifying.
DR. NELSON:
Okay, do you want to vote on this one, on this revised question?
DR. SMALLWOOD: The revised question reads, is an open label study for safety and
efficacy following OLT sufficient for licensure. Dr. Allen?
DR. ALLEN:
Yes.
DR. SMALLWOOD: Davis?
DR. DAVIS:
Yes.
DR. SMALLWOOD: Dr. Doppelt?
DR. DOPPELT:
Yes.
DR. SMALLWOOD: Dr. Klein?
DR. KLEIN:
Yes.
DR. SMALLWOOD: Dr. Laal?
DR. LAAL:
Yes.
DR. SMALLWOOD: Dr. Chamberland?
DR. CHAMBERLAND: Yes.
DR. SMALLWOOD: Dr. Harvath?
DR. HARVATH:
Yes.
DR. SMALLWOOD: Dr. Hoofnagle?
DR. HOOFNAGLE: Yes.
DR. SMALLWOOD: Dr. Liang?
DR. LIANG:
Yes.
DR. SMALLWOOD: Dr. Linden?
DR. LINDEN: Yes.
DR. SMALLWOOD: Dr. Mc Gee?
DR. MC GEE:
Yes.
DR. SMALLWOOD: Dr. Quirolo?
DR. QUIROLO:
Yes.
DR. SMALLWOOD: Dr. Schreiber?
DR. SCHREIBER: Yes.
DR. SMALLWOOD: Dr. Whittaker?
DR. WHITTAKER: Yes.
DR. SMALLWOOD: Ms. Knowles?
MS. KNOWLES:
Yes.
DR. SMALLWOOD: Dr. Nelson?
DR. NELSON:
Yes.
DR. SMALLWOOD: Dr. Strong, your preference?
DR. STRONG:
Yes.
DR. SMALLWOOD: The results of voting for the modified question two is a
unanimous yes.