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- Current Thinking on Draft Guidance for Nucleic Acid 173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

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

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.