FOOD AND DRUG ADMINISTRATION

P R O C E E D I N G S (8:02 a.m.)

Agenda Item: Welcome, Statement of Conflict of Interest, Announcements.

DR. FREAS: Good morning. I would like to welcome everyone to this 83rd meeting of the Blood Products Advisory Committee. I am Bill Freas, and I will be the acting executive secretary for today.

Now, before the meeting begins, I have two quick announcements. One is a very fortuitous announcement. We do have a new executive secretary of the Blood Products Advisory Committee, and that is Donald Jehn.

Donald Jehn has just joined FDA, and he is from the army's toxicology laboratory at Fort Meade, Maryland, and he will officially be starting his exec sec duties on Monday bright and early.

The second announcement I have is that tomorrow, in this room, we will be having a subcommittee of the Blood Products Advisory Committee.

That subcommittee will consist of four members from today's committee supplemented with experts in their field, and they will be discussing the review of research programs in the Office of Blood, Research and Review. The morning portion of that is open to the public, and the public is more than welcome to attend.

Getting back to today's meeting, I would like to introduce the distinguished guests and members seated at the head table. I will go around and call their name, starting on the right-hand side of the room. That is the audience's right.

In the first chair is Dr. Harvey Klein, chief, department of transfusion medicine, NIH. The next chair is Dr. Kenneth Davis, professor of surgery and clinical anesthesia, University of Cincinnati Medical Center.

In the next is Dr. Keith Quirolo, hemoglobinopathy pediatrician, Childrens Hospital and Research Center, Oakland, California. The next chair is empty right now, but will be filled with temporary voting members throughout the day.

In the next chair that is filled is Dr.Donna Whittaker, director, Robertson Blood Center, Fort Hood Texas.

In the next chair will be Dr. Matthew Kuehnert, assistant director of blood safety, division of viral and rickettsial diseases, CDC.

At the end of this section of the table we have Dr. Liana Harvath. Dr. Harvath is a temporary voting member for the entire day today, and she is also deputy director, division of blood diseases and resources, NIH.

Around the corner of the table we have Dr. Judy Lew, assistant professor of pediatrics, University of Florida.

In the center of the table we have our chair, Dr. James Allen, president and CEO, American Social Health Association, Research Triangle Park, North Carolina.

Around the corner of the table we have Ms. Judith Baker, our consumer representative. She is also regional coordinator, Federal Hemophilia Treatment Centers, Region IX, Los Angeles, California.

In the next chair we have Dr. Catherine Manno, professor of pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine.

In the next chair we have Dr. Samuel Doppelt, chief, department of orthopedic surgery, the Cambridge Hospital, Cambridge, Massachusetts. The empty seat will be filled by temporary voting members as the topics change.

In the next chair, we have Dr. George Schreiber, associate director of health studies, Westat, Rockville, Maryland.

Next we have Dr. Suman Laal, assistant professor, department of pathology, New York University School of Medicine. in the empty chair, that will soon be filled by Dr. Donna DiMichele, associate professor of clinical pediatrics, Weill Medical College, Cornell University.

At the end of the table we have our non-voting industry representative, Dr. Louis Katz. He is executive vice president, medical affairs, Mississippi Valley Regional Blood Center, Davenport, Iowa.

FDA Is continually trying to improve the conflict of interest procedures and screenings for our advisory committee meetings.

We are implementing a new procedure right now and I have Jenny Slaughter, who will come and read to you the conflict of interest disclosures that will be required for this meeting.

DR. SLAUGHTER: Good morning. The Food and Drug Administration is convening today's meeting of the Blood Products Advisory Committee under the authority of the Federal Advisory Committee Act of 1972.

With the exception of the industry representative, all members of the committee are special government employees or regular federal employees from other agencies, subject to the federal conflict of interest laws and regulations.

FDA has determined that members of this committee are in compliance with federal conflict of interest laws, including, but not limited to, 18 USC 208 and 21 USC 455(n)(4).

The criminal conflict of interest statute, 18 USC section 208, is applicable to all government agencies, and 21 USC 355 is applicable only to FDA.

Congress has authorized FDA to grant waivers to special government employees who have financial conflicts when it is determined that the agency's need for the particular individual services outweighs his or her potential conflict of interest.

Members who are special government employees at today's meeting, including special government employees appointed as temporary voting members, have been screened for potential financial conflicts of interest of their own, as well as those imputed to them, including those of their spouse, minor child, employer, and all of these are related to the discussion of today's meeting.

These interests may include investments, consulting, expert witness, contracts, grants, cooperative research and development agreements, teaching, speaking, writing, patents and royalties, and primary employment.

Today's agenda includes the following topics. The first topic will be discussion of the management of donors and units that test positive for hepatitis B virus by nucleic acid tests.

The second discussion will be of the scientific basis for review of the varicella zoster immunoglobulin and, three, a discussion of dextran 1 pretreatment for safe use of dextran 40/70.

In addition to the participation of today's committee members, and pursuant to the authority granted to the committee charter, the director of FDA's Center for Biologics Evaluation and Research has appointed the following SGEs as temporary voting members:

Dr. Liana Harvath as a temporary voting member for all of today's discussions; Dr. Philip LaRussa and Jane Seward as temporary voting members for the committee's discussion on topic two related to the scientific basis for review of varicella zoster immunoglobulin; Dr. Gerald Levy as a temporary voting member for the discussions on topic three related to the safe use of dextran 40/70, and Dr. Michael Miller as a temporary voting member for the dextran safe use discussions.

In accordance with 18 USC 208, general matters waivers have been granted to the following participants: Dr. James Allen; Ms. Judith Baker; Dr. Donna DiMichele; Dr. Catherine Manno; Dr. George Schreiber; Dr. Donna Whittaker; and Dr. Philip LaRussa.

A copy of these waivers may be obtained by submitting a written request to the agency's freedom of information office in Room 12-A-30 of the Parklawn Building.

With regard to today's guest speakers, the agency has determined that the information provided by these speakers is essential.

The following information is being made public to allow the audience to objectively evaluate any presentations and/or comments made by the speakers:

Dr. Mona Marin is participating as an invited speaker for Topic two, and is employed by CDC's national immunization program;

Dr. Carl-Gosta Ljungstrom is participating as an invited guest speaker for topic three, and he would like to disclose that he is a scientific advisory to several Swedish companies marketing clinical dextran. He receives no remuneration.

As guest speakers, they will not participate in committee deliberations, nor will they vote.

In addition, there may be regulated industry and other outside organization speakers making presentation. These speakers may have financial interests associated with their employer and other regulated firms.

The FDA asks that, in fairness, that everybody address any current or previous financial involvement with any firm whose product they may wish to comment upon. These individuals were not screened by the FDA for conflicts of interest.

For this meeting, Dr. Louis Katz is serving as the industry representative, and Dr. Katz is acting on behalf of all related industry, and is employed by the Mississippi Valley Regional Blood Center.

In the event that discussions involve any other products or firms not already on the agenda, for which an FDA participant has a financial interest, the participants are aware of the need to exclude themselves from such involvement, and their exclusions will be noted for the record.

Finally, we ask that all other participants, in the interests of fairness, address any current or previous financial involvement with any firm whose products they may wish to comment upon. This statement that I have just read will be available for review at the registration table. Thank you.

DR. FREAS: Thank you, Jenny. Before I turn the meeting over to the chair for the official opening, would you please take a few seconds and check your cell phone, your pager, you beepers, and put them in the silent mode so they will be less disruptive to the meeting. Dr. Allen, I turn the meeting over to you.

DR. ALLEN: Thank you, Dr. Freas. Before we launch into our formal agenda for the day, I would just like to make one brief note.

As I think most people in blood banking and transfusion medicine know, Dr. Tibber Greenwalt, known as Tibby, died at the age of 91 last Sunday, July 17.

He was one of the giants of model blood banking in the United States, and was a mentor to many people currently working in the field. I would like to call on Dr. Salso Bianco from America's Blood Centers to make a brief statement and then we will have a moment of silence.

DR. BIANCO: Thank you, Jim. Jim had initially asked Jim McPherson, that worked with Tibby for five years, to speak, but Jim had a conflict. I am not representing my organization, but I think I represent everybody who is here, and the entire transfusion community.

Tibby Greenwalt, who headed the University of Cincinnati Hawksworth Blood Center from 1979 to 1987 passed away on Sunday, July 17.

From 1997 to 2003 he served as director of the research department at Hawksworth. In 2003 he became the emeritus director of research. He was also a professor of medicine and pathology at the University of Cincinnati.

Until his recent illness and hospitalization, he kept regular office hours each day, continued to write papers and explore new developments in blood transfusion research.

He was born in Hungary in January 1914, and immigrated to the United States in 1920, when he was six years old.

He earned his MD from New York University, studied hematology at New England Medical Center, and continued his interest in blood diseases while serving with the U.S. army in India during World War II.

He then became the medical director of what is known today as the Blood Center of Wisconsin. Dr. Greenwalt served as vice president of the American Association of Blood Banks, of which he helped found, and national director of the American National Red Cross blood program.

He is credited with organizing all the medical systems, and created the rare donor registry for both organizations.

He directed research into hepatitis and the storage of red cells, an interest that he had until the end of his life.

Tibby was also a very important international figure. He became the president of the International Society of Blood Transfusion in 1966, and he was the president for six years.

In 1976, he became the RSBT historian, and in 1995 he published a history of transfusion medicine that is absolutely delightful.

He has published 200 major research papers, books in the scientific literature, and he became a member of the Institute of Medicine, National Academy of Sciences, in 1984.

In 2005, he was awarded the Lunsteiner Memorial Award. He is a major driver of a lot of what we do today, a lot that we have, influenced many of our lives.

One thing that Jim said, that I thought was very important is that he had a special gift, that everyone that got to know him thought that they had a special relationship with Tibby and, in a way, they did.

I want to ask that we have a moment of silence in honor or Tibby Greenwalt. [Moment of silence observed.] Thank you very much.

DR. ALLEN: Thank you, Salso. We will launch right into the agenda, because we have got a very full agenda today, starting with a number of committee updates.

I would like to remind all of the speakers, please, to make the points that you need to make with brevity and clarity, and then allow sufficient time for questions and discussion by and among the committee.

It really is going to be essential that our speakers keep to the time limits, if we are going to get through the agenda in good time today.

Our first update will be by Dr. Jerry Holmberg, executive secretary of the Advisory Committee on Blood Safety and Availability, summarizing the May 2005 meeting.

Agenda Item: Committee Updates. Summary of May 2005 Meeting of the DHHS Advisory Committee on Blood Safety and Availability.

DR. HOLMBERG: The last meeting of the Advisory Committee for Blood Safety and Availability covered a lot of ground.

Unfortunately, a letter that had not reached my office yet appeared days after the meeting. One of the things that is unique about the Advisory Committee for Blood Safety and Availability is that we not only listen to what the other advisory committees have put forward, such as your committee here, but we also look at the science and the ethics and the economics of various decisions.

One of the letters that had arrived after the meeting was in regard to some of the changes associated with CMS and the medicare modernization act.

In response to the MMA, Dr. Biato had sent Dr. McClellan a letter asking for clarification on the MMA and some of the issues addressed in the MMA and also in the committee discussion.

As we all know, there have been various misuses of terminology, different formulas used, some disconnects out in the community between the various contractors.

I am pleased to say that this letter was responded to on the 13th of May, just days before the last meeting, in which Dr. McClelland sent back to Dr. Biato a memo, and also included in that the CMS manual directive that goes out to all the contractors in the country to address various reimbursement.

Now, this is the coding specifically for the outpatient hospitalization as it deals with red cells and some other blood products, primarily the products that are red cell associated.

A lot of the things we had asked for were corrected in this directive. This directive was established in March with a lot of work and a lot of input behind the scenes, and also it became effective July 1 of this year, and implementation to be effective on the fifth of July. So, it is in place at the present time.

That is not to say that we still do not have other issues that we have to address with our medicare reimbursement, but we are, just to let you know, working behind the scenes trying to work together as one department to make sure that patient care is not impaired.

One of the issues that came up at the last meeting was the issue of the availability of IVIG. You will hear me refer to it as IGIV or IVIG. It depends on who you are talking to but, if you hear me interchange the two acronyms, please understand I am talking about the same product.

Your committee has heard about the economics of the plasma industry before. I think it was probably a year ago where this was addressed to the committee.

What we have been hearing is that there have been shortages of IVIG and also access to treatment by some of the patient groups.

At our meeting, we listened to distributors who have complained that they do not have the inventory that they once had and they are limited on their distribution.

Also, there is the issue that the CMS is not reimbursing at the rate that they have to charge the providers.

We also heard from the Plasma Protein Therapeutic Association, who represents the manufacturers. Once again, just to emphasize the importance of the manufacturers and some of the things that go on with the economics of fractionation is that there is a need, to be profitable, to be able to produce the IGIV, albumen and also the coagulation factors.

So, what we have seen in the manufacturing realm is that there has been consolidation of the manufacturers. Now we have five manufacturers. The American Red Cross has gotten out of the plasma protein fractionation business, and there are five major manufacturers.

There is also an increasing -- I should also say, during the meeting there was also some discussion about the value of albumen, and I am pleased to see that, on today's agenda, there will be some discussion and update on the use of albumen.

There are also issues with CMS as far as a change in formulation. We also heard from the immune deficiency foundation, providers, pharmacists and, of course, patients.

As a result of that, the committee made a recommendation to the secretary -- and this was the only recommendation that was made to the secretary during the two day meeting, and that is that the committee finds that, since our prior recommendation of January 2005, there is a worsening crisis in the availability of, and access to, IGIV products, that is affecting, and placing patients' lives at risk, patients with immune deficiencies.

Changes in reimbursement of IVIG product under MMA since January 2005 have resulted in short falls in the reimbursement of IGIV products and their administration. Immediate interventions are needed to protect patients' lives and health.

We therefore use the Secretary to declare a public health emergency so as to enable CMS to apply alternate mechanisms for determination of the reimbursement schedule for IGIV products, and otherwise to assist CMS to identify effective short and long term solutions to the problem of unavailability of, and access to, IVIG products in all settings.

Of course, as you can guess, no one likes to hear about a public health emergency, and this gained a lot of attention at the secretarial level and throughout the various agencies.

We did quite a lot of investigation on the situation with IVIG, and several of the things that I want to point out to you today in my short time that I have is that there has been an increase in off label use of IGIV.

A survey from the Immune Deficiency Foundation indicates that between 40 and 60 percent of the patients that receive IVIG are receiving it for off label use.

In our discussions with some of the pharmacists we have also realized that, at some facilities, over 100 percent of the use is off label use.

There have also been changes in the industry, as I mentioned before, consolidation. There are changes in business practices.

To be honest with you, and again, from my point of view, with what I have seen after my investigation of this issue, is that there is a market correction in the IVIG supply and distribution and pricing.

The manufacturers have reduced their inventories to a more workable level and they have also decreased the number of distributors that they have distributing their products.

What we have also seen as far as distributors is that there is not only a primary distributor market, but there is also a secondary, or a gray, distributor market that has taken advantage of the reduced supplies of IVIG.

I won't say it is a shortage, but a reduced supply of IVIG, and the secondary and gray market distributors have raised the price on the product.

As far as the medicare modernization act, which was effective in January 2005, it changed the medicare part B, which is the physician office environment, to 106 percent of the manufacturer's average sales price. That is the manufacturer's average sales price.

So, the six percent is to cover the distribution chain and to be able to get the product to the provider at the cost, at 106 percent.

Obviously, this is not working, in the sense that, when we start having other dynamics play and interact, especially with the secondary, or gray, market, that the price is increasing.

One of the things that medicare has done, and will continue to do, is that they are updating their payments on a quarterly basis.

Recently the July pay schedule, reimbursement schedule, is that there has been an increase of nine percent in the increase for unauthorized IGIV for this month, or I should say for this quarter.

What we have found is that there are sufficient supplies of IVIG for patients who need the treatment. It also suggests that, under the manufacturer's allocation process, physicians might best serve their patients by communicating their supplies directly to the manufacturers, and also the department has taken a position that, to ensure that the IVIG is prioritized -- let me rephrase that.

The department has taken the position that the physicians should ensure that the IGIV treatment is prioritized toward FDA labeled use, and those diseases or clinical conditions that have been shown to benefit from IGIV, based on evidence of safety and efficacy.

What we are asking the community to do is to report denial of treatment, delay of treatment, or forced reduction in dosage to either the FDA, and there are the numbers there for reporting the shortage, or also through the web site.

If it is a CMS issue of denial of care on a medicare patient, the provider can call the 1-800-medicare number, and this will be tracked.

In the month of June, there were over one million calls into the 1-800 number, and approximately 50 of those calls related to IVIG.

The committee also continued on to addressing some of the issues of where are we going in the 21st century to reduce the risk of transfusion transmitted diseases.

In the past we had talked about surveillance, appropriate research, product development, global information sharing, transparency in policy, and risk communication.

We continued our discussion to talk specifically about the pandemic action plan, the coordination that must take place within the blood community between the National Association of County and City Health Officials, the Association of State and Territorial Health Officials, and the Council of State and Territory Epidemiologists.

We also looked at models of disease reporting and adverse event surveillance. We also had a great talk on the NHLBI's reds two study, and its role in detecting emerging threats.

There was quite a bit of discussion on orphan test development, and also some recommendations were put forward, but we decided we needed to have further discussion on this issue at the next meeting. So, the next meeting we will devote to the issue of emerging infectious diseases.

We also had an update on the release tests for bacterial detection, and the extension of platelet dating, and I am pleased to notice that one company has placed their plan on their web site, and this has been cleared by the FDA for the process for moving forward in this direction. That is all I have, if there are any questions?

DR. ALLEN: Any questions, quickly? Obviously, the issue with the immune globulin intravenous presents a conundrum, doesn't it? Medical practice doesn't stop with the labeling, and I am sure there are many documented indications today that may not be on the label, and that presents the difficulty.

DR. HOLMBERG: That is why the department took the position of not only the labeled use, but also those clinical diseases or conditions which have been shown to have safety and efficacy in treatment.

So, once again, CMS does cover reimbursement on those diseases or conditions that there have been controlled studies performed.

DR. ALLEN: Other questions or comments quickly? Thank you very much, Dr. Holmberg. The next update is by Dr. Anne Gaines, Food and Drug Administration, disseminated intravascular coagulation associated with acute hemoglobinemia following anti-D IGIV administration for idiopathic thrombocytopenic purpura.

Agenda Item: Update: Disseminated Intravascular Coagulation Associated with Acute Hemoglobinemia Following Anti-D IGIV Administration for Idiopathic Thrombocytopenic Purpura.

DR. GAINES: It is my pleasure to be here this morning and to have the opportunity to make this presentation to the advisory committee and members of the audience.

The presentation today, the topic for the presentation today, resulted from routine post-marketing surveillance, or ongoing product safety monitoring that is conducted within the center for all CBER licensed or approved products.

The product under discussion today is RHOD, immune globulin intravenous human, is its proper name. I will refer to it as anti-D IGIV.

It was licensed on March 24, 1995. It was licensed under the trade name of Winrow. It is currently marketed under the trade name of Winrow SDF. The differences in trade names reflect differences in the viral inactivation methods that are used during the manufacturing process.

At the time of licensure, it was licensed for two indications. The first of those was suppression of RH ISO immunization, and this became one of multiple other intravenously or intramuscularly administered anti-D products licensed by CBER for this indication.

It was also licensed for treatment of immune thrombocytopenic purpura, or ITP, in RHO-D positive, non-splenectomized children with acute ITP, children and adults with chronic ITP, children and adults with ITP secondary to HIV infection.

At the time it was licensed, and currently as of today, it remains the only anti-D product licensed by FDA for the ITP indication.

As listed in the package insert, anti-D IVIG contains known red blood cell or RBC antibodies. The primary ingredient is high titered anti-D, which really serves as the active ingredient for the product.

In addition, there are low titered anti-A anti-B, anti-C and anti-E antibodies. All of these antibodies are qualitatively and quantitatively assayed before product release for product distribution, and must meet the standards set by CBER for the titers of these antibodies.

As reported in the literature in 2000, however, anti-D IGIV may also contain other low titered RBC antibodies, for example, duffi A and kid-A.

None of these other RBC antibodies are qualitatively or quantitatively assayed before release of product for market distribution.

The presumed mechanism of action of anti-D IVIG in ITP involves the extravascular hemolysis of anti-D sensitized RBCs by splenic macrophages.

This results in decreased splenic destruction of auto-antibody coated platelets because of competitive binding between the platelets and the RBCs.

In patients who respond therapeutically to anti-D IGIV, this mechanism of action results in a correspondingly increased platelet count.

Expected adverse events that are consistent with the extravascular hemolysis mechanism of action include a decreased hemoglobin concentration and positive direct and indirect antiglobulin tests, as well as other laboratory hematology and chemistry findings that would be expected with extravascular hemolysis.

Routine post-marketing surveillance of anti-D IVIG has detected two serious, unexpected adverse events since licensure.

The term serious, as defined by the FDA, refers to adverse events that are characterized as life threatening, requiring medical intervention, among other criteria.

The term, unexpected, again, as defined by FDA, refers to any adverse events that are not listed in the package insert.

Most of these serious, unexpected adverse events involve the administration of anti-D IGIV for treatment for ITP.

The first of those is acute hemoglobinemia and/or hemoglobinuria, which will be mentioned here because it serves as a prelude for the second serious unexpected adverse event of disseminated intravascular coagulation, or DIC.

In terms of hemoglobinemia and/or hemoglobinuria, the clinical trials of anti-D IGIV for ITP identified two cases that were described as acute onset hemoglobinuria consistent with intravascular hemolysis.

Following licensure of the product in 1995 through the present, cases suggestive of acute hemoglobinemia and/or hemoglobinuria -- which I will shorten to acute hemolysis, henceforth -- have been submitted to FDA's adverse event system, known as Medwatch.

Cases of acute hemolysis received by FDA through April of 1999 included 15 patients, 11 of whom experienced complications.

Seven of those patients developed sufficient anemia to prompt orders for packed RBC transfusions, although only six patients were transfused.

Eight patients had onset or worsening of renal insufficiency, and two of those patients underwent dialysis. One patient died from pulmonary edema and respiratory distress, secondary to exacerbated anemia, and six of these patients had two to three of these complications concurrently.

A review of those 15 cases suggested that acute hemolysis seemed inconsistent with the extravascular hemolysis mechanism of action of ITP, based on the time of onset of signs and symptoms, as well as the signs and symptoms themselves.

Review of these cases also suggested that the acute hemolysis seemed much more consistent with intravascular hemolysis associated with acute hemolytic transfusion reactions. Again, based on the onset of the signs and symptoms, as well as the signs and symptoms themselves.

It was also apparent, from a review of these cases and the literature that, as of the moment, the mechanism by which acute hemolysis occurs cannot be readily explained in terms of immune mediated or other mechanisms of hemolysis.

Risk communication efforts that were undertaken to make physicians, other health care professionals and patients aware of the acute hemolysis adverse events were twofold.

The first of those was an FDA initiative that resulted in the cases being published in the journal Blood in April of 2000, with the suggestion that patients be monitored for acute hemolysis, clinically compromising anemia, renal insufficiency, and other potential complications of hemoglobinemia, particularly DIC.

The second risk communication effort involved revisions to the package insert, and revisions to the package insert were distributed by the manufacturer, along with a dear health care professional letter to, hematology and transfusion medicine physicians, as well as pharmacists.

That brings us now to DIC. As mentioned earlier, there were two patients in the clinical trials for anti-D IGIV for ITP who experienced acute onset hemoglobinuria consistent with intravascular hemolysis. However, neither of those patients experienced DIC or any other complications, for that matter.

Between licensure and present, cases of DIC associated with acute hemolysis have been submitted to FDA. Cases of DIC received by FDA between May 1999 and November 2004 included six patients.

Of those patients, five died with DIC or acute hemolysis assessed as having caused or contributed to each death.

Four of those patients had onset or worsening of renal insufficiency, and two of those patients underwent dialysis.

Four of those patients developed sufficient anemia to prompt packed RBC transfusions. Five of those patients had two to four of these complications concurrently.

A review of these six cases suggested that DIC seemed consistent with the recognized potential complication of acute hemolysis as seen in acute hemolytic transfusion reactions or other clinical situations with hemoglobinemia.

Review of these cases, based on information that I haven't presented here today, also suggested that previous uneventful anti-D IGIV administration does not preclude acute hemolysis upon subsequent anti-D IGIV administration in the same patient.

Risk communication efforts to inform physicians, other health care professionals and patients of the DIC adverse event have either been undertaken or are in progress.

The first of those is the FDA initiative of publishing these cases in the journal, Blood. They were published on line in May 2005, and will be published in print form in September 2005.

The suggestion was that patients experiencing acute hemolysis be monitored for DIC. In addition, at the present time, appropriate revisions to the package insert are under consideration.

In closing, I would just like to mention adverse event reporting. Physicians, other health care professionals, and patients are encouraged to submit adverse events, particularly serious adverse events for anti-D IGIV or any FDA approved or licensed product.

Adverse event reports can be submitted directly to FDA by internet, by telephone, by fax, or by mail. Alternatively, adverse event reports can be submitted to manufacturers or, in some cases, distributors of FDA approved products.

Contact information for reporting adverse events is generally available in package inserts, on manufacturer or distributor sponsored web sites. I thank you for your attention. Are there any questions?

DR. DI MICHELE: I was just wondering if there has been any evaluation of these events with respect to potential predisposing causes in the patients who have these unusual adverse reactions.

Ms. GAINES: Yes, we have looked at risk factors and, to date, we have not found any risk factors, be it age, sex, even previous history of renal insufficiency.

Unfortunately, many of the reports we receive aren't very well documented. So, it is not always possible to have a complete medical history or even dates and times of all the laboratory tests that may have been done during the patient's clinical course.

To the extent that it is possible for us to assess the reports we received back in the initial study, as well as subsequently, we have not been able to determine any sort of risk factors.

DR. MANNO: Do you have any idea of how many doses of Winrow are given per year in the United States?

DR. GAINES: We have only a very vague estimate that is derived from commercially available distribution data, and the distribution data is calculated in terms of vials, for example, distributed, which doesn't necessarily account for doses or how many patients are treated.

So, any estimate we have is, at best, a ball park figure, and probably not very accurate. I did recalculate the estimated number of infusions for this most recent paper, and I can look it up and get back to you. I brought a copy of it with me.

I don't remember the number, but it is hard to know for sure, and it is hard to know for sure whether the doses are given almost exclusively for ITP or whether some significant proportion of doses are also given for the suppression of RH ISO immunization indications. We don't have any information about the usage for those two indications. I will be glad to get that information to you.

DR. ALLEN: Other comments or questions? Thank you very much, Dr. Gaines. Our next update, by Dr. Lawrence Landow, FDA, is an update on safety of albumen.

I will just take a moment, while we are getting set up, to point out that the Plasma Protein Therapeutics Association has put out a brief statement on this, which normally would be read in an open public hearing. We don't have an open public hearing associated with these updates, so I will just point out that it is a statement which is available.

Agenda Item: Update: Safety of Albumen.

DR. LANDOW: Thank you. On May 16 of this year, FDA posted a notice on its web site that I am sure most of you have seen, that was consistent with the recommendations made in the previous meeting held here on March 17.

The prior safety concerns raised by the Cochran injuries group in their meta analysis from 1998 have been resolved based on the safe study results. As you will recall, Dr. Finfer came here and delivered a very nice presentation on this subject.

However, we also noted in this notice that we cannot comment on the use of albumen in burn patients, since they were not included in the safe study and, second of all, further evaluation of albumen in patients with traumatic brain injury and septic shock will have to be performed to ascertain the safety of albumen in these populations.

As you recall, the subgroups of these two populations -- brain injury and sepsis -- were small, and were not totally persuasive, in terms of safety or lack thereof, of albumen. That is all that I have. Thank you.

DR. ALLEN: Comments or questions for Dr. Landow? Thank you very much. Our next update, by Dr. Alan Williams, FDA, is a summary of the July 2005 workshop on leukoreduction. That was yesterday. Alan?

Agenda Item: Update: Summary of June 2005 Workshop on Leukoreduction.

DR. WILLIAMS: We had, I think, a very informative and very lively discussion yesterday. We had 168 participants at Lister Hill.

The driving goals for the workshop were to review new evidence regarding the medical value of leukoreduction for non-targeted populations, commonly known as universal leukoreduction, as well as to review failures and adverse events associated with the process, and to have a discussion about practical, effective process control measures that would both cover the targeted patient needs, as well as the high throughput needs of use for general transfusion recipients.

The agenda started with an opening by Dr. Jay Epstein, summarizing some of the prior considerations of universal leukoreduction.

I followed that by reviewing regulatory considerations and the two blood products advisory committee considerations of aspects related to leukocyte reduction procedures.

The first major talk was an extremely thoughtful review of the literature, particularly the recent literature presented by Dr. Rob Davenport of the University of Michigan.

He summarized data showing that, in fact, for the three generally accepted indications of reduction of febrile non-hemolytic transfusion reaction, allo-immunization and CMV exposure, that leukoreduction continued to show value with virtually all studies that were presented.

In the larger picture and for other indications, although there seemed to be trends in favor of leukoreduction, favoring other outcomes, the trends typically did not reach statistical significance and that, in fact, to be able to show significance for many of these other outcomes, such as hospital stay and other medically related outcomes, it would take an exceedingly large study to show a significant difference.

In fact, once that was done, whether or not the significance would be medically compelling any more than it is now is questionable.

So, all in all, it was a very good overview of the current pros and cons related to universal leukoreduction, and a good critical review of the literature.

Dr. Ed Snyder presented an update on the continuing universal leukoreduction program at Yale New Haven Hospital, and the value that it has had in reducing febrile non-hemolytic reactions and CMV exposure in their institution.

It not totally eliminated, but certainly reduced, particularly in platelet recipients, and Dr. Snyder made the case that, in fact, this was, in and of itself, enough value to justify, at least within their institution, a universal leukoreduction program.

Dr. Avery Nathans from Seattle presented a very elegant study, a double blinded, randomized trial of leukoreduction versus non-leukoreduced units, administered to trauma patients, and showed essentially no difference between the two arms of the study, a very well designed study.

Dr. David Stronsak from the Department of Transfusion Medicine at NIH summarized adverse events and manufacturing failures known to be associated with the process, and summarized some of their in-house work showing that filter blockages related to cycle hemoglobin could, in fact, be prevented in an atmosphere of high oxygen tension, or lesser acidity, as could be obtained by titrating citrate addition in an automated collection procedure.

We had several talks in the afternoon summarizing some of the practical aspects of leukocyte reduction in blood establishments.

At FDA's suggestion, and with some FDA suggested questions, America's Blood Centers and the American Red Cross administered a small survey to their membership.

Just to update some of the data related to that, within America's Blood Centers, 64 percent of the centers leukoreduced red cells from whole blood, 94 percent red cells from aphoresis, 100 percent platelets from aphoresis, and 14 percent random donor platelets.

The distribution within the ABC centers was not uniform, and it really ranges from less than 20 percent at some centers to over 100 percent at others.

Within the American Red Cross, the overall leukoreduction is around 95 percent currently. It varies a little bit, with the lowest figure being 78 percent for red cells collected by automated procedures but, overall, about 90 percent.

Notably, the entire Red Cross system uses the Njet Conning Chamber for quality control for residual white cells, which has an impact on the ability to higher numbers of quality control leukocyte counts, which was relevant to a major part of the afternoon discussion.

FDA, after that, introduced some current considerations with respect to process validation and quality control measures, and that stimulated really quite a lively discussion among participants with regard to the practical aspects of investigating failures that did occur, and the simple mechanics of counting residual white cells in a leukoreduced product, particularly with the manual systems that are in place.

We then focused that same discussion with a group of well-established and experienced investigators in the field, including Dr. David Devine, who was at the workshop from Canada, Dr. Larry Dumont, Salso Bianco, Dr. Mike Bush, Harvey Klein and Gary Moroff.

I think we ended up with a very good summary of the discussion. This ended 14 hours ago. So, we haven't had a lot of time to discuss it, but the take home message that I got was, number one, there were no compelling new data with respect to the value of universal leukoreduction.

I think there is an emerging recognition that there may be unknown subpopulations within the transfusion recipient population that, although not definable at the time that they appear for transfusion, particularly if they need subsequent transfusions, we may, in fact, be providing better medical care by providing a leukoreduced product.

Now, whether that is standard of care or practice of medicine still remains a lively debate, and some of that took place yesterday.

Another observation was that, with a large part of the country now, in fact, doing leukoreduction for products, it is almost easier to move to 100 percent inventory. It is simply simpler to maintain within blood centers, and some centers are moving in that direction for that reason, and that point was brought out yesterday.

I think, finally, the data review showed that, in fact, there is no clear evidence, at least, that leukoreduction was harmful clinically, at least, in any of these situations.

We had two talks at the end of the day summarizing the current status of prion reduction by filtration, Dr. Lisa Gregory(?) from the University of Maryland and Dr. Jerry Ordelano from Polk Medical.

These talks described advances in systems that are capable of reducing prions as shown by a hamster scrapie model, where high titer prions are added to blood components and then shown to reduce, by filtration, on the order of between three and four logs.

Hurdles remain, the bioassays, which take months to years to perform, even in the rodent model, and there was some discussion of concerns at the high titer model being used.

It did not necessarily reflect the very low titers likely to be evident in blood borne prions in a natural infection.

Overall, I think a very successful workshop, and the transcript will be available in a couple of weeks, I understand.

DR. ALLEN: Thank you, Alan. The estimate presented at the workshop yesterday was that currently about 80 percent of all red cell units -- is that correct -- are currently leukoreduced?

DR. WILLIAMS: I am not sure we produced a national estimate. Within the Red Cross system, it was 90 to 95 percent and, within ABC, I believe it was 64 percent from whole blood red blood cells within ABC. It would be easily calculated, but I don't believe it was.

DR. KATZ: I think, for the committee, maybe it is important to understand that there was an undercurrent at this meeting that I think should be explicit, and that is there are people in the blood community that I am aware of that think that the reduction produces bad things.

What we are talking about here is the ability to pay for it, and the reimbursement system that has not kept up with the rest of the developed world where, in fact, universal leukoreduction is very prevalent.

So, it sounds like there is some resistance to a clinical intervention that has a consensus that it is not a bad thing and probably a good thing. It is important to understand what the core of that resistance is.

DR. ALLEN: Thank you, Dr. Katz. I think that was an important summary statement from the meeting also, which surprised me. Other comments or questions? Okay, thank you very much.

I apologize. I skipped one of the presentations here. So, we will go back and pick that up, summary of the June 2005 workshop on biological therapeutics for rare plasma protein disorders presented by Dr. Mark Weinstein, Food and Drug Administration.

Agenda Item: Summary of June 2005 Workshop on Biological Therapeutics for Rare Plasma Protein Disorders.

DR. WEINSTEIN: I would like to give you an update on this workshop for biological therapeutics, or rare plasma protein disorders, that was held at the NIH on June 13-14.

The population that we are discussing at this point consisted of patient populations on the order of tens or hundreds in the United States. So, these are a very limited number of patients that we are considering treating.

The purpose of the workshop was to help to advance the availability of products to treat these very small populations.

Our objectives included learning about the current availability of these products, and the need for them, identifying challenges to bringing new biotherapies to patients, discussing current product development procedures from the perspectives of regulators and sponsors, exploring opportunities to facilitate clinical trials, and obtaining new ideas that would help to encourage the manufacture of these products.

Now, we started off with a presentation from a patient representative about the need for these products, and the challenges he faced in obtaining them.

A major issue is that some products are available to treat these diseases but not in the United States. Personal importation is one means of getting them, but there may be no insurance coverage, and these products may be very expensive. Consequently, the patient may have to spend many thousands of dollars of his personal funds to obtain them.

We next had a presentation to give us an international perspective about the need for these products. There are a large number of rare bleeding disorders that are autosomally recessive with a prevalence of about one in 500,000 to one in two million. These include deficiencies of fibrinogen, factors 5, 7 and 8, factor 10, factor 11, and factor 13.

Internationally, the number of patients affected by these diseases is uncertain because of poor data collection.

The prevalence of these diseases differs among countries, and some areas, like the middle east and southern India, may have considerably larger frequencies because of consanguineous marriages, on the order of maybe 20 times greater than in the average population.

The current treatment for these diseases is primarily replacement therapy or non-transfusional means. The mainstay is fresh frozen plasma, but fresh frozen plasma has many drawbacks and amongst them, of course, is the fact, at least in the United States, that it is not a virally inactivated product. Again, some products are available in Europe but not in the United States.

Next, a physician described her experience and the need for products, and the challenges that she had in obtaining them.

These included the lack of efficacious products and the lack of knowledge about the appropriate replacement strategies.

Insurance may not cover the use of imported or off label use of the product, and this is a factor that makes long term importation of product a poor solution to the problem.

The physician described in some detail challenges that she encountered in preparing an IND submission for a product to treat a rare plasma protein disorder.

These problems included the time and expense that was involved in preparing the submission, and the fact that a manufacturer who had this product available in Europe was not particularly interested in bringing it to the United States.

Factors that weighed into this decision by the manufacturer included the expense of preparing a submission and, from their perspective, the lack of a potential market.

We next had a representative from industry, who talked about the issues that sponsors consider in developing a product for a very small market.

These included the number of patients who required treatment, the expected reimbursement and the competition from other sponsors.

The cost of manufacturing also has to be considered, especially if the manufacture of the new product will affect the production of other biotherapeutics.

So, a product made from a single unit of plasma, if there are several different pathways to obtain that product, manufacture of one product may affect the availability of other products in that same manufacturing scheme.

The CMC preparation and clinical trials may be costly. The sponsor also has to think about the life cycle of the product, including the time it takes to launch the product, its time of peak distribution and the potential of new technologies to compete with the product.

However, an important point is that companies also take into account non-financial factors and, in fact, companies do act benevolently occasionally in providing some biotherapeutic products, and several instances of this benevolence were mentioned at the meeting.

Now, there are many challenges in designing clinical trials for these very small populations and, of course, one of them is, in fact, a very limited number of patients to work with, and this means it is difficult to obtain sufficient numbers of patients.

There is also the fact that we are usually dealing with a chronic replacement therapy, which can mean that trials have to be of very long duration.

Another question is, are patients willing to participate and switch from their current therapy. The trials often involve frequent monitoring that has to be done at a hospital or other clinical settings, and this may involve extensive interruption of work or other life activities to participate in the trial.

The patient may have no personal incentive to participate. There is a question about whether or not there is a suitable comparable and, again, the question of the expense of the trial may be quite high.

At the end of the day, industry would like to know what information is needed to convince health care purchasers to buy the product once it is manufactured.

Following the presentations at the workshop on the need for, and challenges to be met, in developing products that treat rare plasma protein disorders, we had presentations about regulatory pathways and incentives that are currently available to aid development.

We compared regulatory pathways in Europe to those in the United States. The European Medicinal Authority uses a number of pathways to license products when very limited clinical data is available.

One of these processes is called the exceptional circumstances, where marketing authorization is granted when comprehensive data cannot be provided.

The authorization is reviewed annually to consider the risk benefit ratio, but the file remains open without the expectation that it will ever be complete.

The EMEA also has conditional marketing authorization, where authorization is granted before all the data is collected, but the expectation is that all the data will be collected to complete the dossier at a certain point in time. This is very similar to our accelerated approval mechanism in the United States.

The workshop included a number of presentations from the Department of Health and Human Services organizations on regulatory pathways to facilitate product development for these rare plasma protein disorders.

These included reviews of clinical trial designs from the Office of Blood Research and Review, the FDA's accelerated approval process, statistical considerations for very small trials, orphan drug provisions and incentives, research support and small business grants offered by the NIH, and a review of the payment program supported by medicare through CDR.

We then, following these general overviews, we had a series of case study presentations where sponsors talked about their personal experience in developing products for very small populations.

These included presentations on protein C, factor 13, antithrombin 3 and treatment of glandsman(?) thrombopenia and fabares disease.

The last section of the meeting was devoted to exploring future opportunities for product development, which focused on means of enhancing data collection.

The reason for this focus was that better data collection could make clinical trials more feasible by expanding the number of patients potentially available for study, improving our understanding of the natural history of the diseases, and providing mechanisms for post-marketing surveillance that would help in collecting safety and efficacy data on products used to treat these patients.

We heard about the experience of FDA, EMEA and LFB in france collecting post-marketing data, the experience of sponsors collecting data through third parties, post-marketing surveillance by a consumer group, and opportunities for data collection through international registries and through the CDC.

The following two slides describe some of the outcomes of the meeting and identify areas where we can direct some of our future efforts.

In the area of improving patient registries and data bases to identify patients for future studies, and to obtain data on the natural history of the diseases, we believe that efforts should be directed toward harmonizing the format of data collection and linking data bases to improve accessibility.

We need a forum to discuss the different data needs of regulators, industry, physicians and consumer organizations.

At present, this topic is discussed on an ad hoc basis at various meetings. Amongst those will be the meeting of the ISTH in Sydney coming up in a couple of weeks, and the World Federation of Hemophilia meeting in Montreal later this year.

The trick is to get the right parties together at the table, and to have a defined agenda with clear goals. An important point that was raised by industry representatives is that we have to distinguish between routine post-marketing surveillance versus post-marketing surveillance commitments by sponsors directed toward assuring the safety and efficacy of specific products.

It is imperative that the data be accurate, to assure that the products under review are not falsely associated with adverse events, and this requires time for full investigation before information is made public.

The workshop describes similarities and differences in approaches to licensing products for rare plasma protein disorders between the United States and Europe.

This was a start in identifying potential areas of harmonization and clinical trial design. It would help if there was an established forum to discuss harmonization issues.

One idea that was put forth, to further increase the incentives for industry would be to provide grants for the development of products for very small indications, similar to grants that are now available for small businesses.

Sponsors were also encouraged to take another look at the financial incentives offered by the orphan drug provisions.

Finally, at the workshop, FDA encouraged sponsors to have a one on one meeting with the FDA to discuss product development for rare plasma protein disorders.

This will give us the opportunity to review a sponsor's individual experience with given products, and develop plans for future progress.

Now, I am happy to report, in fact, that several manufacturers have come forward and have scheduled meetings with the FDA to discuss their opportunities.

Slides for this workshop will be available at the cited web address. A docket site is in preparation to receive comments on the workshop, and a transcript of the workshop will be available soon on the web as well.

DR. ALLEN: Thank you, Dr. Weinstein. Comments or questions? Your concluding statements about the potential opportunities, particularly the need to enhance registries and data bases, the need for forums to discuss harmonization and the development of these, obviously it take resources to do that. I would assume that that is a critical need?

DR. WILLIAMS: Indeed.

DR. ALLEN: I agree with you that it is an extremely important step for the FDA to try to effect, and if there is anything that we can do to try to encourage the availability of resources for that, please let us know. Comments or questions? Thank you.

We will move on, then, to the last of our -- well, there is one additional, but our penultimate set of presentations, an update on west nile virus guidance. We will have three speakers, Dr. Alan Williams from the FDA, Dr. Maria Rios from the FDA, and Dr. Matthew Kuehnert from the CDC.

Agenda Item: Update: West Nile Virus Guidance.

DR. WILLIAMS: Thank you. The slides provide a summary of the two previous blood products advisory committee discussions on the subjects, and I am not going to detail those here.

What I will start with is, in April of 2005, FDA issued draft guidance for industry on donor suitability and blood and blood products safety in cases of known or suspected west nile virus infection.

The parameters covered included discontinuation of the previously recommendation of the fever with headache in the past week question that was discussed at prior sessions, and included a 120-day deferral for west nile virus infected based on where, indeed, a single observation by IDT NAT of viremia up to 104 days.

In addition, it included a recommendation for west nile individual donation NAT negative tests, at some time during the 120 day deferral, to permit reentry of that donor, in light of unknown potential viremia that might take place after the acute infection.

Following issuance of that draft guidance, and in response to a discussion at the prior blood products advisory committee meeting, concerns about the timing of the issuance of policy and the ability of blood establishments to put changes into effect, FDA took the rather unusual step of implementing an immediate implementation guidance with respect to the discontinuation of the donor question.

What this did was allow blood establishments to drop the question immediately, rather than waiting for the draft guidance comment period, and issuance of the final guidance.

So, this was issued in May of 2005, and was then withdrawn in June of 2005, consequent together with the issuance of the final guidance, with the same name as the draft guidance.

The June 2005 guidance, again, formally discontinued the recommendation for querying donors about fever with headache in the past week question, and it included the 120-day deferral for west nile infection, again based on not only the 104 day observation, but also in vitro data developed in CBER's laboratories demonstrating that west nile virus circulating in blood was, indeed, infective in a culture system in the presence of west nile antibodies, and Dr. Maria Rios will present some of those data following my talk.

I think, just to comment on the implementation issue, it perhaps would be interesting for the committee to query the blood community as to what the timing was of these policy recommendations, whether in fact that establishments have been able to make the changes to drop the donor question, change the SOPs and provide sufficient training, just to round out the extensive discussion that took place at the last meeting.

The details with respect to the current guidance discuss a 120-day donor deferral for donors with diagnosed or suspected acute west nile virus, infection or illness, also donors with presumptive west nile virus viremia based on screening tests, donors with suspected post-donation west nile virus illness, and donors who may have been implicated in transmission of west nile virus infection.

One change that took place between the draft and the final is that reentry is permitted without additional testing within the 120-day period, but FDA still considers that IDT testing by NAT of donors prior to reentry is scientifically useful where it is possible.

In terms of product management, current recommendations that, in instances of diagnosed west nile infection or illness in a donor, retrieval and quarantine of end date products should occur 14 days prior to onset of illness, reflecting the incubation period, and 120 days after diagnosis or onset of illness, whichever is later, reflecting the potential for prolonged viremia.

Product management for donors who are potentially associated with transfusion transmitted west nile infection, these donors are defined as donors of suspect donations, that have been received by a recipient up to 120 days prior to the recipient west nile infection.

The recommendations for retrieval and quarantine of other donations by potentially associated donors, 120 days before and 120 days after the suspect donation.

For undiagnosed post-donation illness in potentially exposed individuals, the recommendation is for medical director judgement regarding product quarantine and retrieval, considering the possibility of west nile virus exposure potential.

What we did was, in fact, eliminate the likely endemic time period, recognizing that this could vary depending on a local situation, but also a donor coming from a different geographic area could have potentially been exposed to west nile and be donating in a local area, and that clinical directors should be aware of that possibility.

When quarantine and retrieval of end date products is conducted, it should occur 14 days prior to, and 120 days after onset of donor symptoms, and product quarantine and retrieval is not recommended for pooled source plasma, recovered plasma, or source leukocytes.

With respect to notification of prior transfusion recipients about possible west nile virus exposure via transfusion, establishments should consider tracing records and notifying transfusion services of relevant units.

The relevant units are those collected 14 days prior through 120 days after the onset of diagnosed west nile illness in a donor, or units collected from a donor 120 days prior, to 120 days after, a donation from that donor is identified as the likely source of a west nile virus transmission by transfusion. Thank you.

Mr. ALLEN: Alan, I am going to ask you one quick question before we move on to the others. In the product management section, for donors who are potentially associated with transfusion transmitted west nile virus infection, what is the thinking behind the recommendation to retrieve and quarantine for 120 days before onset?

DR. WILLIAMS: I think, because one cannot necessarily -- it represents a potentially extended viremic period within that donor, which may have been associated with that transmission.

It is not incubation period. It is potential viremic period that that donor may have transmitted infection.

DR. ALLEN: We will move on to the other two presentations, and then take questions and discussion for all of them. Dr. Rios?

DR. RIOS: Good morning, and thank you for the opportunity to present this data here today. As Alan said, I am going to present some laboratory data that we gathered in the past few months.

All reported cases of west nile transmission by blood transfusion has occurred during the acute viremic phase.

Therefore, that is the most appropriate strategy to interdict infectious donations. Therefore, the screening of blood donor status started in the mini-pool NAT.

The mini-pool NAT rates of positivity triggers ID NAT testing, and ID NAT testing leads to identification of additional low viremic units that are often antibody positive.

Low titer viremia can present for up to two months after seroconversion, and there is a lack of data on west nile transmission by later donation, currently identified as mini-pool NAT negative, ID not positive, and then antibody positive.

So, there are some standing questions regarding west nile inactivity. One of those is, what is the minimal infectious dose for west nile, and are antibody positive mini-pool not negative, and ID not positive units ever infectious?

There are options to address these issues that can be recipient look back on clinical model or in vitro studies.

The recipient look back would be the most representative for human transmission is costly and complex. Regarding animal models, there are more animal models that were established, but these small animals do not take enough volume of plasma, or the volume of plasma, that would represent the decision practices.

So, ideally, the large non-human primates would be necessary to be used to address this question, and they demand BSL3 level practices, and that is a very costly study.

So, we arranged to perform some in vitro studies, to address the effective function of antibodies to west nile infection.

We used viral cells(?) and another system of infecting human macrophage that were developed in our laboratory.

Viral cell infection leads to cytopathic sets in ELISAs of these cells which is readily identified by light microscopy, but macrophage infection does not lead to cytotoxicity, easily identifiable. So, the testing for identification for macrophage infection is performed after a period of infection.

So, the infection was perceived as shown there, on 80 percent confluent viral cells and, for the macrophage culture, single donor monocytes were cultured with monocyte colonies simulating factor to fully differentiate these cells into macrophage for 10 to 14 days prior to infection.

These cultures, the viral cells were observed daily for cytotoxic effect, and the supernatants were harvested daily from the macrophage infected culture. We also performed some tachman(?) in the viral cells.

We studied 48 specimens that were provided by the American Red Cross, and different blood system laboratories. In these 48 samples, 33 were antibody negative and 15 were antibody positive.

So, of the 33 antibody negative specimens, 31 were also positive in mini-pool NAT. In 27 of these 31 infected viral cells, we also tested six of these 27 to macrophage systems, and they infected the macrophage. So, our total was 29 of 33 RNA positive antibody negative specimens infected during culture.

So, of the 15 specimens in the antibody positive samples, eight of those were mini-pool or high titer positive, and two of those infected viral cells in two infected macrophages being one of these four samples.

One of these specimens infected both macrophage and viral cells. So, we have three mini-pool positive, ID positive and antibody positive infectious specimens.

Mini-pool, not positive, and mini-pool negative, seven specimens were tested. Three infected macrophage but failed to infect the viral cells.

So, we have six specimens from the 15. That represents 40 percent of RNA positive antibody positive specimens which infected cells in culture.

That leaves 60 percent, or nine specimens, that were non-infectious and that showed the protective function of some, but not all, antibody present in positive RNA specimens.

So, the conclusion for these studies is that several west nile positive plasma containing antibody were infectious for viral cells or human macrophage.

Of the viral infectivity does not imply infectivity in vivo, it demonstrates the presence of live virus which is capable of infecting an in vitro system and, therefore, raises concern about potential risk for transfusion transmission.

The potential transfusion risk from low titer antibody positive donation needs to be further studied, either through recipient look back, or through inoculation in large non-human primates to simulate blood transfusion. Thank you.

Oh, I have to make one comment, that these experiments were repeated several times, and they included positive and negative control in parallel. Thank you.

DR. ALLEN: Thank you, Dr. Rios. Our final presentation on west nile virus is by Dr. Kuehnert.

DR. KUEHNERT: Thanks. It is a pleasure to speak at BPAC. I note on the agenda I was promoted to PhD from my usual country doctor status. That is okay.

I will be providing the west nile surveillance update today, on behalf of my colleagues at Fort Collins that couldn't be here. Terry Smith provided the slide. So, I am much appreciative of that. I will be primarily summarizing data from 2004, with a small peek at this year's activity. I wanted to thank those that supplied the data in 2004. Most of these people are involved this year as well.

First, just a brief explanation on what ArboNET is, our national electronic surveillance system established to assist state and local public health authorities.

So, west nile activity is reported to CDC from state and local health departments and then aggregated, composed of data sources that are both ecologic, such as mosquito pools, animals, animals with disease and sentinel birds as well as human data, which are divided into disease reports such as west nile fever and west nile neuroinvasive disease. Then, in another category, those that are infected and detected by blood donation.

Some of these then fall into these other categories if they develop disease, but are in their own category of asymptomatic infection.

So, what did last year's disease activity look like? This is a map summarizing 2004 spread of west nile activity westward, is what you see here geographically.

It resulted in human cases reported in almost all states in 2004, or in prior years you see absence of human activity in Washington, also in the New England states as well.

There were 2,470 west nile fever cases, and over 1,000 neuroinvasive cases, 100 deaths. This was in 505 counties in over 40 states, including the District of Columbia as well.

When one looks at the incidence of disease -- so, what you saw before were the absolute numbers. This takes into consideration the denominator of population.

You see relatively higher rates in the midwest, which is what we saw in 2003, and certainly that trend continued with high incidence rates in those areas.

Here is the map going back again to absolute numbers looking at presumptive viremic blood donors or PVDs, and you see a high foci of activity in southern California, Arizona, western Colorado, and also in the midwest, which I presume the rates would be quite high if they were calculated on this map.

I just also wanted to go through the numbers here actually, since I don't have a slide on that, for the interests of time.

There were 224 PVDs reported to ArboNET in 2004. The first PVD was donated in Arizona April 23, the last PVD donated October 26 in Louisiana.

Of these 224, 66, or 30 percent, developed west nile fever. Four, or 1.8 percent, developed neuroinvasive disease, and that pretty much is in line with what we see generally in the population.

Over 50 percent, 59 percent, to be exact, were reported from four states, Arizona, California, New Mexico and Texas.

As far as transfusion associated transmission investigations, there were 14. Eight were found to be non-cases. Five were inconclusive to be able to determine cause, and one was a probable case.

This was described in the MMWR in September of last year. It came from Maricopa County, Arizona. It was a case of west nile neuroinvasive disease, status post red cell transfusion, and this was the first human infection detected in the individual's county of residence.

There is one thing I wanted to point out is that, it happens that the first indication of human infection is in blood donors or in transfusion associated transmission. So, that is an important point I wanted to make.

Looking this year, there have been 19 presumptive viremic donors reported on ArboNET as of July 18, two in Arizona, four in California, one in Louisiana, one in Mississippi and ten in Texas.

Then we have also had one in Iowa, and I believe there are additional ones still to be confirmed, including one, I believe, in Illinois.

The presumptive viremic donor in Iowa, actually, my understanding is it is the first evidence of human activity in that state.

So, then the next question is, what is going to happen in the future and where are we now. I just wanted to make the point that, when we look at human disease activity, we are always behind.

So, in the beginning of the year, the lag isn't that great but, as the numbers increase, you get a longer lag time between the onset date and the report date.

So, when we talk about what is happening now, we are actually talking about what happened a couple of weeks ago or even a month ago.

So, the PVDs are really the ones that are more in real time. So, in some ways, you can tell us what is happening, rather than the other way around.

That said, compared with 2004, certainly this is the comparison for week 28, which is last week. There have been less human cases and PVDs reported compared with last year, but approximately the same number of states were associated with those.

Looking at this week, you can see we are on a pretty quick off ramp. So, we have 41 human cases. Of these, 28 are west nile fever and 12 are neuroinvasive cases. There has been one death. These have been reported in 15 states, which you can see below listed here, and are distributed throughout the west, midwest and south.

I just wanted to add that five or more of these are in California, Colorado, South Dakota and Arizona. So, that might give you some idea of where the hot spots are currently, or at least where the reports are.

So, in summary, in comparing this year with 2004, certainly it looks like the 2005 season is starting slower in terms of human activity.

There might be more geographic variation compared with prior years, but similar patterns. The south, midwest and west are now affected. There is speculation that the north may have increase in activity later in the season.

Just a message that PVD activity in areas without known west nile disease this season may provide some prevention opportunity.

For more information and continued updated data, I would direct you to the CDC web site, www.cdc.gov, and punch in west nile virus in the search, or I think there is a menu where you can point to it and get to the arboNET data. That is it. Thanks.

DR. ALLEN: Thank you, Dr. Kuehnert. Questions or comments for any of the three presentations, Dr. Williams on the donor suitability guidance, Dr. Rios on the in vitro infectivity tests, or Dr. Kuehnert on surveillance?

DR. LEW: I am curious. Do you have any ideas of why there is not more west nile over the past couple of years?

It does look like it is decreasing. Do you know whether the vectors have all been infected and now have antibodies? I expected more over the last few years.

DR. KUEHNERT: I might not be the best person to answer this, but I will say that there have been multiple vectors implicated.

So, I am not sure what predominant vector is now, but I think that it is not because every bird is infected, or everyone has immunity. That is really quite certainly not what is going on, because when you do seroprevalence studies, the numbers that have seroconverted are fairly low, in the one to two percent range.

So, I don't think we fully understand why we are seeing a decrease in activity, and it remains to be seen how much of a decreased activity we are going to see this year compared to other years.

It may just be a slow start. As you saw in 2003, there was a slow start, but it turned out to be a huge year. So, I think it is too early to say whether this is going to be a so-called slow year or not.

DR. KATZ: [Portion of question off microphone.] In my understanding in both places, they have been able to discontinue questions about fever and headache after an appropriate framing. Has that had a direct effect?

DR. STRAIMER: Susan Straimer, American Red Cross. We have not struck the question. We have extended the deferral period to 120 days, according to the May 2005 draft guidance. We are in the process of dropping the question, but it will be a while yet.

DR. KATZ: It is that CPMT sort of question, that if we use a computer to do our screening, we haven't dropped the question, but we are ignoring the answer.

More problematic for us is to have a CPMT approach to the extension of deferral. That, of course, gets into the queue in many centers in their IT departments for changes in software configurations to allow an automated approach to the extension of deferral.

In the meantime, we use a manual work around, which doesn't make us happy, but it is the way of the world. So, a 30-day implementation time frame from FDA is not as easy as it would seem, given the relatively straightforward changes that we think we are going to make.

DR. BUSCH: Mike Busch from Blood Systems. Maria Rios' data, I think it is important data, the demonstration of in vitro infectivity from these seroreactors.

To balance that out, there have been no reported cases of transmission recipient infection attributable to seroreactive units, and there were large studies that both Red Cross and Blood Systems did, that will actually be in the New England Journal in about two weeks, that report extensive retrospective testing and the identification of these low viremia seroreactors.

Unfortunately, due to look back, there are only, I think, a half dozen recipients that were actually found and none infected.

The other thing that we have done is, we know through follow up studies the length of the mini-pool yield phase and then the persistent low level viremia detected by IV NET after seroconversion.

The mini-pool phase is about seven days, and then there is about a 12-day period after seroconversion, where you can detect RNA by singlet ID NAT, and then you can add another six days if you do multiple replicates, which is the approach that led to the detection of these delayed seroconverters.

Then, if you take the number of mini-pool yield cases, which has been 934, in the last couple of years, and you use the relative lengths of these window periods, you can project how many units were actually issued and not detected because we weren't doing routine ID NAT, and certainly not replicate ID NAT.

If you run those numbers, it is about 3,400 estimated transfusions of these low viremia units took place in the last couple of years on the back end of the NAT yield phase.

I think the absence of overt infections, both from the look back cases and the sort of epidemiologic modeling would strongly suggest that these seroreactive viremic units are neutralized and not infecting people.

So, although these studies clearly are important and need to be done, I think the bulk of the evidence would indicate that these are not infecting humans.

DR. ALLEN: Thank you. That is an important comment. In the Blood Systems' laboratories, how many counties or areas are having single donor, individual donor versus mini-pool?

DR. BUSCH: To my knowledge, we have only triggered ID NAT in one region, which is actually in Rapid City in the Dakotas.

So, the Arizona area has not triggered, which we require two positives in a zone in order to trigger the ID NAT.

DR. RIOS: I think it is a very important issue that Mike just mentioned, but I did not expect that all the units that have been transfused, as he said, in look back would transmit.

As the in vitro data shows, not all units that have antibodies transmit infection. However, the lack of evidence of further transmission without testing the entire population that received the transfusion is not evidence of non-infection.

The point that I would like to make is that I do not deny that there is a protective function of the antibodies, and I think they do, but it is not all the cases. I would just like to make this statement.

DR. HOLLINGER: Dr. Blaine Hollinger from Baylor College of Medicine in Houston. Dr. Rios, I have another question about those interesting studies on the macrophages. Can you tell me, again, the macrophages that were done, you said you used either CPE or Tachman. I imagine, for the macrophages, you used Tachman, because you wouldn't see CPE probably.

If you did use Tachman, how did you avoid determining -- or how did you determine that this was not just release of virus that might be attached to cells over time.

What kind of levels did you get in terms of raises of, or increases of the west nile nucleic acid and so on, to determine if this was really an infection, or did you even look in the cells, the cytoplasm or other things to determine infection versus just mechanical changes?

DR.RIOS: I am glad you asked that, because my time did not permit to go into details. We actually did negative RNA and macrophages, to show that there is replication in there.

For those of you that are not familiar with the negative RNA, west nile is a positive RNA strain and, for replication, undergo to a complementary negative strain, and that was detectable.

Second, the viral load raises within three days, sometimes six days, but there is a great variability from donor to donor.

We match actually with the clinical data that not everybody that gets infected with west nile would have any symptomatology at all.

Thirdly, those supplemental that we collect later on were capable of infecting viral cells, showing that the macrophages were, in fact, releasing complete virions. I hope that answers your questions.

DR. ALLEN: Last comment, Dr. Katz.

DR. KATZ: Dr. Rios, is there anything characteristic of the infectious samples, in terms of the antibody profile or anything that you could find?

DR. RIOS: It is still preliminary -- I mean, it is not preliminary any more. We are in the beginning of the process.

We are trying to do that, perhaps to look at some host factors, look at antibody class and so on, perhaps get together with the people who provided our general specimens and go and do further study of that.

All of that takes some dollar amount to perform this study, and some research support, which we are praying to get, but I think it is an important issue to be addressed.

DR. ALLEN: Any other burning questions or comments? All right, we are going to move from mosquitoes to gnats. Dr. Paul Meade will give a brief FDA guidance on nucleic acid amplification tests.

Agenda Item: Nucleic Acid Amplification Tests.

DR. MEADE: Thank you, Dr. Allen. I would just like to announce that the draft guidance for industry document, Nucleic Acid NAT for HIV-1 and HCV testing, product disposition and donor deferral and reentry was posted on CBER's web site on July 19, 2005.

This draft guidance is being distributed for comment purposes only. It is not intended for implementation at this time, and you can access this document directly at www.fda.gov/cber/guidelinesgdlns/nathivhcv.pdf. Thank you.

DR. ALLEN: Dr. Bianco?

DR. BIANCO: I just want to say thank you. We are all waiting for it.

DR. ALLEN: Any other questions or comments. We are going to move on, then to topic one, management of donors -- this is an open committee discussion -- management of donors and units that test positive for hepatitis B virus DNA by nucleic acid tests. Dr. Robin Biswas, FDA, will give the introduction and background.

Agenda Item: Open Committee Discussion. Management of Donors and Units that Test Positive for Hepatitis B Virus DNA by Nucleic Acid Tests. Introduction and Background.

DR. BISWAS: Good morning. For the remainder of the morning, we will be discussing HBV NAT, management of donors and units that test positive for hepatitis B virus DNA by nucleic acid tests.

I will give the introduction and background, and then there will be three speakers. Larry Pietrelli from Roche Molecular Systems, Richard Smith from National Genetics Institute, and Larry Mimms from Genprobe, and they will be giving some data.

Now, we are seeking committee advice on the management of donors and units, on a proposed algorithm to permit reentry of some donors when a donor tests positive for hepatitis B virus DNA by a nucleic acid test.

The donors we will be talking about today are both donors of whole blood and components for transfusion and donors of source plasma for manufacture into injectable plasma derivatives.

Let me just say right at the very beginning that source plasma is pooled, and it is these large pools that are manufactured into plasma, into injectable plasma derivatives.

The reason we are bringing it to you today is because FDA recently licensed an HBV NAT, the Roche COBRAS ampliscreen HBV test for whole blood and source plasma donations.

Currently, HBV NAT donor testing is optional, but it could be recommended in the future. The reason we haven't issued guidance recommending use is that the current mini-pool NAT format that really has improved the safety of blood as far as HCV and HIV is concerned, there is only a marginal increase, a very marginal increase in blood safety in regard to HBV transmission.

However, technology marches on and more sensitive HBV NATS could be available. So, it could be recommended by us in the future. So, we would like to get a quick start and discuss this.

Now, consistent with the current regulations and guidance documents, whole blood and components for transfusion are tested for hepatitis B surface antigen, HBsAg, and also for antibody to hepatitis B core antigen, anti-HBc or anti-core.

However, source plasma for further manufacture is tested for HBsAg only. We do not recommend that source plasma be screened for anti-core, and the reason for that is, if units that are reactive for anti-core were excluded from these donor pools that I just mentioned, the anti-HBS, the antibody to hepatitis B surface antigen, the neutralizing antibody, those titers would go down.

It is believed that anti-HBS in the pools contributes to the safety of plasma derivatives, such as immunoglobulins and clotting factors.

Now, a center that would implement, that might have already implemented HBV NAT will be testing for HBV, if they implement HBV NAT and, for HBV, they will be using an extra test.

So, for whole blood and components for transfusion, they would be testing for HB SAG, anti-core and HBV NAT, and source plasma centers would be testing HB SAG and HBV NAT.

Now, because of this, centers will need to make decisions regarding donor and unit management based on the various test result combinations and, as I said, we would like to discuss that early on.

Now, our current position in relation to HBV NAT testing is, if a unit tests HBV NAT negative, the donor and unit management should be consistent with current FDA requirements and recommendations for HB SAG and anti-HBc.

In particular, the recommendations I am referring to are the HB SAG guidance memo of December 2, 1987, where everything is spelled out in great detail, and the one for anti-core is September 10, 1991, where anti-core testing of donors is spelled out in detail.

Now, units that test NAT and serology negative may be used. If a unit tests HBV NAT positive, units that test NAT and/or serology positive are not used.

I should say, up front, that that will not change. However, at the moment we are saying that donors should be indefinitely deferred if they are HBV NAT positive, irrespective of the serology results, I should add, that is what we are going to be discussing today.

Now, the proposal is that an algorithm can be developed to determine the eligibility of donors who test HBV NAT positive based on subsequent negative HBV NAT and serologic test results.

Now, this is just an overview of how donors and units would be managed for whole blood and blood components for transfusion, and I will go through it a bit step by step, quickly if I can.

For category one and two, you have an HBV NAT positive result in both the categories. The HB SAG result, there is a repeat reactive.

This is neutralized in the confirmatory neutralization test. So, it is a confirmed positive in both cases.

Irrespective of the anti-core result -- in one it is non-reactive, and in two it is repeat reactive -- the donor would be permanently deferred. That is actually consistent with our HB SAG testing memo that I just mentioned.

In regard to three and four, for category three you have a positive HBV NAT result. You have a repeat reactive, but not neutralized HBsAg result. The anti-core result is repeat reactive. In that case, the donor would be permanently deferred.

Here, you have a positive NAT, you have a repeat reactive anti-core, a couple of tests there flagging something.

In any case, in our HBsAg memo, if you get a repeat reactive, even if it is not neutralized and the core test is repeat reactive, that donor is, anyway, permanently deferred.

In regard to four, you have a positive NAT, you have an anti-core that is repeat reactive. The HBsAg is non-reactive. Here, because of the two flags that you have, we believe that it is prudent to permanently defer the donor.

Now, category five and six, for both of these, the NAT is positive. In the one case, HBsAg is non-reactive. In the other case, it is repeat reactive but not neutralized.

The anti-core tests are non-reactive in both and, in that case, the donor would be indefinitely deferred but there would be a possibility of reentry.

Very quickly, in regard to source plasma, there are less tests, so there are less combinations. Category one, you have a positive NAT, you have a positive HBsAg and neutralized HBsAg test result. The donor would be permanently deferred.

For two and three, you have positive NAT, you have a non-reactive HBsAg and, in the other case, a repeat reactive that is not neutralized. It is a negative HBsAg test and, in that test, the donor would be indefinitely deferred with possibility of reentry.

Now, during the clinical trials of the Roche COBRAS test under IND, seroconversion studies showed that the maximum period of time that HBV DNA preceded HBsAg detection, was 143 days.

The donor follow up study showed that the maximum period of time that HBV DNA preceded HBsAg, detection was 17 days and, for anti-core, it preceded the core test by 48 days.

Now, I should say additional data will be presented. When I made the slides, I didn't have the fully story on the rest of the data that will be presented.

So, because of this, FDA is considering recommending a minimum six month waiting time after a positive HBV NAT result with negative serology results, prior to re-testing, to ensure that if a true infection exists, and seroconversion to HBsAg and/or anti-HBc occurs.

So, a sample -- and it is a sample, not a donation -- is collected at six months after the index donation, the NAT positive donation.

For whole blood and components for transfusion donors, the sample would be tested for HBsAg, anti-HBc, and HBV DNA by individual sample NAT. For source plasma donors, the sample is tested for HBsAg and HBV DNA by individual sample NAT.

Now, if the period when you are testing, six months or more after the positive NAT index donation, if the HBV DNA by individual sample net is positive, irrespective of the serologies, any test result, the donor is, at that point, permanently deferred.

If the DNA is negative, if the individual sample NAT is negative, and if the serologies are non-reactive, then the donor would be eligible for reentry.

If the sample tests negative for HBV NAT, and if any of the HBsAg tests are repeat reactive, further evaluation would be done, as described in the FDA recommendations.

Let me just briefly explain, because there have been questions. For example, you have a DNA negative test result.

If the person was anti-core, if that sample was anti-core repeat reactive, if it was a first time reactive, the donor could actually donate, consistent with the anti-core memo.

If it was a second anti-core repeat reactive, it would be the second strike, and the donor would be permanently deferred.

In regard to donor testing before the end of the six month waiting period, this may be performed for notification or medical reasons.

If a positive NAT is obtained, the donor should be permanently deferred, irrespective of serology results. Negative or non-reactive results may be used for counseling.

Only negative individual NAT and negative serologic tests collected at six months after the index donation, however, qualifies the donor for reentry.

Now, this is a repeat slide, and the reason I put it up there is because Dr. Epstein wanted me to mention a couple of things.

That second bullet, for whole blood and components for transfusion donors, the sample is tested for HBsAg, anti-core and HBV DNA by individual sample NAT.

Now, if the donor is negative in all those tests, the idea is that the index donation, the initial NAT positive was, in fact, a false positive, and that the individual, this donor, had a false positive and, not only that, probably never had hepatitis B in his or her lifetime.

Now, the situation is different for source plasma. Here, you are testing for HBsAg, and you are testing by individual sample NAT, but you are not testing for anti-core.

Remember, I explained the reasons that we are not testing for anti-core. The neutralizing anti-HBS would go down in the pools, and safety could be a problem.

Of course, they undergo -- these plasma derivatives undergo -- validated viral removal and inactivation procedures.

However, the point is that a source plasma donor, who is HBsAg and HBV DNA positive, after a negative, could be a recovered from an HBV infection.

So, we do want to mention that. The other thing is, for whole blood and components for transfusion, the donors are tested for HBsAg anti-core and HBV DNA, and this is very similar to what -- the tests are exactly the same, as would be done as we presented last October for the anti-core reentry algorithm. Here, the waiting period would be six months and, for the anti-core, we suggested eight weeks.

So, that is the end of this presentation. Dr. Allen, should we look at the questions or how do you want to do it?

DR. ALLEN: Yes, let's go ahead, quickly review the questions, and then we will have a chance for any questions of clarification to you before we move to the next presentation.

DR. BISWAS: So, question one, based on the scientific data, does the committee agree with FDA's proposal that -- I hope I can read all this -- a donor of whole blood and blood components for transfusion, who tests HBV NAT positive, anti-HBc non-reactive, and HBsAg non-reactive, or HBsAg repeatedly reactive not confirmed by neutralization, may be reentered if, after a minimum period of six months, a sample from the donor tests negative for HBV DNA by individual sample NAT non-reactive for anti-HBc and non-reactive for HBsAg.

Based on the scientific data, does the committee agree with FDA's proposal that a donor of source plasma for further manufacture into plasma derivatives, who tests HBV NAT positive and HBsAg non-reactive, or HBsAg repeatedly reactive, not confirmed by neutralization, may be reentered if, after a minimum period of six months, a sample from the donor tests negative for HBV DNA by individual sample NAT, and non-reactive for HBsAg.

Question two, very important, please discuss any alternative approaches FDA should consider.

DR. ALLEN: Any clarification questions for Dr. Biswas? Thank you. The next presentation in the series will be by Larry Pietrelli, Roche Molecular Diagnostics. He will be discussing HBV seroconversion panel results, and HBV NAT positive and serologic negative donors.

Agenda Item: HBV Seroconversion Panel Results and HBV NAT Positive/Serology Negative Donors.

DR. PIETRELLI: The focus of today's talk will be an overview of the COBRAS Ampliscreen HBV test performance on 40 commercially available seroconversion panels as compared to hepatitis B surface antigen.

In addition, a summary of the clinical data on donors who were found to be HBV DNA positive and serology negative, and who were enrolled into the follow up study, will also be presented.

This slide summarizes the data on the 40 seroconversion panels. The blue bars represent the difference in the number of days between when a sample is HPV DNA positive by individual testing as positive, and when hepatitis surface antigen is positive.

The red bars represent one to 24 dilutions of the panels and, therefore, mimic mini-pool testing. It should be noted that no samples were hepatitis B surface antigen positive prior to HBV DNA.

The next three slides will summarize panel results. This is the typical panel results, where you have a sample that becomes positive by individual NAT testing first, followed by pool testing two days later. Then, on the next bleed, which is day 13, the subject is positive by hepatitis B surface antigen.

On this slide, the first panel member is positive by both individual and mini-pool NAT testing. All subsequent bleeds were also positive by NAT. The subject became positive by hepatitis B surface antigen on day 108.

Since all the samples were positive by NAT, there is no way to determine the number of days from when NAT first turns positive until hepatitis B is also positive.

On this slide, again, the sample is positive by individual and mini-pool NAT on the first bleed. However, this panel had intermittent positive results in subsequent bleeds.

The subject finally converts and is hepatitis B surface antigen positive on day 143. Again, since the first bleed is positive, there is no way to determine the number of days from the first NAT positive result to when hepatitis B surface antigen is also positive.

When you take a look at the results of the seroconversion panels, comparing the COBRAS Ampliscreen HPB test and the Ortho hepatitis B surface antigen test system three, the mean difference in the number of days when NAT is consistently positive, and hepatitis B surface antigen is positive, is 15 days. By individual testing it is 20. The median is 14 and 18 days, and the max range is 30 and 53.

However, if you look at these results when NAT is first positive, and when hepatitis B surface antigen is positive, this number changes from 15 to 20, signal changes from 20 to 26, and more important, the maximum range increases to 143.

In the HBV clinical trial, there were 23 donors that were positive by HBV DNA and negative for serology. These donors were eligible for the follow up study.

Follow up testing included IGM, anti-core, total anti-core, anti-HBS, hepatitis B surface antigen, and HBV DNA.

Of the 23 donors, 14 were enrolled in the follow up study and two were confirmed window cases. Here is the first window case. This donor converts to hepatitis B surface antigen positive on day 17, anti-core is repeat reactive on day 48.

This donor was previously vaccinated against hepatitis B. No samples were positive for hepatitis B surface antigen, and the donor did convert to anti-core repeat reactive on day 22.

After the study, three sites continued testing for HBV under the IND, and an additional three window cases were identified.

The first one here, hepatitis B surface antigen was positive on day seven. Anti-core was repeat reactive on day 26. Similar results on the next one.

Hepatitis B surface antigen is positive on day seven, anti-core results were repeat reactive on day 28. The last one was hepatitis B surface antigen positive on day 14.

In conclusion, four of the five window cases became hepatitis B surface antigen positive. The time from mini-pool NAT to hepatitis B surface antigen positivity was seven to 17 days with a median of 11. One donor did fail to seroconvert.

The remaining 12 donors were negative for all markers at the end of the six-month period, and were determined to be false positives. Thank you. Any questions?

DR. KUEHNERT: You have here the 12 false positives. I am wondering how many of those false positives, were there any that had multiple NAT that were positive, or was it only one test for all of them?

DR. PIETRELLI: Eight of them had a repeat sample taken from the plasma bag. The net sample came back negative. Ten of them also had alternate NAT done. All alternate NAT on the index donation were negative as well.

DR. KUEHNERT: So, were there any where the same test was positive twice?

DR. PIETRELLI: No, this was done individually.

DR. KUEHNERT: Do you have any possible explanation for the laboratory findings, whether it was laboratory error, cross contamination?

DR. PIETRELLI: In one case, actually eight of them were associated with 13 positives that were at one site one day. I am not sure exactly what went on, but something obviously happened there.

DR. CLEMENT: Larry, I have a question about the seroconversion panels. Can you tell me what the source was? Then obviously there are these two panels with very different results from the other 38, numbers 39 and 40 that you showed, and if you know anything more about those particular panels?

DR. PIETRELLI: They are from Bioclinical Partners, and actually there are a couple of additional panels that had similar results as those two that I presented. I just presented those two. No, I do not have any additional data.

DR. CLEMENT: So, were these presumably panels that were triggered on -- were they collected based on NAT results in the source plasma industry, or were they collected based on surface antigen positivity?

DR. PIETRELLI: They are based on surface antigen positivity.

DR. TEGMEYER: Gary Tegmeyer(?), Community Blood Center, Kansas City. Matt, I just wanted to speak to your question about the false positives that Larry showed.

I think that the bulk of those came from our lab and were the result of a single contamination episode. We were doing a reproducibility study concurrent with the equivalency study, and I believe we had some super-hot positives in the repro panel, one of which got loose in the lab, and basically accounted for those 12 false positives.

So, we tested plasma, bagged plasma, from those donors. They were negative. We got follow up samples on the donors and they were negative as well. So, it was an exogenous contamination, not an intrinsic false positive.

Mr. ALLEN: Thank you for that explanation. Other questions or comments? Okay, thank you very much. We will move on to the next presentation. I understand that Dr. Richard Smith from National Genetics Institute is not available. Will you introduce yourself, please? The topic is temporal association of HPB NAT and HBsAg reactivity in prospectively screen source plasma donations and retrospectively screened seroconversion panels.

DR. SMITH: Hi, this is Dr. Richard Smith, National Genetics Institute.

DR. ALLEN: Thank you. I didn't have current information. I would like to take a moment here to ask Dr. Biswas or anybody from the blood banking community, with regard to asking a donor to come back six months after what is believed might be an erroneous sample result and give a sample, what is the experience on that, in terms of the donor response and whether reentry -- quite apart from the laboratory testing issues, the practical aspects of discussion with donors about reentry. Anybody who would like to make a comment?

DR. KATZ: At my blood center in the midwest, we are highly successful at getting people to come back, but I think that is not generalized.

I mean, some places say that they have a great deal of difficulty getting a high proportion of donors to return. So, I think you can get an answer any way you want, depending on who you ask.

We think that the critical issue, at least in my mind, isn't so much to have the donor back and donating blood, but to have closure for them on these false positives in terms of the medical information. So, we make a lot of effort to bring them back so that we are confident that they are comfortable.

DR. ALLEN: Thank you. We will continue that point of discussion after the presentation. Dr. Smith?

Agenda Item: Temporal Association of HBV NAT and HBsAg Reactivity in Prospectively Screened Source Plasma Donations and Retrospectively Screened Seroconversion Panels.

DR. SMITH: Thank you. Good morning. This morning I have a limited set of data to present from a study to examine the utility of HBV NAT for screening source plasma donations.

These data were selected in response to Robin's very specific question, namely, how long after initial detection of HBV DNA is it until the appearance of hepatitis B surface antigen.

Only those donors in which HBsAg was eventually detected, after detection of HBV DNA are included. I just want to mention that there were many donors who were consistently, or intermittently positive for HB DNA, but in whom HB SAG was never detected, in other words, persistently or chronically infected individuals, and these were excluded from the following slides.

Data presented in the following slides are broken into three sets. First, source plasma donors identified initially by HBV NAT screening who subsequently converted to HBsAg reactive during follow up testing.

Next we have samples from seroconversion panels that were retrospectively tested by individual HBV NAT. Last, we have source plasma donors identified through HBV NAT or HBsAg screening and investigated through testing of look back samples.

Data for seven donors initially identified through HBV NAT screening, and followed until HBsAg seroconversion are shown in this slide.

Each bar on the graph represents one donor. The left end of the bar is identified by the first HBV DNA positive bleed, and the right end is defined by the first HBsAg reactive bleed. So, you can see the days to seroconversion from the initial DNA detection.

Surface antigen was detected in donors from this group an average of 11 days after initial DNA detection, and the longest time to seroconversion was 16 days. The initial -- just to reiterate, the initial DNA detection was done in a mini-pool setting, in this case.

Samples from this group as well as the next were retrospectively tested by individual HBV NAT, in order to find the earliest signs of HBV DNA.

The average time from DNA detection to appearance of HBsAg in this group is 28 days, and the maximum is 94 days.

This last group of donors is part of a look back study, in which samples obtained from plasma units removed from production due to either an HBsAg reactive, or an HBV DNA positive result were tested by individual NAT.

The average time between earliest DNA detection and HBsAg reactivity in this group is 60 days, with one clear outlier ta 253 days, this top donor.

As I said earlier, the data that I currently have access to regarding this study is limited. However, this one donor stood out so significantly from the rest that it really calls for more explanation.

In this slide, which did not translate as well from Excel as we had hoped, I have added vertical bars for each sample tested.

I don't know if you can make it out at the back, but they are different colored bars. The black bars represent HBV DNA positive samples, yellow bars are negative for HBV DNA, and the red bars at the end represent the first HBsAg reactive samples.

As you can see, most of the samples from the outlying donor are within six weeks of the HBsAg reactive donation there at the end.

Three samples from six months earlier were included in the study, of which the earliest two were found to be DNA positive at very low levels, and the third was negative. So, that is back here.

It is important to recall at this point that these data are from a from a retrospective study. When I was able to identify these particular samples in the NGI data base, I found that the majority of samples whose data appear on this slide were all actually submitted on the same date in a very large group of over 260 samples for HBV DNA quantitation by PCR. Many of the samples in that group had very high viral titers, some greater than 500 million per milliliter.

This is a slide showing the quantitative values obtained for the samples from the 253 day donor. The one DNA negative sample shown in yellow down here, the other at this end were 100 copies per milliliter respectively. The first HBsAg reactive is shown in red.

Assuming that all the 260 of the retrospective samples were aliquotted for submission to NGI at approximately the same time, and given that they were processed through our system as a group, there certainly exists the possibility that some contamination could account for the two early DNA positive samples.

This possibility illustrates the reason for the proposed donor reentry algorithm. Just looking at the data from the last 60 days from this donor, we see a fairly standard looking ramp up and acute infection dropping off quickly, probably as antibody develops.

Another point to make here is that, since all of these studies were performed in the context of source plasma donations, there are no anti-HBc data, as source plasma donations are not screened for antibodies to the core antigen.

Finally, this summary table shows the average number of days from HBV DNA detection to HBsAg detection in those donors who did seroconvert, either in follow up to mini-pool NAT detection -- the source plasma I group -- or based on retrospective individual NAT testing. That is all I have.

DR. ALLEN: Thank you. With regard to that outlier donor, is there any -- if your presumption is correct, that maybe those first two NAT positives were, in fact, false positives, is there any chance that that donor actually became infected at a later stage? Did anybody interview him?

DR. SMITH: That donor definitely became infected at a later stage. The issue really was that samples that were retained from six months earlier were gathered at a later point and sent in with other samples that were known to be very strong positives for HBV, greater than 500 million in some cases.

So, my presumption is that there is a possibility of cross contamination for those two. However, unfortunately, the only samples that I have are the aliquots that we did receive, and I have been unable to determine if those units still exist.

DR. ALLEN: Other questions or comments for Dr. Smith? Yes, Dr. Epstein?

DR. EPSTEIN: You probably said this, but in the prospective study you were looking at the time from mini-pool positivity to HBsAg, whereas in the retrospective study you were looking at the time from ID testing to HBsAg; is that not the case?

DR. SMITH: That is correct, yes.

DR. EPSTEIN: So, that is presumably what explains the difference in the average and the range.

DR. SMITH: Certainly, in the averages, absolutely, and that one outlier, but the other, I assume, explains the difference, because our mini-pools are 512 member pools.

DR. EPSTEIN: You also had a maximum in the retrospective study of 94 days, which seemed to be an outlier also, and you haven't commented on that case.

DR. SMITH: Yes, you are right, that did look somewhat like an outlier. Unfortunately, I didn't have the complete data set for that. All I had was the minimum and maximum. I am working to get the rest of those data. I just wasn't able to get them for this presentation.

DR. BUSCH: Thank you for including those graphs which have sort of the tick marks indicating when bleeds were available in those intervals, because obviously these data can be really influenced by a rare outlier.

I think this intermittent detection is something that we have seen in a number of studies, and each of the manufacturers is showing evidence for that kind of intermittent viremia.

In most of these cases there are ample volumes from these plasma units to go back and corroborate, and in the earlier studies with FDA I think we saw these, and they were often seen with the more sensitive assays pretty consistently.

So, it seems like it is real. I am just wondering if you have done anything -- I know we have tried to do this together on HCV and HIV, but obviously if you could actually sequence the virus from that intermittent viremic blip, if you will, and the downstream unequivocal ramp up, you could investigate whether this is the same virus, whether maybe it is added contamination or some aborted infection.

DR. SMITH: Right, of course that is a very good suggestion. I am in the process of trying to locate those retention samples. These were tests done a couple of years ago, actually, and I have been able to identify that we should have aliquots in freezers that are off site. So, I am in the process of trying to get those.

Again, these were single amplification reaction positives, resulting in the quantitation of 100 copies per milliliters. If we only have a milliliter, or a mil and a half of the sample, we will try to amplify again, but it is unlikely we are going to be able to sequence off of that.

DR. CAUGHLIN: Jerry Caughlin(?) FDA. Clearly now, on these samples, do you plan to perform anti-core? Are those anti-core positive?

DR.SMITH: Yes, that is a good point and I mentioned that there were no anti-core data for these. I would like to get anti-core data on this whole sample set. Unfortunately, I am not the only party involved, and the samples really don't belong to us.

DR. CAUGHLIN: Then the contaminants, did you sequence the early detections? Do you know that it is the same sequence?

DR. SMITH: No.

DR. CAUGHLIN: Can you do that?

DR. SMITH: It is possible.

DR. ALLEN: Any other committee questions or comments for Dr. Smith? Okay, thank you very much. Our final presentation before break is window period detection of HBV with the procleix ultrio assay, Dr. Larry Mimms, Genprobe.

Agenda Item: Window Period Detection of HBV with the Procleix Ultrio Assay.

DR. MIMMS: Thank you very much. I would like to talk about some of the data that we have generated during our clinical trials concerning the HBV seroconversion.

Those studies were done with neat samples, as well as the seroconverters diluted one to 16, and one to eight, one to 16 to mimic our mini-pool size.

I will also show you a little data from the IND study comparing HBV DNA detection with seroconversion, and finally some studies for routine donor testing performed outside the United States.

These studies were done with the Ultrio, the Procleix ultrio assay, which is a test developed by Genprobe Chiron, under contract with National Heart, Lung and Blood.

The test allows the simultaneous detection of HV-1 and HCV RNA and HBV DNA, and then we also have discriminatory assays to differentiate the three markers.

These are data generated from 10 commercially available seroconversion panels from Bioclinical Partners. I think they are called Zeptometrics today.

The data are given as number of days between detection by HBV DNA with ultrio and surface antigen detection. Both samples run neat and at dilutions of one to sixteen.

You can see that the mean window period closure for neat samples is around 18.5 days, a median of 19 days, and a range, depending on the seroconversion panel, from 11 to 29 days.

Compare that to those samples diluted one to 16, where the mean is 10 days, the median is 8.5, and the range of values is from zero to 29.

These are very closely spaced bleeds in these panels. So, for example, in the largest window period case of 29 days, the previous bleed was at 26 days. So, we know that that window period closure is somewhere between 26 and 29 days.

The next slide shows the seroconversion -- those were data compared to the Ortho test. These are data comparing the window closure between ultrio and the Abbott prism test, and the results are very similar, with a mean closure of 17 days, a median closure of 17, with, again, a range of 10 to 29 days of closure.

Finally, to mimic dilutions that we see for customers in Europe, we ran samples -- the same seroconversion series at a dilution of one to eight and, not surprisingly, found intermediate values of closure between those determined neat and one to sixteen.

These were the clinical data generated during the U.S. trials. These data have now been submitted to the FDA for review for the ultrio assay.

I want to point out line number five, which were seven donations that were positive for HBV DNA by ultrio, but negative for anti-core and surface antigen.

We thought that we might be able to determine some information on window closure period from these seven potential yield samples. However, we were disappointed in the follow up results.

These are the actual data of those seven. I should mention that six of these seven potential yield samples were form one site in Florida.

We were not able to bring back the donor in four of the seven and, therefore -- I should point out also that that donation two was not only positive by individual ultrio assay, but also in the discriminatory assay, as well as, in many cases, by an alternative nucleic acid testing.

However, the donation was not available. The donor was not available and lost to follow up and, therefore, we weren't able to confirm whether or not there was a seroconversion event.

We believe that it is likely that -- and in three cases that are starred here, we were able to bring the donor back at various time points, and in no case was that donor positive for anti-core surface antigen or HBV DNA and, therefore, we believe that most of these results probably arose from contamination of the specimen tube.

We have some preliminary data from routine donor screening outside the United States. This test has been implemented in Europe, South Africa and in Asia for routine screening, and we do have some data from those sites, primarily from Italy and from Spain.

A total of 417,000 donations have been examined, and 262,000 of them were tested by individual donor testing with the ultrio assay.

Four serology confirmed -- I should say NAT positive only in the index donation, but confirmed in subsequent call back from those donations -- have been identified, and I should point out that most of these donations occurred in countries where anti-core screening has not been routinely implemented.

Therefore, we did testing of some additional HBV NAT positive samples with an anti-core test, and found that there were 49 of those donations negative for surface antigen, positive for anti-core and HBV NAT.

In one to eight dilutions, those countries using one to eight pools, there were 155,000 donations examined, and no HBV NAT positives that are anti-core negative and surface antigen negative have been identified to date. However, 10 that were both NAT positive, surface antigen negative, and antibody positive have been found.

We have been able to look at two cases specifically from Madrid in great detail, and we have found that, in the call back in the first case, four days after the initial index donation, the next bleed at that time point was both DNA positive by ultrio and, in fact, surface antigen positive. So, within four days a seroconversion to surface antigen had occurred.

In the second well documented case from Madrid, we found that a call back at seven days had remained surface antigen negative, but was DNA positive, but a seroconversion event was documented at day 32, at which surface antigen was positive and DNA was positive.

So, in conclusion, from testing seroconversion panels with the procleix ultrio assay, we see a maximum window period to closure of 29 days, and that of course depends on the donation and the donor.

We have identified seven DNA positive surface antigen negative, anti-core negative donations in the procleix ultrio assay trial, but none were informative concerning the window period, and were likely contamination of the donor tube.

There were four NAT yield cases from Europe. I should mention three were from Spain, one was from Poland, and the window closure that was documented in two cases was between four and 32 days. So, I think all of these data are consistent with the previous two presenters. Thank you very much.

DR. ALLEN: Thank you, Dr. Mimms. Questions for clarification?

DR. KUEHNERT: There was the one donor you had there that I think had what you were calling a false positive, but it looked like there was a positive on one testing NAT sample, and then it said the alternate NAT was also positive.

DR. MIMMS: Right, those were from the same tube. So, when the same tube was tested by both discriminatory HBV and the alternate NAT, that tube was, in fact, confirmed positive.

However, when that donor was brought back for subsequent bleeds, all serological and NAT markers were negative in that donor. So, we suspect a contamination of the tube. We don't know that, but that is the suspicion.

DR. ALLEN: Other questions or comments? Okay, thank you very much. We will bring this phase to a close in just a second. Dr. Freas has an announcement he wants to make.

DR. FREAS: I just want to correct the public record. The conflict of interest statement that was read this morning, Ms. Baker and Dr. Whittaker did not receive a waiver. They do not have any financial conflicts of interest, and the conflict of interest statement will be changed, and that has to be read into the public record. Thank you.

DR. ALLEN: We are about 20 minutes behind at this point, not too bad, actually, considering. We will have a 20 minute break, and I would like people to check their watches and begin to come back in the room in 15 minutes, please, so that we can get underway in exactly 20 minutes.

[Brief recess.]

DR. ALLEN: Dr. Freas?

Agenda Item: Open Public Hearing.

DR. FREAS: As part of the FDA advisory committee process, we hold open public hearings, for members of the public who would like to address the committee on the topics of discussion pending before the committee to have a chance to make that presentation.

We have received three written comments that will become part of the public record, from the Plasma Protein Therapeutics Association.

For this morning's open public hearing talk, we have received one request to address the committee, and that is from Dr. Roger Dodd, chair of the AABB, Transfusion Transmitted Diseases committee. Dr. Dodd?

DR. ALLEN: Roger, you have to wait a minute, because I have to read the open public hearing announcement for general matters meeting, and it is probably longer than your statement.

Both the Food and Drug Administration and the public believe in a transparent process for information gathering and decision making.

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 open public hearing speaker, at the beginning of your written or oral statement, to advise the committee of any financial relationships that you may have with any company or any group that is likely to be impacted by the topic of this meeting.

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 at the meeting.

Likewise, FDA encourages you, at the beginning of your statement, to advise the committee if you do not have any such financial relationships.

If you choose not to address this issue of financial relationships at the beginning of your statement, it will not preclude you from speaking. Dr. Dodd.

DR. DODD: Thank you very much, Dr. Allen. I have received some consulting fees from Roche and from Genprobe at a minor level.

DR. ALLEN: As defined by whom? [Laughter.]

DR. DODD: I am, indeed, Roger Dodd, and I am chair of the AABB transfusion transmitted diseases committee, and I am representing AABB, America's Blood Centers, and the American Red Cross in this statement. I will not read the entire statement, but do ask that it be read into the record.

AABB, America's Blood Centers, and the American Red Cross very much appreciate the opportunity to address the blood products advisory committee on the issue of management of donors and units that test positive for hepatitis B virus DNA by nucleic acid tests, NAT.

AABB, ABC and ARC support FDA's position on the desirability of an algorithm for reentering donors with false positive HBV DNA results.

I think you have heard the evils of rampant HBV samples in a production lab already. So, we very much support the reentry protocol, provided that the HBV serology -- that is, HBsAg and anti-HBc -- results be negative.

We agree in general with the proposed reentry algorithm, but request a clarification with respect to item 3-1-C, which reads, if a negative individual sample HBV NAT result is obtained, at least six months after the original donation, together with a repeatedly reactive HBsAg result, and/or a repeatedly reactive anti-HBc result, the donor should be further evaluated as described in the FDA recommendation.

We note that FDA's guidance documents do not yet address reentry of donor of blood and blood components intended for transfusion who test anti-HBc repeatedly reactive on more than one occasion.

We interpret this statement to mean that, if such a donor tests anti-HBc reactive with no other HBV markers, then that donor is reentered and eligible to donate as per the HBV NAT reentry algorithm.

We recognize that such a donor will be recorded as having a single hit for anti-HBc, and that a subsequent reactive anti-HBc result would disqualify the donor.

In fact, immediately prior to this meeting and during his presentation Robin Biswas did affirm the truth of this statement. So, we thank the FDA staff for clarifying that point.

With regard to anti-HBc reentry, AABB, ABC and ARC urge FDA to issue a guidance document addressing anti-HBc reentry that supports the proposed algorithm endorsed by the blood products advisory committee at its October 2004 meeting.

We continue to encourage manufacturers of HBV DNA tests to qualify such algorithms in tandem with anti-HBc screening tests having improved specificity.

We agree with the FDA that the major motivation for re-testing an HBV NAT positive donor prior to the six month reentry interval is to obtain information for accurate and appropriate donor counseling.

In addition, early re-testing will provide important scientific information about early HBV infection and about HBV NAT performance. We urge early re-testing when it can assist with donor counseling.

In conclusion, accurate donor counseling messages, along with reentry of donors testing falsely positive for any HBV marker, whether HBV DNA, HBsAg, or anti-HBc, should be encouraged. Thank you very much.

DR. ALLEN: Thank you, Dr. Dodd. Any questions from committee members from committee members for Dr. Dodd on his statement? Okay, thank you very much.

DR. FREAS: Is there anyone else in the audience who would like to address the committee on the topic pending before the committee at this time?

DR. ALLEN: Okay, if not, the open public hearing is closed, and we will move on to the open committee discussion. Dr. Hollinger.

DR. HOLLINGER: I tried to get up real quick.

DR. ALLEN: You have got to be fast.

DR. HOLLINGER: Just a couple of comments, if I could. I think it is important, at least as I view it. First of all, as you look through the serologic profiles that were presented, or you look at chimpanzee studies, in which chimps have been infected with HBV, or you look at post-transfusion hepatitis studies, there is nothing unusual about the serologic profiles. They are all typical, and you expect them to be typical.

We often chase these unusual patterns that we think are representative, sometimes, of hepatitis B infections, and the fact is they do not represent usually these infections.

It often is because of false positivity, or it is because of tests that aren't sensitive enough or things of that nature, that we see these issues. I would like to just have that as sort of a starting point.

The second thing is, I think when people present data here, particularly when they have negative data, I think it is important that they indicate the sensitivity of the assays that they are using.

We have come along way, for example, in hepatitis B surface antigen assay. The Japanese assay might only detect three nanograms or 10 nanograms per ml, whereas some of the newer tests may go down to two tenths to maybe seven tenths or even less nanograms per ml.

So, when we particularly talk about something that is HBS antigen negative and NAT positive, it is in those that we need to know what the sensitivity of the assays are.

The third thing has to do with Robin Biswas' very good discussion about some of the categories. There is a category that he didn't mention that is indicated by both the Genprobe data that was presented here. There was also a study that I think Steve Kleinman and Mary Coonts and I think Mike Busch was on also and others, in which there were some individuals that were hepatitis B surface antigen positive, and NAT negative.

That is not in a category here. All the categories here are NAT positive categories. In the Coonts study, there were three percent of their samples that were HBS antigen and ant-core positive, were negative for NAT at 1.3 copies per ml.

Then the procleix, or the study that was presented, they had four in that group. I don't know the sensitivity of their assay for -- well, that was with HBS antigen that was positive. So, that is the second thing.

Finally, I am not sure -- it was commented that these donors who are positive for NAT and positive for neutralized surface antigen and so on should be permanently deferred.

I am not sure that permanently deferred might be the correct term that we ought to use here. I would much prefer indefinitely deferred for one reason, and that is, there are other countries -- Japan for example -- that are transfusing blood that is anti-HBc positive, high titered anti-HBc and HBS positive, that is negative by individual donor NAT testing, and HBS antigen negative, without much difficulty.

Most of the data have suggested that this is not infectious blood. So, I think instead of saying they are permanently deferred, we ought to still indicate that these are indefinitely deferred, giving us the opportunity in the future, perhaps, that these people could be reintroduced into the donor field if that ever comes about. Those are my comments.

DR. ALLEN: Thank you. Your comments, of course, are now into the record, and I suspect they will be considered by the FDA. Yes, would you introduce yourself, please?

DR. STOREY: Thank you, Andrew Story, Cangion(?) Corporation. Regarding Dr. Gaines' update this morning, there was a question from the committee regarding the number of doses of Winrow SDF distributed in the United States per year, and I would just like to provide that number.

It is approximately 30,000 to 40,000 doses. We don't have exact numbers. From that we derive an incidence rate, approximately, for this AE to be above 0.003 to 0.005 percent.

DR. ALLEN: Thank you very much. All right, the open public hearing is now closed. We will move into the open committee discussion.

Agenda Item: FDA Perspective and Questions for the Committee.

DR. ALLEN: Before we go back to Dr. Biswas, why don't we have an opportunity just for any additional comments or questions by the committee members?

DR. WHITTAKER: I would just like some clarification. When it says you are positive for HBV NAT, if a center is doing single donor testing, is that just one positive single donor test and it is considered a positive?

DR. BISWAS: Yes, currently that would be so, yes, but there are other considerations that we might want to take.

For example, what would constitute a supplemental test in that case, and that is something that needs to be thought about and further discussed.

DR. WILLIAMS: Any other questions and comments in terms of the general nature of discussion? Dr. Tegmeyer, could I ask you, you talked about the 13 false positives that you had in that one single probable contamination incident. What did you do with those donors in terms of counseling them, and did you ask any of them to come back, and did they come back for additional samples?

DR. TEGMEYER: I did comment on that during my remarks, but I will reiterate that the donors were deferred. Plasma bags were obtained from the donations where available.

I don't think we recovered 100 percent, but we had the great majority of them and, when tested, the plasma bags were negative for HBV DNA.

When the donors were followed, we obtained two follow up samples, not the regime that Larry outlined in the procedure.

We were only able to get them back because we knew they were false positive, they were not terribly engaged in the process. So, we did inveigle them to come back at three and six months, and they were negative for serologic markers for hepatitis B, and negative by INAT for HBV DNA.

DR. ALLEN: It is a special situation.

DR. TEGMEYER: Yes, and I think, just to emphasize the point, we were doing a reproducibility study which had panels of samples, some of which were very high titered, and I am certain what happened -- although I can't prove it unequivocally -- was that one of those samples got loose in either the isolation lab or at the analyzer level.

We decontaminated thoroughly after that and, thereafter, had no further evidence of contamination problems.

DR. EPSTEIN: If I could ask Gary a question while you are at the mike, you know, it is clear that the impetus behind the reentry algorithm is the problem of false positives, due largely to contaminations, because true positives do eventuate into seroconverters.

So, the question really is, how readily does the blood center or the testing lab have access to the original unit?

The unit is slated for discard once you have a reactive screen. So, it is not going to be used clinically, but there is a great value in determining the donor status, if you could go back to the original unit, rather than the sample tube.

DR. TEGMEYER: Actually, that is what we did, Jerry.

DR. EPSTEIN: Right, but what I am asking is, how accessible are those samples in general, if that were part of the paradigm?

DR. TEGMEYER: I think it depends on what center you are in. I mean, we have had ongoing clinical trials at our place for years and years, and our quarantine people are accustomed to setting those units aside for us, instead of tossing them into a biohazard container.

There are some centers where they are locked down to the point where that option isn't open. So, I think it is center dependent, or maybe system dependent. At our place, we can retrieve them, but I don't believe that is universally true.

DR. KATZ: Gary, were you able to do any sequence data on the ostensible contaminants?

DR. TEGMEYER: No sequencing was done.

DR. KATZ: To illustrate what Gary was saying about accessibility of the units, remember that in many settings the samples are coming from other blood centers in centralized testing systems.

So, there is a communication issue, the aggressiveness with which some of the centers are willing to go and look for these things.

Our west nile presumptive donor in Iowa, that you saw on Dr. Kuehnert's map, my component people had already locked that in a biohazard and shipped it off by the next morning, when I realized that there was a unit that Maria Rios wanted. So, it is going to be all over the board.

DR. BIANCO: Again, completing that sequence, that thread, most of the centers are very concerned about the potential for release -- or all the centers whether ABC centers or not -- about the improper release of a unit.

So, the computers block down those units, and the only place you can ship those units to is a biohazard bin. That actually is in contrast to a concern that FDA has where all the preentry protocols ask that the donor donate only a sample because of a fear that I don't understand, that donors may donate and then the unit that is potentially positive would be released. All computer systems today used in all blood centers prevent that release.

DR. EPSTEIN: Not all centers are computerized. You remember the data from Jeanne Linden on inappropriate unit release which was -- I don't remember the exact figures, but it was above a percent, and it was a contributing cause to ABO mismatches, and it was shown especially in the setting of autologous donations, but it was found also with allogeneic.

So, we do recognize that some systems are less error prone than others, largely dependent on the degree of automation.

There was a disparity between large and small centers, but I have not seen any more recent data on the subject.

I mean, Mike Busch presented some data using NAT to look back at how often there was an error, at least of testing, and some of those errors turned out to be recordation errors, things of that sort.

I think we do have to acknowledge that there is some finite level of improper unit release. It is hard to be able to put a number on it because of the wide spectrum and the fact that we are looking at old data, but it exists.

DR. BIANCO: It exists, and the studies by Jeannie Linden showed these in the hospital environment, of registered establishments, not among FDA licensed establishments. So, maybe you have to find out where you get control of the registered establishments.

DR. ALLEN: I think the point that was made by Dr. Katz, however, is certainly very valid, that a smoothly functioning, and highly efficient system will account for every single unit, and they will get one that is not approved out of that system and into the final disposal as quickly as possible.

That, of course, is consistent with what needs to be reported back to the FDA and, obviously, it does result in the destruction of some units that could be of very significant research interests. So, that is an issue that we can't resolve today, but I am glad we have had a few minutes for discussion.

DR. TEGMEYER: Jim, just to follow up on a question you raised earlier about the likelihood of getting donors back in six months, I think you asked some of us to speak on this.

I can speak from our center's experience. We have implemented all the FDA approved algorithms for donor reinstatement, and I would say that, based on our experience over the years with those algorithms, is that donors who are repeat donors, who have a lot of donations under their belts, who get deferred because of false positive test results, will inevitably come back in six months and be sampled, with a reminder that we send them.

First time donors, on the other hand, are not likely to come back, and those in the middle -- that is, some who have a few donations under their belt -- may or may not come back, depending on how persistent we are in terms of trying to get them back.

I think Sue Straimer might also have some comment to make on that subject, based on her recent experience with the core reentry study.

DR. STRAIMER: The success of reentry protocols are directly proportional to the amount of effort that is put into contacting those deferred donors, bringing them in for additional counseling, follow up, re-testing.

So, depending on, again, the amount of work with west nile, we are close to a 90 percent success rate, because west nile is new, the regions were excited about it, they wanted to understand what was happening. We had reinstatement associated with it. So, there was a lot of gung ho enthusiasm for west nile.

We are doing a study with anti-core repeat reactive donors, where we are testing them for DNA and, as part of the protocol, we are asking them to come in for follow up, potentially, to collect data for the use in an anti-core donor reentry algorithm.

Regions are not enthusiastic about anti-core. This represents a lot of donors. They have a lot of work to do. They don't see anti-core reentry as imminent. So, our success rate, in contrast with west nile at 90 percent, is nine percent with anti-core.

Hopefully that will change if there is an anti-core reinstatement procedure but, again, it depends on the test, it depends on the enthusiasm of the regions, how much, at least in our system, our headquarters pounds on the region to do so, but it is a very difficult staff.

DR. ALLEN: Thank you for that clarification. I saw some other heads nodding in the audience. So, I suspect that what you said is a very generalizable statement.

DR. KUEHNERT: I just had a question about repeat testing. We heard the answer about one test connotates a positive test, but I am wondering, do multiple tests count against the donor before the six month period? The answer is yes?

DR. KATZ: I will go out on a limb, Matt. I don't think that most of the people I deal with are going to wait six months. There is sexual transmission, household transmission of hepatitis B, that these issues will be cleared up.

The donor counseling message needs to be dealt with much quicker than the reentry, and the reentry will be the afterthought, after we are confident that it is a re-enterable donor.

DR. KUEHNERT: I guess I didn't understand that before. So, even if it is from the same sample tube and it is the same test -- that is not true?

DR. KATZ: It would be suicidal to use the same sample tube with HBV NAT.

DR. KUEHNERT: It is not completely clear to me, but it sounds like a test that is defined as a discretely different test, whether that is alternate NAT or done from a different sample, would be considered two positives, and then would result in permanent deferral of the donor. Is that right? Okay.

DR. STRAIMER: Matt, I don't know if this is going to help or not, because I was having my own conversation, but as far as one strike and you are out kind of policy, you saw a lot of data presented today where there was source tube contamination.

So, if you go back and re-test that source tube, that is what Lou said would be suicide. That is where you are getting the pool positive, the individual donation positive.

You are getting a discriminatory test positive, you are getting an alternate NAT test positive. Pretty soon you have enough data that you can convince yourself that the donor is positive, when really only the tube was positive.

In contrast, a lot of other false positives come from just running the assay. They are not reproducible, like Gary's contamination, where it is just technique dependent because these are very manual assays.

So, generally, if you bring the donor in for an independent sample and the donor then, again, tests positive, you do have two strikes.

I think that is what the FDA's intent is. If you bring the donor in for counseling prior to six months and you test them and they are positive, they are history, so to speak.

Let me just add one more thing. With tests we do for viruses like hepatitis B and, although we are not routinely testing for parvo, I would throw parvo in the same type of arena.

Agents that produce such high titer viremic phases like hepatitis B, are surface antigen positive, so 10¹⁰, 10¹¹, 10¹² copies per ml, when we do routine testing, we are going to see a lot of intra-assay contamination, a lot of carry over from those types of samples while you are running the tests to two negatives.

This happens when we run HBsAg negatives as well. So, just the manipulation of doing the assay results in a lot of intra-assay contamination.

With HBsAg, where we can re-test the sample again, statistically, if you have a repeat reactive rate of three in 10,000 and then you re-test the sample, it is unlikely that that sample, again, will be one of those three in 10,000.

Something like NAT, where there is one strike and you are out, intra-assay contamination is a much more serious issue.

So, the only re-test algorithm we have, then, to save the donor will be the donor re-instatement. So, for HBV NAT, it is very important.

DR. ALLEN: Thank you for that clarification. Dr. Biswas, do you want to re-state the questions, and we will move on?

DR. BISWAS: Based on the scientific data, does the committee agree with the FDA's proposal that a donor of whole blood and components for transfusion, who tests HBV non-positive, anti-HBc non-reactive, and HBsAg non-reactive, or HBsAg repeatedly reactive, not confirmed by neutralization, may be reentered if, after a minimum period of six months, a sample from the donor tests negative for HBV DNA by individual sample NAT, non-reactive for anti-HBc and non-reactive for HBsAg.

DR. ALLEN: Why don't you go ahead and read 1-B, and then we will consider them separately.

DR. BISWAS: Based on the scientific data, does the committee agree with FDA's proposal that a donor of source plasma for further manufacture into plasma derivatives, who tests HBV NAT positive, and HBsAg non-reactive, or HBsAg repeatedly reactive not confirmed by neutralization, may be reentered if, after a minimum period of six months, a sample from the donor tests negative for HBV DNA by individual sample NAT, and non-reactive for HBsAg.

Agenda Item: Committee Discussion and Recommendations.

DR. ALLEN: Okay, thank you. Questions and comments relevant to question 1-A, or discussion?

DR. LAAL: Could I get a sense of how many donors would reenter into the system if we followed the new algorithm?

DR. BISWAS: I really don't know the answer to that.

DR. ALLEN: I think there are two components. One is that there is a pool of people, a group of people, who have been accumulating over time that might be affected. Then the second would be the incident cases, once that back log was cleared.

DR. BISWAS: Keep in mind that HBV NAT testing is optional, and I don't know how many centers are utilizing it. I do know some are.

DR. KATZ: From my standpoint, the inconceivable eventuality that I would have a contamination problem in my lab like Gary had in his is the worst case scenario, that we wind up with 13 donors one day, and we have identified a high titer HBsAg that was the culprit and we contaminated, particularly if it was a cluster of aphoresis donors in our samples.

This really, before we implement HBV DNA at my center, I think we want to be pretty convinced that the FDA is going to let us move this way, so that we don't have a disaster.

DR. ALLEN: That is a side statement that certainly represents one aspect of the issue under consideration.

DR. KUEHNERT: Just a point of clarification from a comment made before, is there a difference between indefinite deferral and permanent deferral, in terms of what FDA considers them to be?

DR. BISWAS: Well, it is sort of semantic. What we mean currently right now is that, if somebody is permanent, then they couldn't even be considered for reentry under this algorithm. Indefinite means that they could be considered under this algorithm.

DR. ALLEN: The point that Dr. Hollinger was making is not one that really can be applied under current existing guidelines and regulations and rules. So, there would have to be quite a change.

I think it is an interesting point for consideration, but it is not asked of the committee today, and the FDA can take the statement under advisement.

DR. KUEHNERT: I was just wondering specifically for those donors who are NAT positive, and negative for all other markers, but you are saying that we can't even consider that issue, whether they would be indefinitely versus permanently deferred.

DR. ALLEN: You mean NAT positive on more than one occasion?

DR. KUEHNERT: Right. There are a lot of scenarios that I heard today that makes me a little nervous about permanently deferring them.

DR. ALLEN: You can certainly make a comment on that for the record. I think you just did. If you want to strengthen it, you can certainly do so.

DR. BISWAS: Remember, these are considerations and, if there are concerns, please let us know and tell us now, if possible.

DR. EPSTEIN: I would just comment that reentry algorithms exist at the level of guidance. When we say a donor is permanently deferred, that is consistent with current guidance.

We have, in fact, in the past changed guidance regarding reentry. So, we have, in fact, reentered some donors who had previously been categorized as permanently deferred.

I think that the semantic point in the mind of the FDA is exactly as Dr. Biswas has stated, that if there is a reentry algorithm and a donor who is deferred is potentially eligible for reentry, we have begun using the term permanent deferral.

There is some issue of consistency over the last two decades, but still, that is the current concept whereas, if there is no opportunity for reentry under current guidance, we call it permanent.

I think we all recognize that scientific insights change, technology changes. So, guidance may change. So, calling it a permanent deferral does not mean that there will be no rethinking of the subject ever. It just means that there is no current opportunity to reenter.

DR. ALLEN: Thank you. Other questions or comments? Discussion points? Are we ready to vote on 1-A? Do you want to call the roll?

DR. FREAS: I will call the roll, and we will go around the table, starting with Dr. Klein.

DR. KLEIN: Yes.

DR. FREAS: Dr. Davis?

DR. DAVIS: Yes.

DR. FREAS: Dr. Quirolo?

DR. QUIROLO: Yes.

DR. FREAS: Dr. Whittaker?

DR. WHITTAKER: Yes.

DR. FREAS: Dr. Kuehnert?

DR. KUEHNERT: Yes, with the addition of my previous comments concerning NAT positive, and other test negative donors.

DR. FREAS: Dr. Harvath?

DR. HARVATH: Yes.

DR. FREAS: Dr. Lew?

DR. LEW: Yes.

DR. FREAS: Dr. Allen?

DR. ALLEN: Yes.

DR. FREAS: Ms. Baker?

MS. BAKER: Yes.

DR. FREAS: Dr. Manno?

DR. MANNO: Yes.

DR. FREAS: Dr. Doppelt?

DR. DOPPELT: Yes.

DR. FREAS: Dr. Schreiber?

DR. SCHREIBER: Yes.

DR. FREAS: Dr. Laal?

DR. LAAL: Yes.

DR. FREAS: Dr. DiMichele?

DR. DE MICHELE: Yes.

DR. FREAS: And the industry comment?

DR. KATZ: Were I permitted, I would have voted yes.

DR. FREAS: Thank you. That is a unanimous yes.

DR. ALLEN: Let's move on to question 1-B, which is essentially the same question but applicable to source plasma donors rather than whole blood donors.

DR. LEW: Can I have clarification? It is not quite the same, because you don't have --

DR. ALLEN: Sorry, the issue is the same, but yes, the testing algorithm is slightly different because the anti-core is not done. That is correct. Discussion? Questions? Are we ready to vote? Okay, Dr. Freas.

DR. FREAS: Okay, I will go around in the same order. Dr. Klein?

DR. KLEIN: Yes.

DR. FREAS: Dr. Davis?

DR. DAVIS: Yes.

DR. FREAS: Dr. Quirolo?

DR. QUIROLO: Yes.

DR. FREAS: Dr. Whittaker?

DR. WHITTAKER: Yes.

DR. FREAS: Dr. Kuehnert?

DR. KUEHNERT: Yes.

DR. FREAS: Dr. Harvath?

DR. HARVATH: Yes.

DR. FREAS: Dr. Lew?

DR. LEW: Yes.

DR. FREAS: Dr. Allen?

DR. ALLEN: Yes.

DR. FREAS: Ms. Baker?

MS. BAKER: Yes.

DR. FREAS: Dr. Manno?

DR. MANNO: Yes.

DR. FREAS: Dr. Doppelt?

DR. DOPPELT: Yes.

DR. FREAS: Dr. Schreiber?

DR. SCHREIBER: Yes.

DR. FREAS: Dr. Laal?

DR. LAAL: Yes.

DR. FREAS: Dr. DiMichele?

DR. DE MICHELE: Yes.

DR. FREAS: And the industry comment?

DR. KATZ: Yes, I think this is a very valuable approach that the FDA is giving us.

DR. FREAS: Again, a unanimous yes from the committee with the industry agreeing with the committee members.

DR. ALLEN: Dr. Biswas, point number two?

DR. BISWAS: Please discuss any alternative approaches FDA should consider.

DR. ALLEN: I would just make the comment that the discussion I overheard during the break was a question of whether if, for a source plasma donor, you have a positive NAT, whether there should be anti-core testing done, and I won't elaborate on that further, other than to make the comment for the record for consideration at an appropriate time.

Other comments or questions as requested under part two here? I won't call it a question. It is a request. It is not a question.

All right, I guess the committee has no further guidance for the FDA on this issue. This brings us to the close of agenda item number one and we are now 10 minutes ahead of schedule. Can we please be back here at 12:45 to reconvene?

[Whereupon, at 11:50 a.m., the meeting was recessed, to reconvene at 1:00 p.m., that same day.]

A F T E R N O O N S E S S I O N (12:57 p.m.)

DR. FREAS: I would like to thank all the committee members for making it back from lunch very promptly. We do appreciate that. Dr. Allen has done an excellent job keeping us on schedule this morning, but he has really got a challenge ahead of him this afternoon.

Before we get started, I have two brief announcements. The first one is, since the audience has changed in the afternoon, I have to make a brief addition to the conflict of interest statement regarding the rest of the meeting.

This announcement addresses the conflict of interest for topics two and three. Drs. Liana Harvath, Philip LaRussa and Jane Seward have been appointed as temporary voting members for the discussion of topic two.

Dr. Jerrold Levy and Dr. Michael Miller have been appointed as temporary voting members for topic three. Dr. Louis Katz is participating in this discussion as a non-voting industry representative, acting on behalf of industry.

The Food and Drug Administration has prepared general matter waivers for special government employees participating in this meeting who require such waivers under 18 US Code 208.

Regarding speakers, Dr. Mona Marin is a speaker for topic two, and is employed by CDC's national immunization program.

Dr. Karl Ljungstrom is a speaker for topic three. He is a scientific advisor for Swedish companies marketing clinical dextrans.

In addition, there may be regulated industry and other outside organizations speaking and making presentations.

These speakers have financial interests associated with their employers, and with other regulated firms. They were not screened for these conflicts of interest. Waivers are available under the written freedom of information act.

At this time, if I could, I would just like to introduce the two new temporary voting members. They are, on the right-hand side of the room -- that is the audience's right -- we have Dr. Philip LaRussa. He is professor of clinical pediatrics, Columbia Presbyterian Hospital, New York, New York.

On the other side of the room we have Dr. Jane Seward. She is chief of viral vaccine preventable diseases, disease branch, National Immunization Program, CDC. Thank you for joining us. Dr. Allen, I turn it over to you.

DR. ALLEN: Thank you. Topic two, the first topic for this afternoon, is the scientific basis for the review of varicella zoster immunoglobulin.

As we will learn very quickly, there is going to be a change in the production of this, and the committee is asked to recommend alternatives for the FDA and other government agencies. We will start with a background presentation by Dr. Dorothy Scott of the Food and Drug Administration. Dr. Scott.

Agenda Item: Scientific Basis for review of Varicella Zoster Immune Globulin. Background.

DR. SCOTT: Good morning. I will try, best as I can, to lay out the issues for you. What we are asking you to discuss is the scientific basis for review of a new varicella zoster immunoglobulin product.

First, I want to give you some background on the current product. VZIG, as it is called -- it is an IM product -- was licensed in 1981 by FDA.

It is an intramuscular preparation source from selected high anti-varicella antibody plasma units. In other words, all plasma units are tested that come in, and the ones that meet a certain titer cut off are used for this. So, it is a specific immune globulin.

The indications in the package insert are for prevention or modification of severe varicella disease in susceptible people, that is, people who have not had varicella before, in general.

These include immune compromise children and adults, premature infants, selected infants less than one year of age, and selected non-immune pregnant women and healthy adults. You will be hearing about these in more detail. It should be administered within 96 hours of varicella exposure.

How did we go about licensing VIG in 1981? That was a long time ago, but there was a clinical study. The study subjects are immune compromised children with household exposure to varicella. Many of these were cancer patients.

The trial design was random access, double blind study, but there were two comparators. Obviously, you couldn't blind the historical controls but, compared to the new VZIG product, were historical controls from a paper by Feldman et al, which was essentially the natural history of varicella infection in immune compromised children.

The other comparator was zoster immunoglobulin. This is an interesting product. It was an unlicensed immunoglobulin, although it was under study, and it was prepared from plasma of people that were convalescing from shingles. So, these would be adults who had been re-infected or have self-reinfected, if you will, with varicella.

Now, the problem with that is that it was very difficult to get people who were convalescing from shingles in sufficient quantities to get as much plasma to make as much product as was needed. That is why it is called ZIG. It was not pursued.

These are the results of that first study, which was considered the pivotal trial for licensure. I will just orient you to this slide.

What we are looking at is readouts or end points that signify severe varicella disease. These include pox count greater than 100, pneumonia, hepatitis, encephalitis and, of course, death. These are the comparators. The ZIG product, the zoster immune globulin, and the historical controls.

What you can see is that, if you compare VZIG to ZIG, you get a very similar rate of pox count greater than 100, in the 15 to 16 percent range, of pneumonia around four percent, no hepatitis, encephalitis, and no death.

Now, subsequent to this, there was another study that compared different doses of VZIG and, in your package insert, I believe that those numbers actually have the data from that second study as well.

So, these will be slightly different but the point is, really, in comparison to the natural history of this disease in immune compromised children, you have quite a great difference in terms of substantially less severe disease, pox count, and organ system involvement and, very important, fatalities.

So, what brings us to you today? Well, the sole U.S. manufacturer of this product is Massachusetts Public Health Biological Laboratories.

Their fractionation facility is scheduled to close. Dr. Ambrosino will be talking to you about the current supplies of VZIG and when we anticipate we might run out of that, and you will have an update in more detail about the supply.

The questions they are asking are, whether there are alternative effective therapies to prevent severe varicella disease. In other words, do we need VZIG.

The other question that we would like the committee to discuss is what scientific evidence would be needed to support licensure of a new product.

Dr. LaRussa is, again, going to go into this in detail, but I just want to put it out in front now. What are the possible alternatives to VZIG to prophylaxic and severe varicella infection.

There really are two kinds of candidates. One is the antiviral medications, such as acyclovir and other drugs in that family, and the other is immune globulin intravenous.

Now, why immune globulin intravenous? Well, just like VZIG, it is made from plasma of normal donors and, of course, it is not selected in particular for antivaricella antibodies, but it contains antivaricella antibodies, because most people, by adulthood, have been exposed to, and infected by, varicella.

What we did in advance of this is, we asked some of the folks at CDC to take a preliminary look at the titers against varicella that are in the different immune globulin products that are licensed.

So, these are your general immune globulin products that are used primarily for treatment of primary immune deficiency and ITP.

These are the results. This is from an assay called a GP ELISA. So, it is an ELISA against the glycoproteins of varicella which contain important neutralizing epitopes. This, incidentally, is the same kind of ELISA that was used for the vaccine studies.

Here we have the GP ELISA titer. It is times some dilution factor, and here we have the IGIV products, and here we have VZIG.

So, what you are looking at here is, the higher the titer, the more antibody in the product and for VZIG, here, we have a titer at the top and, for the other IVIG products -- we looked at eight different products.

I think you heard that there were five major manufacturers, but some make more than one IGIV, and these are blinded.

There are a couple of points here that I think are important. One is that there is lot to lot variation, both within one particular product, and among the different products.

What you can see here is, this is a titer in the 200 range, this is 800 and 400. Most everything fell into this general range, but what you are looking at is four to even eight-fold differences in titers, considering this is a serial two-fold dilution. It wasn't assessed more precisely than that.

So, what does this mean? This means that if you take any immune globulin off the shelf that is not a titered product, you don't know if you are going to be giving your patients something like this, or something like this.

The other thing that we don't learn from this is whether or not there are any differences in antibody affinity among these products or antibody function compared with VZIG.

So, now on to the licensure questions or, rather, what information would be needed to support licensure. There are many possible target populations for study.

Naturally, these will be exposed, presumably non-immune subjects, the kinds of people who would receive VZIG now.

For example, immune compromised children or adults or both, pregnant women for prevention of severe infections in the mother, but also neonates. I should have made that a separate line, for prevention of severe infections in children, or neonatal infections. Premature infants would be included, or non-immune, otherwise healthy individuals but, of course, the rate of severe varicella here is not very high.

So, our question to you will be, among other things, what populations would be the most informative or important to study, and I think you will get a lot of that information from Dr. LaRussa's talk to help you think about it.

Another question is whether surrogate markers can be useful predictors of efficacy. Well, where does that question come from?

Well, there are a couple of potential paths for licensure and, right now, FDA doesn't particularly favor one over the other, but one mechanism of licensure is based on surrogate markers.

This is defined in the CFR where you can have an approval based on adequate and well controlled clinical trials, showing that the product has an effect on a surrogate end point that is reasonably likely to predict clinical benefit.

An example of a surrogate marker study, for example, would be a pharmacokinetic study or comparison of one product to another, with a kind of measurement or output, a PK measurement of antibody titers, or antibody function.

So, that is what I am talking about in this situation when I say a surrogate marker study. It would still be a clinical study. You might not have to have the immune compromised populations but, again, that is something I think we would like to hear from the committee on.

Potential surrogate markers would include serum antivaricella antibody tests, and there are a number of these, which I have listed here, and Dr. LaRussa will mention as well.

They have varying ease and varying specificities. The GP ELISA, in particular, I mention because that is correlated with protection in vaccine studies, but the levels needed for protection in immune compromised patients are really unknown because, of course, the vaccine studies were on healthy subjects.

In vitro neutralization tests are also possible. These are typical plaque assay types of tests. Animal models are very difficult, because humans are the only natural host of this infection. Great apes can also be infected.

The animal models that have been described either involve normal cell cultures or ganglion cultures, and SCID human mice with human skin, as well as human systems.

These don't seem particularly practical to use as an assay in a case like this, where you would have multiple samples.

So, these are the questions we are asking you to think about. Please discuss what laboratory and clinical data would be sufficient to demonstrate efficacy of a new preparation of VZIG for prophylaxis of severe varicella infection.

In particular, we would like to have comments on which target populations are most informative, what surrogate markers would be appropriate for assessment of efficacy, and other considerations that you would have that you think are important for a clinical trial.

We would also like you to comment on whether the available scientific data support the use of IGIV or acyclovir as a substitute for VZIG for prophylaxis of severe varicella infection in any clinical setting.

We are very fortunate to have some excellent speakers who have worked with VZIG and with varicella for a number of years, in some cases.

First, we will hear from Massachusetts Public Health Biological Laboratories. Dr. Donna Ambrosino will discuss the supply situation and the discontinuation of manufacturing. Katherine Hay will discuss some aspects of manufacture that are important to know about for the sake of a new product.

Dr. LaRussa will tell us about severe varicella zoster disease, the correlates of protection, or rather, what is known about that, and post-exposure prophylaxis options.

Mona Marin from CDC will tell us about the ACIP and red book recommendations for post-exposure prophylaxis. Thank you very much, and I will take any questions.

DR. ALLEN; Dr. Lew?

DR. LEW: On the table that you showed us, actually the graph, you compared the levels by the GP ELISA titer in the different IVIGs. I am assuming you did this recently?

With time, as everyone gets immunized, all the children, and they grow up and they are the ones doing the donation, it may change.

DR. SCOTT: That is right, and in fact, based on the age of donors, we might expect that a lot of these people would not have been immunized and this reflects more the natural infection. That is absolutely the case.

I think the point that you are also making is that if we take you can take an IVIG off the shelf, or if we even say a certain product usually has high titers, that this could become a moving target one way or the other.

DR. SEWARD: I just want to comment that these tests were all done this year. They were all done earlier this year.

DR. SCOTT: Thanks to Scott Schmid, who works a lot on these viruses at CDC. We are very grateful to him for accepting the samples and running them.

DR. ALLEN: Other clarification questions for Dr. Scott? Okay, we will certainly have a chance to discuss that more fully at a later point. Thank you very much.

Why don't we, at this point, move on to the presentations by Dr. Ambrosino and Dr. Hay. Welcome, and tell us about VZIG manufacture, potency, testing, and the current supply status, please.

Agenda Item: VZIG Manufacture, Potency Testing and Current Supply Status.

DR. HAY: Good afternoon. I am Catherine Hay and, as Dr. Scott mentioned, we have been invited here to talk about the manufacturing process and the supply issues.

I will be discussing the plasma screening assay, the manufacturing process, and the potency assay, and then I will hand over to Dr. Ambrosino, who will address the supply issues.

As Dr. Scott mentioned, before any plasma is accepted for use in manufacturing, it is screened for the presence of antibodies to varicella zoster virus.

The assay that we use is a complement fixation assay and, for units to be accepted for further manufacturing use, they have to be positive at the one to 50 dilution. We are currently approved to use both recovered plasma and plasma obtained from phoresis.

The complement fixation assay is the standard -- it is an in-house assay, and it is the standard assay based on the CDC's method that is described in the reference given on this slide.

This slide just shows some recent data from our screenings of the last two years. The plasma is supplied by the American Red Cross, New England region, and these figures represent initial screens of random plasma samples.

You can see that, for both 2003 and 2004, the percentage of positives has remained fairly constant at around six percent.

On to the manufacturing process. Briefly, we use the Cohn-Oncley method, the cold ethanol precipitation process.

This is followed by a solvent detergent viral inactivation step. The product is then formulated to content 10 to 18 percent IgG at a pH of 6.4 to 7.2 and 0.3 mole of glycine.

This next slide is a very simplified manufacturing process flow diagram. You can trace the progress through the fractions from the plasma pool to the fraction three supernatant.

At this point, there is an ultra-filtration step which concentrates the product to seven percent IgG before it is subjected to the solvent detergent viral inactivation step using Trion butyl phosphate and Triton X-100.

After the TNBP and Triton have been removed by chromatography, there is a further concentration by ultra-filtration, and then the product is formulated, sterile filtered, and filled.

Before we release the product for distribution, we perform 11 assays on the final filled products, but the one that I want to address today is the potency assay.

We originally used the FAM(?) assay to perform this assay but, since 1984, we have changed to the Virgo Immunofluorescence assay.

We use a kit that is manufactured by Hemogen, and basically it is a slide test. The first step, you form your antibody antigen complex. You then add a fluorescein labeled anti-human antibody and, if there is a positive reaction, you get an apple green fluorescence.

We get positive and negative controls from the kit and the in-house standards is one of our previous lots of VZIG, and they are qualified for use by comparison to the previous standard.

We make two-fold dilutions of the test samples and the standards and run them in the assay, and the end point is the highest dilution showing a positive reaction. That is the apple green fluorescence.

In order for the assay to be acceptable, both the positive and negative controls have to meet predefined acceptance criteria, and our in-house standard titer has to be 8192 plus or minus one two-fold dilution.

For the final product to meet the potency specification, it has to be at least 80 percent of the in-house standard.

I just wanted to show you some potency data from some lots of VZIG that were manufactured from 1997 onwards. You can see that the titer of the lots remains fairly reproducible and constant throughout this time period.

That was my very brief overview of the manufacturing process, and now I will turn you over to Dr. Ambrosino to discuss the supply issues.

DR. AMBROSINO: One comment about the technical questions. We were hoping to keep that simple, but we do have a technical expert, Dr. Stan Cruz, who is the senior director of manufacturing and development, is here with us, and he and I could answer additional questions you might have. There are many, many steps to the fractionation.

Dot was kind enough also to allow us -- I only have six slides in four minutes -- to tell you why we stopped manufacturing VZIG, and I thought that was important for the committee to know.

The biological laboratories is the only non-profit FDA licensed manufacturer of both vaccines and biologics in the United States. It is a rather unique organization.

We have three product streams, essentially TD vaccine, which we make 20 percent of the United States need, we develop new monoclonal antibodies, and our third product line with blood products.

Now, we have a long past history, as you can see by these pictures, showing my office which, I must tell you, is pictured in that first picture, unchanged at the top of the hill there.

It was very clear to us some years ago that we needed a new manufacturing facility to continue to manufacture products. As you can see in the lower picture, our newer facility will open in the next year or so.

When we designed all that, we had to make some choices of how could we continue to manufacture the three product lines we had.

We decided we had already made a commitment for tetanus vaccine. There was a shortage that you all remember in 2001, and we had promised the Centers for Disease Control that we would continue to manufacture TD and, frankly, ramp up from one to nine million units of vaccine for the country. We thought TD vaccine was something we needed to preserve.

We also made monoclonal antibodies with these two missions in mind, orphan products, also known as too small for big pharma, and urgent public health need.

We have three or four of these products in clinical studies and manufacturing that we feel are crucial and, thus, we are committed to this new technology, monoclonal antibodies.

Then the final list, therefore, raw blood products, which we list here for you. Today we are only talking about VZIG.

We didn't take this choice lightly. This was a thoughtful, very intense with world experts joining us to make the final decision of what it would mean if we closed down fractionation.

After all of that, the group and, at the end, me, decided that it was the wisest thing to do to stop making blood products at the biological laboratories. We are only 150 people. Now we have grown to 300.

Given that, where are we with VZIG? I am showing in this graph here the distribution of VZIG by units. These are pediatric units. You divide by five to know how many adult doses you would need.

Bottom line, as you can see, since the development of the product by us all the way through the licensure, the need was going up.

As vaccine got licensed and chicken pox dropped dramatically in this country -- what a wonderful success story -- the number of immunocompromised people being exposed and, therefore, needing VZIG, dropped like a stone as well.

We are delighted, and the blue bars there show the last three years of actual sales. That data is the strongest and definitive.

As you can see, in the last year we dropped yet a half again, 20,000 the previous year, 10,000 units this last calendar year.

Ten thousand units means, divide by five, 2,000 adults were all that requested VZIG in the United States and Canada.

I have to tell you that is requested. We don't really know if those were used. Sometimes hospitals just buy this from our distributors and then it outdates. So, we don't really know how much is used, but no more than 2,000 adults last year were treated.

So, what is our current supply? I can give you very complicated numbers, but I have to tell you that what we do is, we are making a conservative estimate here.

We say, well, what if we sell exactly what was sold last year, assuming that is, in fact, an over-estimate, given that the disease continues to drop.

If we take that estimate of exactly what we sold last year, the supply that we have in hand will last at least through January. In fact, probably a few months longer than that, but we wanted to be conservative.

The pediatric doses, there used to be pediatric doses as well as adult. For the last six months, there have only been adult doses available. Therefore, the 600-something units, vials, are what is available, and this estimates through January are taking that into account.

In those very brief comments, I wanted to add that I also would be glad to answer questions after you hear from Dr. Marin and Dr. LaRussa. This was a very challenging decision for the biologic laboratories.

I am charged with making the decisions of what products we are making will matter the most and, thus, when we have to make difficult choices, at the end of the day, make the difficult choices, but we will be glad to tell you why we don't think we need VZIG any longer, but would obviously defer to the other speakers first. Thank you.

DR. ALLEN: Clarification questions for Dr. Hay and Dr. Ambrosino? I have got two quick questions. You showed -- Dr. Hay, you showed a slide that had the antibody screening, and only six percent were positive for antibody.

I assume that you continued just to get the recovered plasma from the Red Cross, rather than trying to identify specific donors and asking them to come back as source plasma donors.

DR. AMBROSINO: It is a complicated question. The answer is in between that. In fact, it is Red Cross that decides this.

I tried to get numbers, frankly, of has that percentage changed over the 20 years. We don't have accurate numbers because we can't, from the records, determine how many were known positives before that came back.

So, all I can tell you that that last number, that it is six percent, and it is a mixture, but we think it is around six percent of random donors.

DR. ALLEN: Okay, and the second question in the manufacturing process, your final liquid formulation is 10 to 18 percent IgG. I assume that that is adjusted to give you the titer that you want. Is that correct?

DR. AMBROSINO: No. The specs, the product is manufactured first into the final concentration. That is what is allowed, 10 to 18 percent. Actually, it is almost always 16 percent.

Then, once you have made the product at 16 percent, you then test the titer and the titer, as you saw, is always around the 8,000. You don't formulate to the titer, you formulate to the specs, that you want around 16 percent IgG for injection.

DR. ALLEN: Thank you.

DR. LA RUSSA: I just want to make a comment, in case anybody is left with the impression that only six percent of the adult population has lasting immunity to varicella.

The beauty of using complement fixation is that it is not a terribly sensitive test. So, you are actually screening for high titer units.

DR. ALLEN: Thank you for that clarification.

DR. KATZ: That is kind of my question because I am not familiar with the comp fixed titers. Approximately, what is one to 50 in a FAMA? Do we know?

DR. AMBROSINO: Similar, I think would be the fair assessment, similar, and it depends on how you run your FAMA. I think, to answer your question appropriately, similar. Dr. LaRussa, I think, will go over some results there that will specifically address that a little better in terms of when you give product to patients and measure in different ways, what do you see.

DR. LAAL: Are you making murine monoclonal antibodies or human monoclonal antibodies?

DR. AMBROSINO: The question is what kind of monoclonal antibodies. We are making only human monoclonal antibodies to SARS, C-difficile, as well as rabies at the moment.

DR. LAAL: So, you have not considered making human monoclonal antibodies to this?

DR. AMBROSINO: I think it is a very good question. We did consider it, and our judgement, frankly, is that it is not a wise path. We really feel that IVIG used in the right way will, in fact, substitute and is a good alternative. I only said that because I was asked the question.

DR. EPSTEIN: Can you comment on the correlation between the comp fixed titer and the GP ELISA titer?

DR. AMBROSINO: Not well. I can tell you -- Dorothy, maybe you can tell me if I remember correctly -- the range in titers there, for the VZIG, and I don't have that up here, were done as GP ELISA for that product.

I can tell you that product had an 8,000 or so titer by our test, the kit, essentially. I think if you look at that then -- Dorothy, do you remember what the VZIG was on that graph -- 9,000? So, close.

DR. ALLEN: Other questions for clarification? They will be here later in the discussion. So, we can certainly come back to you for a resource. Thank you very much.

The next presentation will be by Dr. Philip LaRussa, severe varicella zoster disease, correlates of protection and post-exposure prophylaxis options. It will be a 45-minute presentation.

Agenda Item: Severe Varicella Zoster Disease, Correlates of Protection and Post-Exposure Prophylaxis Options.

DR. LA RUSSA: My job today is to remind you all what varicella used to be like before we had an effective vaccine, to tell you a little bit about what the vaccine has done to the epidemiology of disease, tell you what little we know about correlates of protection, and then discuss some of the options for post-exposure prophylaxis.

At the end of the presentation I added a bunch of slides to sort of fill out some details on some of the options, because we won't have time to go over every study that was ever done.

I think it is probably worthwhile spending a minute talking about the pathogenesis of varicella, because it makes it a little easier to understand why some preparations work at some points and not at other points.

What we think is going on is that you come in contact with the virus probably mostly through the mucosa of the oral pharynx.

Then pretty quickly we know that virus gets into the lymphocytes and the regional lymph nodes, and there is a short period of replication there, probably a day or two.

Then there is a small primary viremia that spreads the virus and, for lack of a better term, to anywhere where there is a reticular endothelial system, probably tissue monocytes and macrophages.

The virus then lays dormant there for a while and just prior, probably 24 to 48 hours, before the individual develops rash, there is really a large secondary viremia which we think spreads the virus to the skin, and then you develop the rash.

So, you really have two opportunities for post-exposure prophylaxis. One is to effect this small primary viremia in the beginning, and the second is to effect this larger, secondary viremia much later on.

I will give you the punch line now, is that we think VZIG probably works at this point, because once you give it beyond this point, it doesn't seem to have a whole lot of effect.

We think the antivirals probably work at this point. It is kind of interesting. You will see that, although they don't do a whole lot to decrease the frequency of infection in individuals who are exposed, they do quite a good job in preventing severe disease, and probably what they are doing is limiting this secondary viremia.

So, this is a typical case of varicella in the normal kid. This was actually my son, and he developed over 300 lesions. The average is about 300 in the normal kid.

You can get new crops of lesions for up to a week afterwards. Usually then the lesions crust over and the crust eventually falls off.

It can be quite an annoyance to the child, and also to the parents who have to take care of that sort of cranky individual.

The other thing I should say is that there is quite a variation in the range of disease, from kids that have five lesion and absolutely no constitutional symptoms to kids with much more severe disease, that I will show you in a minute.

I wanted to show you this. This is from Ave Ross' study in 1962, just so we cement the idea that varicella is highly contagious.

In his study, 81 percent of the children who had a household contact with a negative history came down with disease.

Zoster is the reactivation of latent virus as you get older and your immune system stops working as well as it should.

You get a reactivation in the dermatomal distribution that represents reactivation from the dorsal root ganglia.

As you all probably know, there has been some very exciting news about the effect of a high titer varicella vaccine in limiting reactivation of virus, and hopefully we will be doing more of this in the future.

So, what about healthy kids? How severe can disease be? In the pre-vaccine era, the severe complications were things like cerebellar ataxia, which occurred in about one in 4,000 kids who developed varicella.

Encephalitis developed in about one out of 50,000 kids with varicella. All the ataxias pretty much got better, although sometimes it would take months for that to happen. Many of the kids with encephalitis were left with permanent damage.

Hemorrhagic varicella occasionally occurred in a healthy child, but a more pressing problem was invasive group A strep infections and, at one time, it was estimated that about 13 percent of invasive group A strep infections occurred within a month after varicella.

These are the old figures from the old pre-vaccine era, 10,000 to 15,000 hospitalizations per year, 50 to 100 deaths per year, and about half of these in healthy adults.

This is a healthy child. I took care of this kid. We worked this kid up for probably six months afterwards to figure out what immunodeficiency she had that caused such severe varicella.

Eventually her mother got disgusted with us and took her away, and she essentially was the other end of the bell curve in terms of lesions.

Immunocompromised individuals have different problems, and I want to go over a couple of these studies, not so much to tell you what you already know, but when you start to look back at the old literature, which a lot of the recommendations for VZIG are made, you get to start to see the holes and gaps in knowledge.

So, Sandy Feldman did a study where he looked at kids with cancer. Most of these were leukemic kids. This was in the pre-chemotherapy era. About a third had severe disease, and about seven percent, altogether, died. Again, pretty small numbers.

He went back again and looked in the post-chemotherapy era, and showed that treatment, at least with acyclovir, the frequency of severe disease decreased.

There is a common base that is buried in the back of this paper where he says something like, even with the availability of high titered anti-varicella immunoglobulin preparation, the incidence of varicella in the immunocompromised children has not changed much over time, although the incidence of severe varicella with pneumonia decreased.

I think that is something we need to remember when we start to think about replacing VZIG, is that this is not a product that always prevented varicella. What we relied on it for was preventing severe disease, and I think you need to keep that in mind when you start designing new products.

I have the HIV infected kids down here on the list. In fact, those kids now do pretty well. Our problems with them was more chronic disease than severe and fatal disease, and now that they are all on highly active anti-retroviral therapy, they actually do very well.

I just mention that when their CD4 counts are over 25 percent, and they are susceptible to varicella, we actually vaccinate them.

Neonates are also a problem, and older studies describe 30 percent mortality in the period of time when the mother had varicella four or five days prior to delivery and, in some studies, two days after.

We think why it is that period that is a problem, in essence, at that point in time, the fetus gets a large intravenous load of virus, but the mother has not made an antibody response yet.

If, in fact, you look at infants whose moms had varicella, let's say seven, ten or 14 days prior to delivery, in essence, those babies get virus and antibody at the same time. They still develop varicella, but they don't develop severe or fatal disease.

Normal adults also get more severe varicella. There was one study where the mean number of lesions in adults was about 400 compared to about 300 in children, and I will show you some cases.

This is a child at our institution who had varicella and leukemia, and you can see he obviously wasn't doing very well. These are hemorrhagic lesions here.

I only show you this is because, if you are thinking in the back of your minds that we can get away with using antivirals for treatment, and that we don't need to prophylax, what I will tell you is that varicella goes so quickly in the immunocompromised patients that you often don't have time to treat or, if you do treat, your treatment is ineffective.

I just want to make the point that prophylaxis is a very important thing. This is a child with juvenile rheumatoid arthritis who is on a bucket of steroids, came in with varicella in the early afternoon, and was dead by that evening.

Healthy adults, again, I just want to make a point. If you look at what their problems are, hemorrhagic varicella, pneumonia, they are all getting their varicella from children or family members who are children. Hopefully, there will be less of this in time, but just remember that even young adults are relatively immunocompromised to herpes viruses compared to young children.

This is the adult. This is actually an old slide of Dr. Gershon's from Bellview. This is an adult with severe varicella. Here is his x-ray, and you can see the classic bilateral interstitial pneumonitis.

What about pregnancy? I think when you talk about prevalence, you have to remember not to forget the mothers. What happens is that obviously they are adults, and they will be at risk for severe varicella because they are adults.

You also have to remember that there are studies showing that there is a progressive increase in specific immunodeficiency toward herpes viruses as you go from first to second to third trimester.

So, pregnant women may be even more at risk for severe varicella than age matched non-pregnant women. Then the other thing I want to mention here is, if you think this problem is going to get to be less important as time goes on, just remember that a lot of our varicella susceptible women come from tropical countries, and there the incidence of varicella is much lower. So, we have a higher pool of susceptible women coming in from those regions.

This is a typical case of congenital varicella. The usual story here is the mother develops chicken pox during the first or early second trimester.

This has rarely happened when the mother develops zoster, but almost all these reports are with maternal varicella, atrophy and hypoplasia of the limb. This child had visceral disease and obviously did not do well.

This is varicella around term. So, this is when the mom develops varicella in that risk period I talked to you, five days before, two days after, and you can see that this child developed fatal hemorrhagic varicella.

Finally, the last thing that you need to remember is that children who are exposed to varicella in utero, that is their first contact with the virus.

It has been estimated that up to 18 percent of those children who were actually infected in utero will go on to develop zoster during the first year of life.

So, one slide to show you what varicella with vaccine has done to the epidemiology, these is Jane Seward's slides. There are more updated slides.

The important point here is the downward trends. What I think I need to remind you of is this vaccine has been extraordinarily successful, despite what you may read in the paper or elsewhere.

I think this program is being tweaked to make it even more successful, but my hope is that we are going to see less and less varicella as time goes on.

I can tell you, in northern Manhattan, where I practice, it is now rare that I get called about children with varicella. So, it really does work, even in inner city populations.

Now, it comes to the less satisfying part, where we talk about correlates of protection. I am going to try to give you examples here that point out some themes.

So, the first attempt was by Ave Ross in the 1960s, and basically what he did was, he looked at secondary contacts of individuals who had varicella.

He did this by history. If you were history negative, then you were assumed to be susceptible. If you were history positive, you were assumed to be immune.

Using that kind of definition puts a little bit of noise in the system that you wouldn't have if you had looked at serologic titers.

Be that as it may, he showed that you could use immune serum globulin to sort of temper the severity of varicella, but it didn't do a whole lot to prevent varicella.

What he did show was that the more immune serum globulin you used, the more likely you were to have milder disease.

Gershon, in the 1970s, compared zoster immune globulin and immune serum globulin. What they did was, they looked at two preps of zoster immune globulin.

You can see that the titers here were about 5:512 to 1:1024. These are within one tube of each other. So, they are pretty similar.

Compare that to immune serum globulin that had a titer of 1:128. I think these were done -- this is 1978. It was probably done by complement fixation. I am sorry; it was FAMA.

Basically, why I show you this is that this is the first attempt to try to figure out what is going on in the patient.

With this dose of ZIG, all of the exposed individuals seroconverted, although there was quite a range. This is the geometric mean titer here.

About half of them came down with disease, but all of them had mild disease. With this preparation, almost all of them converted, but some of them didn't. The geometric mean titer was lower.

Here is the first attempt to look at what happened in the patient. In the few did that did not have a seroconversion, two of three of them came down with severe disease, where all the ones that did have a seroconversion, all of them had mild disease, and the attack rate was about 50 percent.

They then compared that to immune serum globulin, one titer, but two different doses. Basically, what they found here is that everybody converted. The geometric mean titers were a bit lower than here, and there was some varicella, but all of it mild.

Her conclusion from this was that, if you were very careful about the lots of immune serum globulin that you used, you probably could get away with using some of it.

Now, Walter Orenstein, in 1981, took this a little bit further. Basically, what he showed was that, if you looked at recipients of zoster immune globulin who had a four-fold rise in CF titers at 48 hours, compared to those that didn't, the ones that had the four-fold rise were less likely to develop varicella than those that did not show it. So, 22 percent versus 44 percent.

What he said in the paper was that 45 of the 48 of the four-fold rises were from less than two to four. What is interesting about that is that there is this background of people with positive CF titers that still come down with disease.

We tend to think about complement fixation as a relatively insensitive test, and I am not bothered by someone who is comp fixed negative and positive by a more sensitive assay, but it was a surprise for me to go back and see that the specificity of comp fix was not that great, at least at these titers.

Walter also showed that, if you got high titered ZIG, you were more likely to have a four-fold rise in titer, and that complications were more complicated in recipients of low titered ZIG.

So, again, this is evidence that the more varicella specific antibody you give, and the higher the titer the patient ends up with, the more likely you are to impact the severity of disease.

It is interesting that John Zaya, in a 1983 study, could not find a correlation with infection rate and titers at 48 hours post-administration. Some of that may have been due to small numbers.

So, what do we know about the correlates of protection? Well, we can say pretty convincingly that if you have a FAMA titer less than two, that you are going to be susceptible and likely to come down with disease.

The problem is, what do you say about people who have positive titers, whether they are positive FAMAs, positive GP ELISAs or positive other tests?

The confusion here is that most of the data we have here actually comes from either vaccine trials or people that had wild type disease earlier in life.

The problem here is that you are trying to focus in on antibodies, which are obviously important for this question of prophylaxis, but you can't separate out what the effect of the cell mediated immune response is.

We know that is important. We first noticed that many years ago when people noticed that children with A gammaglobulinemia and hypogammaglobulinemia did perfectly fine when they developed varicella because they had an intact cell mediated immune system.

A second piece of evidence -- this is, again, from Ann Gershon's vaccine studies in the leukemic kids -- again, very, very small numbers, but she looked at leukemic vaccinees who had either different combinations of positive antibody in CMI, varicella specific CMI, at the time of exposure and found that, if you had neither, you didn't do well as far as the attack rate.

If you had both, you did do pretty well, but you could get away with antibody and still not come down with disease most of the time and, if you had CMI, that was also good.

Again, I don't want to make too much of this because the numbers are so small, but the bottom line is, everything we look at in terms of vaccine data is really sort of clouded by the cell mediated immune response.

So, what are the options? Let me just say first here that neither of these -- I put these here just to be complete. Neither of these, I think, should be considered as an option for the reasons that I have talked about before.

So, what about intravenous gammaglobulin? There are some advantages. There is some data to support its use, and I will show you some of that in a minute.

Currently, it has good anti-varicella antibody titers, and if we figure out what the appropriate dose is on a per milligram of IgG dose, we probably can do a pretty good job with IVIG, and we will probably need something in this range.

We can argue about whether this is 200 to 400, and I put the volumes here, so you can start to think about what that would mean to small children.

It is usually in ample supply, although that is not always the case. Last year we did have shortages of IVIG, and did have to come up with a hierarchy of who was going to get it and who would not.

There are problems on the other end, and when I mean the other end, the people who are going to use the IVIG and the patients who have to get it.

Cost and difficulty of administration, you need to put an intravenous line in to give it, you can't give it quickly, you have to run it in slowly.

You may at least want to think about the volume of administration in newborns, if you are going to give eight mls per kilo to a three kilo kid, that is 24 ccs. That is a decent volume of fluid, not something that is a huge problem, but we should think about it.

As was talked about before, it is not titered for VZV antibodies. So, it will be a moving target as time goes on.

Not only as time goes on, but from lot to lot, and this is obviously going to happen as antibody titers go down over time.

This was one paper in the literature from 1984, and these were oncology patients who were susceptible, but they had not been exposed. Again, very small numbers, given either VZIG or two different quantities of intravenous gammaglobulin.

The findings were that the antibody titers were good for four to six weeks after IVIG, and were equivalent to the titers measured at three to four weeks after VZIG. So, what that means is you got to the right level and you actually kept it there for a longer period of time.

The maximum antibody titers were similar in all three groups, but they were achieved more quickly with IVIG. So, there is some potential advantage there.

I will just quickly go through a couple of these studies in high risk individuals. Again, very, very small numbers, five kids here, given IVIG at 200 milligrams per kilo within three days, no varicella after seven exposures, 52 pages with 79 exposures, prophylaxed within six to 24 hours, and they did relatively well. Although there was some infection, the varicella was mild.

I just wanted to point this out. This is another approach that some people have used, is to give VZIG at the time of exposure and give IVIG later on.

Some people have also given VZIG and then, in the second half of the incubation period, also given an antiviral to try to cover all bases.

When you look at your presentation, just correct your spelling. This is Ferdman, not Feldman, as I put in the handout.

This is just one of those cautionary tales of three patients who developed varicella. They were getting, I think, monthly IVIG and they had received their last dose seven and 11 and 30 days before exposure. All of them were mild.

It just reminds you that you do need an intact immune system to have a good response to varicella, and that you shouldn't expect that these preparations are actually going to prevent varicella.

I put vaccine here just for the sake of completeness, but also because healthy adults are in your high risk groups, and we may at least want to think about doing some studies where we potentially could use vaccine in healthy adults.

There is some data in the paper that Barbara Watson and Jane Seward wrote. They looked at kids 13 years of age or less, and gave vaccine at less than 36 hours post-exposure.

This was done, I think, on the basis of history -- right, Jane, not serology -- and none of the 42 vaccinated kids came down with varicella as opposed to one of the unvaccinated kids. I did not include an effectiveness analysis up there because of those numbers.

The advantage here is that you are giving long-lasting protection. So, it is not temporary, like you would have with an immune globulin preparation, and it is easy to use.

The disadvantage, it is not appropriate for immunocompromised patients, pregnant women or newborn, and we really don't know what the efficacy would be with one dose in adults.

That is something we should look at, but remember, we need two doses of vaccines in adults and adolescents over the age of 13 to get a good immune response. So, I don't know what one dose would do, but I think it is something we should look at.

What about antivirals? Well, there is some data in healthy children, and I will show you some of that. There are good antiherpes antivirals available, and the major advantage of this is that, if you have missed the window where you can give an immune globulin preparation, you can still come back and give an antiviral for prophylaxis.

The disadvantages are that there is really limited data in immunocompromised patients. They are class C drugs in pregnancy.

I would be very hesitant to use them by the oral route in the newborns, not knowing whether they would be absorbed, although there is one study that did do that.

Most of the data is with acyclovir, absorption of POA cyclovir runs about 18 percent at best. When we used POA cyclovir for treatment of varicella in immunocompromised patients, we used a dose that was four or five times the recommended dose, so that we would get the appropriate levels, and that level of drug causes a decent amount of GI upset.

So, you might way, well, we have FAM cyclovir and VAL-A cyclovir that have PO absorptions of about 70 percent. The problem is, there are no liquid formulations of those. So, you would limit its use in young children and infants.

Finally, and sort of a contrast with what you have with immune globulin preparations, where you give it and you know the person has gotten it, here you are relying on the person to take this drug for a multiple day period and, I think outside of the study setting, you might get lower efficacy than you have seen in some of the studies.

Now, the studies that were originally done in Japan were actually not done to test its usefulness as a prophylactic agent.

They were actually done to test the hypothesis that there were two viremias during varicella, and that the second one is most important.

So, the original study looked at this by giving acyclovir in the first three days, six to 10 days after exposure, and no acyclovir.

Where you can see that the infection rates were not a whole lot different, the clinical attack rate was much lower with the six to 10-day period, which would roughly correspond to when the second viremia is, and clinical disease was described as milder. So, we think that is where the antivirals are having their effect.

So, what about VZIG? Its advantages are that its benefits and its limitations are well understood, and we have a lot of experience with this.

It is useful in those that can't be vaccinated, or when antivirals are not appropriate, and it has a small volume. The disadvantages are why we are her today, so I won't dwell on those.

So, then what I did was, I went back to the high risk groups and I said, if I had my choice, what would be my first choice, what would be my second choice and what would be my third choice. I have to tell you, this is purely my personal opinion, it is not the result of any expert panel review.

For the immunocompromised patients, I would still like to use VZIG. I think we could probably get away with IVIG at the appropriate dose, and I think antivirals might work, although my guess is, I would want to see studies to see if they did work, or I would want to see studies where these were used in combinations, one of these plus an anti-viral.

Neonates, I think VZIG is the core choice. Again, we could probably do with IVIG if we had to. I really don't know about antivirals.

Pregnant women, again, probably VZIG, and we probably could get away with IVIG. Other adults, the same. In fact, we might want to think about vaccine studies at this point. I would not recommend that we try that as a substitute without studies.

In summary, I think there probably still is a need for VZIG. I think IVIG is probably equivalent in the appropriate dose, although we will have to do those studies.

Antivirals may be useful, especially in the post-VZIG window, and I think vaccine will be of limited utility as a substitute. Thank you.

DR. ALLEN: Excellent. Thank you for a very nice overview. Clarification questions for Dr. LaRussa?

DR. SEWARD: I have a comment on the -- can you go back to the slides on IVIG, the study with the largest number?

I mean, you know, these studies of post-exposure use of any product are as good as the exposure data are strong.

Household exposure data, you really do expect eight or nine out of 10 exposures to result in disease. The numbers here, the second study with 52, is hospital exposures, and there is no control group.

So, unfortunately, the data are really very, very slim in being able to interpret this as being evidence that it works.

You might expect, perhaps you might guess, that the attack rate might be 20 to 30 percent. So, in fact, you may have a half or a two-thirds reduction, but there isn't any control group.

DR. LA RUSSA: This really needs to be studied. It makes sense to me that, if you give the right amount, it should work.

The other problem you should be cautious about in looking at studies in immunocompromised patients is that lots of those patients now get prophylactic acyclovir to prevent CMV infection and other things, or they may get prophylactic gancyclovir, which is highly active against varicella. So, you really need to look at all of these things.

MS. SEWARD: My other question is, I know the recommendations are for use of VZIG in healthy adults, but realistically, do you use it for that?

I get questions -- at CDC we get lots of weekend and night questions about pregnant women exposures, but we never get a question about a healthy adult. So, I suspect it is not being used for that purpose much.

DR. LA RUSSA: I see all the disasters, and I actually think it should be used for healthy adults. My adult colleagues are sometimes of the opinion that, why don't we just wait and see what happens and treat the individual.

I have just seen too many people on respirators with varicella pneumonia to think it is worthwhile saving a couple hundred bucks to see if that is going to happen, but you are right, a lot of people don't do that.

DR. DOPPELT: From a practical standpoint, getting back to the vaccine, how easy or difficult is it to administer within 36 hours of exposure?

DR. LA RUSSA: The question is, how easy or difficult to administer within 36 hours. That is tough. It really depends. The study that I showed you was done in a closed population in a shelter. Right, Jane?

DR. SEWARD: Yes, but there is plenty of data from Japan and other first exposure data in children, very nice, controlled data showing that, within 72 hours, the vaccine prevents 90 percent severe disease, and sort of maybe even up to 70 percent out to five days.

I think if somebody presents within three days, you can give it. As Phil said, with adults there isn't the same data.

I think the currently formulated varicella vaccine, about 90 percent of adults respond after one dose. So, we might expect that it is not going to be bad, and I think it is a pretty good option for healthy adults.

DR. ALLEN: What about immunocompromized children, though?

DR. SEWARD: No, you can't give it. They are the big problem group.

DR. LA RUSSA: The thing with the immunocompromised children is that we really -- well, that also is a landscape that is going to change.

If you think about what is happening now, we have had vaccines since about 1996 and, since most of the use of VZIG for immunocompromised children was in kids with leukemia, the mean age of leukemia, onset of leukemia, is about four to six years of age.

In a sense, we have already sort of tempered that problem, I hope, because now we are going to have a bunch of kids who are vaccinated as healthy kids, who are becoming immunocompromised some years after, and I think we are going to have to look at what happens to them. No, I would not vaccinate a severely immunocompromised patient at the time of exposure.

The other point, obviously, is that neonates would not have had a chance to get the vaccine. On the other hand, if the vaccine is used in the upcoming cohort, we should, we hope, have fewer and fewer susceptible women who would become infected late in pregnancy.

DR. SEWARD: I am not sure that is the case. Pre-vaccine era, only about five percent of adults were susceptible. We will be lucky to achieve that with the vaccination program as well.

MR. LA RUSSA: As I mentioned, in New York City, most of our susceptible women come from areas of the world where the vaccine is not available, and the rate of seropositivity for young adults is much lower than it is in the States. I think we are going to have an ample supply of those.

DR. ALLEN: Dr. LaRussa, let me ask you, what is used for VZIG in Europe, other countries around the world? At least I assume that the supply for Massachusetts is predominantly distributed and used within the United States.

DR. LA RUSSA: I don't know that I could answer that question. I know VZIG-like products are available in Europe, and in Canada there is a manufacturer.

In parts of Southeast Asia, nothing is available. People either do nothing or they use antivirals as an option, nothing that becomes a potential alternative source to be used within the United States, however.

DR. SCOTT: I think I can answer that question. If you look at the web and you look at some of the papers that are available that have been published, what you can see is that current licenses are held by Commonwealth Serum Laboratories in Australia, by Cangene in Canada, by Biatest, by Bering Verka AG(?) in Europe, and by BPO in the United Kingdom.

So, there are other companies that are licensed for this, and it is my belief that some of these are making lots at a low rate.

Some of these certainly could use U.S. plasma, if that became a question and, as everybody knows here, the United Kingdom is already using U.S. plasma for its products, and certainly so are some other manufacturers.

DR. SEWARD: I have another question on IVIG. What would be the procedures for the FDA to change requirements, to require a certain level of varicella immune globulin in there, as they do currently for measles and some other parts of the product?

DR. SCOTT: The purpose of requiring those titers in the products originally was lot to lot consistency and looking at the biological function of antibodies, to make sure that it was intact.

The purpose wasn't really per se to prevent measles or diphtheria, although obviously those would be desirable.

So, back when that lot release testing decision was made for the CFR, people looked at titers of antibodies that you would expect to be in immune globulins, and selected some of those to use for lot to lot consistency, and for antibody function.

Now, in terms of what would we -- what is one of the approaches? The typical approach for licensing for an indication now is to have a clinical study, and rather not to just titer a product and say it is okay for this.

DR. ALLEN: Okay, other questions or comments for Dr. LaRussa? We will have a chance to come back and discuss this more broadly later. Thank you very much, a very nice overview.

Our next presentation is by Dr. Mona Marin, medical epidemiologist with the national immunization program at the Centers for Disease Control. The topic is advisory committee -- well, ACIP, advisory committee for immunization practices, recommendations for post-exposure prophylaxis of severe varicella infections. Dr. Marin.

Agenda Item: Advisory Committee for Immunization Practices Recommendations for Post-Exposure Prophylaxis of Severe Varicella Infections.

DR. MARIN: Good afternoon. So, I will be presenting today the current recommendations for post-exposure prophylaxis in varicella infection.

I will start with two slides that are not in your handout, and I apologize for that, but I want to give you a broader perspective of what we can use for post-exposure prophylaxis.

So, there are two interventions, vaccination and varicella zoster immune globulin. Only shortly about vaccination, varicella vaccine is recommended for healthy, susceptible persons aged 12 months or older.

It should be administered within three to five days post-exposure, and there was here quite a discussion regarding its effectiveness in preventing disease within thee days, but it can be administered up to five days, being effective in modifying the severity of the disease.

Now, regarding recommendations for VZIG, I will first present general indications for the use of VZIG, and then the recommendations of the advisory committee on immunization practices.

I will go over some special situations that are mentioned in the recommendations of the committee on infectious diseases of the American Academy of Pediatrics, published in the red book, and I will end with some recommendations of other expert groups.

As far as general indications for the use of VZIG, ACIP and AIP indicate that the decision to administer VZIG post exposure to varicella zoster virus should be based on whether the patient is susceptible, either by lacking recommendation of vaccination or by having a negative history of disease, the exposure is likely to result in infection, and the patient is at greater risk for complications than the general population. I will next give some details for each condition mentioned here.

As far as susceptibility to varicella, the most recent available data are from seroprevalence studies from the pre-vaccine era, NHANES, which is the national health and nutrition examines survey.

They used an immune assay to detect the IgG, but the epidemiology of disease since then makes us believe that these data are still accurate, especially for adults.

So, by age group, for children age six to 11 years, 86 percent of them are immune, and for those 12 to 19 years, 93 percent of them were immune.

As far as adults, as you can see, five percent of those age 20 to 29 years were susceptible. One percent of those, 30 to 39 years, and an average about .5 percent of those aged 40 years and older.

Another key element in assessing the need for VZIG indication is exposure to a varicella zoster virus, therefore, defining what exposure is, is important.

Unfortunately, the literature data do not support an absolute definition of exposure. In the ACIP guidelines, in the red book, there are included the following types of exposure for which VZIG is indicated for susceptible persons.

Households, that is, residing in the same household with a patient, employment, face to face indoor play, and here experts differ in opinion about the duration of face to face contact that warrants administration of VZIG.

Some suggest a contact of five minutes or more constitutes a significant exposure for this purpose. Other experts consider a close contact at least one hour.

Hospital exposure to a case of varicella is considered being in the same two or four bed room, or adjacent beds on a large ward, or face to face contact with an infected staff member or patient, or a visit by a person deemed infectious.

Exposure to a herpes zoster case is considered as having an intimate contact, such as hugging or touching with an infectious person.

For newborns, exposure is considered onset of varicella in the mothers five days before, or less, or within 48 days after delivery. VZIG is not indicated if the mother has zoster.

The groups identified to be of greater risk of varicella complications, and for which ACIP recommends VZIG are for persons aged less than 13 years, immunocompromised children, including children who have primary and acquired immunodeficiency disorders, neuroplastic diseases, and receiving immunosuppressive treatments.

Data are limited regarding whether routine therapy with immune globulin intravenous yields the persistence of a sufficient passively acquired VZV antibody to protect susceptible immunocompromised persons who become exposed to VZV.

ACIP recommends that these persons, or immunocompromised persons who receive regular IGIV should be administered with VZIG if exposed to wild type varicella zoster virus.

Other recommended groups are neonates whose mothers have signs and symptoms of varicella within five days before to two days after delivery.

Neonates exposed post-natally, specifically, premature infants born to susceptible mothers, because their immune system may be compromised.

These infants should be considered at risk as long as they are hospitalized, and premature infants who are less than 28 weeks gestation or weigh less than 1,000 grams at birth, and who are exposed to VZV should receive VZIG regardless of the maternal history.

VZIG is not recommended for healthy, full term babies who are exposed post-natally, even if the mothers do not have a history of varicella disease.

For persons aged 13 years or older, VZIG is indicated for immunocompromised adolescents and adults. For healthy, susceptible adolescents and adults, although varicella disease is more severe than in children, the decision to administer VZIG should be made on an individual basis.

In this case, VZIG is administered mainly for modifying, rather than preventing, the disease, hoping to induce a life-long immunity. Other high risk groups are susceptible pregnant women and hospital personnel.

In addition to this recommendation, as they are listed here, they are ACIP recommendations, but we can find them quite in the same way in the AIP guidelines.

The AIP mentions in their guidelines some special situations, and these situations refer to patients receiving immune globulin intravenous.

AIP considers that patients receiving high dose IGIF, 400 milligrams per kilogram or greater, are likely to be protected, and probably do not require VZIG if the last dose of IGIV was given three weeks or less before exposure.

Another special situation is that of patients with bleeding diathesis, and AIP recommends that use of VZIG for patients with a bleeding diathesis should be avoided if possible, and IVIG would be an acceptable alternative in this situation.

As far as prophylaxis of healthy adults, AIP considers that VZIG can be given to healthy, susceptible adults after exposure to varicella, but their discussions were here.

VZIG is not routinely recommended. For this situation, AIP would favor administration of vaccine, and if the vaccine is contraindicated, or more than 72 hours have elapsed since exposure, then a seven-day course of acyclovir administered late in the incubation period, seven to nine days after exposure, is recommended by AIP.

In the end, recommendations made by a group of experts regarding post-exposure prophylaxis of recipients of stem cell transplants, varicella zoster virus causes high morbidity in these patients.

There are some recommendations of ACIP regarding prophylaxis or prevention of opportunistic infections in recipients of stem cell transplants, but there are some issues that were not addressed. So, a group of experts was formed to come with consensus recommendations regarding some issues.

One of them is post-exposure prophylaxis against VZV infection in these patients. In their recommendation, the experts stated that extensive clinical experience indicates that acyclovir and valicyclovir are highly effective in preventing VCV activation in transplant recipients, and recommended that, because VZV infection is severe, and VZIG is not 100 percent effective, post exposure prophylaxis with valicyclovir or acyclor, as you can see, between days three to 28 post-exposure be considered, in addition to VZIG to all VZIG sero-negative recipients of hematopoietic stem cell transplants. That is all I have.

DR. ALLEN: Thank you very much. Questions or comments for Dr. Marin's presentation? Okay, no specific questions, thank you very much. Please, if you can, stay for the discussion. We may ask for some clarification.

At this point, we have finished our formal presentations. We are supposed to move to the open public hearing. I do not have a list of any speakers who have requested to speak. Does anyone wish to speak at the open public hearing? Would you identify yourself, please. .This is pertinent to this topic?

Agenda Item: Open Public Hearing.

MR. SINCLAIR: Chris Sinclair, Cangene Corporation. I would like to partially address Dr. Case's question initially.

Cangene is the manufacturer of the varicella zoster immune globulin product in Canada, and we are currently moving forward to fill the unmet need in the Canadian market place, and we are looking at, and evaluating at this point in time, to filling the unmet need of the varicella zoster immune globulin in the United States.

I just wanted to maybe address or make comments to each of the three points of discussion, if I could. With regard to the surrogate markers of efficacy, we do believe that a surrogate marker of efficacy, such as antibody levels in patients following administration, would be an appropriate way of evaluating varicella zoster immune globulins in clinical studies, especially given the difficulties in conducting these studies, as we have heard many times over and over here, that varicella zoster immune globulin does not prevent infection, it just will reduce the severity of infection.

With regard to the true definition of the surrogate end point, I am not sure that bioequivalence per se would be an appropriate measure, possibly because of the fact that some alternative products are available for IV administration as well as IM, and being able to demonstrate bioequivalence is not necessarily going to occur when you are giving a product IV compared to IM.

With regard to the patient populations, we have heard quite a bit about the immunocompromised patients. I think that Dr. LaRussa also talked about the pregnant women and the severity of the varicella infection during pregnancy, especially with regard to pneumonia, and potentially with regard to congenital varicella disease, and I think this would be an alternative patient population that would also be advantage for a demonstration of efficacy of use through a surrogate marker of efficacy.

Finally, with regard to whether or not IVIG or acyclovir would be an appropriate alternative, I think that Dr. LaRussa's presentation demonstrated that VZIG would probably be an alternative, but the preferred alternative, if it is available, and I think that he well defined the risk associated with IVIG as well as acyclovir. Thanks.

DR. ALLEN: A quick question. Can you briefly comment on major differences in manufacturing process between your product and what you heard described from the Massachusetts Health Department?

MR. SINCLAIR: I am not from the manufacturing side. I am from the clinical side. I know that we use the same manufacturing process that we use for our winrow product, as well as our immune globulin products that are currently licensed in the United States, and we use an ion exchange chromatography method as opposed to the ethanol fractionation method.

The potency of the product, we use the Mass State product as our in-house potency standard. So, we have comparable potencies. However, the product manufactured is a five percent product for either IM or IV administration.

DR. ALLEN: Thank you. Let me get Dr. Epstein, and then we will come back.

DR. EPSTEIN: I would like to clarify a regulatory point on the term surrogate marker. There really are two types of surrogate markers, ones that have been validated, and ones that are likely to be valid, but have not been validated.

There is a distinction to be made. If the committee feels that there are validated markers, then we could give final approvals on that basis, but generally the studies would still have to be clinical to show end points based on a validated surrogate.

If the surrogate is likely to be valid, but has not been validated, then the FDA would only be giving what we call an accelerated approval, which is conditional, and the condition being that it would be validated later in clinical studies.

Whichever way you go, you do end up with some level of clinical studies. There is also the subtle point that it would be rather unusual for the agency to give approval to the product based on accelerated approval with an unvalidated surrogate in the situation where clinical studies, in fact, are feasible.

Dr. Scott did make that point. On the other hand, we may have an unusual situation here, if product were otherwise to become unavailable.

Of course, the products could potentially remain available under IND, but that is a more cumbersome mechanism to provide products. I don't know if I made things clearer or more murky, but the term has two contexts.

DR. KLEIN: Since you are on the clinical side, can you tell the committee what clinical studies were done in Canada in order to license it, and whether your product is licensed in any other countries?

MR. SINCLAIR: The last one first, we are not licensed in any other countries, and we have performed a study in pregnant women that have been exposed through household exposures for the majority of cases within, I believe, 96 hours for the majority of patients, as the mother at risk program in Toronto.

We compared the study that was published by Gideon Karan(?) a couple of years ago, and it involved 60 subjects, whereby they were randomized to receive either an IM or IV dose of our product, or an IM dose of the licensed U.S. product, and they had similar rates of infection.

As I guess was discussed previously, the infection rates of natural disease progression, in the absence of therapy, is not well defined.

DR. ALLEN: Dr. LaRussa?

DR. LA RUSSA: Just a few comments. I would be very careful about throwing congenital varicella into the mix there, because you are never ever going to design a study that is going to show that any product is effective in preventing that, since the rates are so low.

I guess the other comment I would make is, I am trying to think of how we would design an efficacy study in the United States to test efficacy against clinical diseases and infection with the rate of varicella falling so much.

We might be able to look at antibody end points but, since we are not really sure what those mean in the patients, unless you looked at a very, very restricted, well described population, what would it mean to have a FAMA titer or a GP ELISA titer of greater than five?

I don't know what that means, and it seems to me that what you have done in the past is, everybody sort of piggy backed on the titer of the first ZIG product, and then gone and said, well, my product has equivalent titers to ZIG.

I am not sure how you get out of that bind now, unless you are going to do the studies in some other country.

DR. SCOTT: If I could just clarify that the ZIG product titers may or may not have been linked to the VZIG titers, but the clinical efficacy was linked. I think we don't feel we are relying still on those archaic ZIG titers, as it were, for the current product, although the product may have been selected based on the VIG titers originally.

DR. LA RUSSA: I just don't see how we could do a study now.

DR. KATZ: A question for one of the pediatricians around the table. I presume there is somebody's accumulated experience with A gammaglobulinemic kids receiving replacement doses of intravenous immune globulin that might be informative regarding their risk from varicella exposures.

Apparently the American Academy thought there was enough to make a recommendation. Can I be enlightened on that?

DR. LA RUSSA: The situation with the kids with A gammaglobulinemia was that they developed chicken pox at the same rate and at the same severity as normal kids.

I don't know that anybody has looked at whether the addition of giving them intravenous gammaglobulin actually reduce that risk, but we could run it.

DR. SEWARD: They are now eligible to get varicella vaccine.

DR. ALLEN: Okay, at this point I think we are about ready to move into general discussion. So, I am going to close the open public hearing section, and ruefully acknowledge that I didn't read the open public hearing announcement for general matters meetings that I was supposed to, but our speaker did identify that he did have industry ties. So, perhaps my oversight will be excused.

We will move at this point into the open committee discussions. Dr. Scott, did you want to come and present us -- they are listed, I guess, formally as questions. They really aren't questions so much as requests for discussion. Do you want to present the questions to us formally, for consideration?

Agenda Item: FDA Perspective and Questions for the Committee.

DR. SCOTT: So, the first question is, to please discuss what laboratory and clinical data would be sufficient to demonstrate efficacy of a new anti-varicella antibody preparation for prophylaxis of severe infection.

Comment, please, especially on which target populations would be more informative and, actually, most important to study, most relevant.

What surrogate markers, if any, would be appropriate for an assessment of efficacy, and what other considerations you have for clinical trials.

DR. ALLEN: Okay, A, B and C are open for discussion.

Agenda Item: Committee Discussion and Recommendations.

DR. DI MICHELE: Actually, I don't want to discuss them so much as actually ask just a few more questions, particularly of our experts around the table.

I guess, in trying to think about this, obviously clinical and laboratory correlates would be good, to have both of them together.

So, based on what we heard so far we had sort of the clinical correlate study with the VZIG versus ZIG studies from the 1970s and 1980s, and it seemed like they looked at things like pox count, pneumonia, hepatitis and stuff.

Looking at severe disease, it looked like that seemed to be some reasonable clinical criteria by which we could maybe look at a clinical trial going forward, but I would like the experts to kind of comment on that, to see if, indeed, my interpretation is correct.

Secondly, I am a little confused, understanding the fact that titers don't mean everything, but I am a little bit confused -- and maybe Dr. LaRussa can clarify that -- because certainly it seems like there are some criteria by which people are considered to be immune, based on FAMA and GP ELISA titers.

I guess maybe I am still a little confused about where those come. Then my third question, actually, is for Dr. Ambrosino, in terms of wondering whether there would ever be enough VZIG for a comparison trial, were we to think about licensing another product.

Lastly, I just want to say that IVIG appears to have some efficacy but, given what we have heard earlier today, and certainly the fact that we may have to be curtailing use rather than expanding use, I am a little concerned about just generally recommending gammaglobulin at this time.

DR. LA RUSSA: I will make a couple comments. I didn't want to give you the impression that antibody is not protective, but you have to realize that most of what we know about antibody is in the context of either natural infection or vaccine, where you are also stimulating a cell mediated immune response.

So, to separate out what actually is an protective antibody titer gets to be a tough problem. That is why looking back -- I was a little surprised, looking back at all the old studies, to see how little data had been accumulated and actually what antibody titer the individual developed, which really would have helped you with this problem.

If you could have said, CF titer one to 50 at 48 hours assured you of protection, then you could have a surrogate marker for a clinical study, and that data is just not there now.

The other thing that you have to realize about varicella is that it is a tightly cell associated virus and, although there are these viremias, most of the spread of virus is from cell to cell.

So, if your antibody gets there quick, it hopefully sops up virus before it gets into lymphocytes and monocytes, but if it gets there too late, then there is going to be this passage of RS from cell to cell, that you can't really do anything about.

That is where I think the antivirals come in, because there are a high intracellular triphosphate levels that work on an intracellular level, and not on an extracellular level.

DR. DI MICHELE: Let's say that, given that, yes, endogenous immunity and titers achieved by endogenous immunity are very different than passive acquisition of titers, but let's say you just take the titers, and you give them passively or you acquire them endogenously.

Of course, the whole cellular immunity issue is not discussed. Certainly, might that not be a good place to start in terms of saying, at least, okay, this is what you get with passive immunity, it is something similar to what you might generate in an endogenous situation.

Let's say you are talking about the immunocompromised pediatric population, which I think I am going to get to a little bit later in terms of being potentially a target for clinical trials.

I mean, yes, that would leave out the cellular immune issue, but it might give us a starting point. Is that not valid at all?

DR. LA RUSSA: I think, unfortunately, in that group, the cellular immune response is so important that looking at antibody titers is going to be very misleading.

Again, if you look at a lot of the older data, the attack rates are pretty high, even in the presence of antibody in the immunized individual.

So, it might actually be cleaner to look at a totally immunocompetent population where you didn't have to worry about -- let me pose a scenario for you.

Let's say you decide you want to study children with leukemia. Well, you then have to think about what kind of regimens they are on, you have to think about what kind of periodic blood products they get, whether they are using effective antivirals as prophylactic agents.

There are so many variables in that situation, that you are either going to have to do a huge study in a place where there is a lot of varicella, or you are not going to really be able to answer your question.

DR. DI MICHELE: Even if, for instance, VZIG, which has been the standard of care -- I mean, VZIG is the standard of care in this population. I mean, we have been giving VZIG to kids with all sorts of cancers, on all sorts of regimens, this whole time. I guess my impression is it has been relatively effective.

DR. LA RUSSA: Yes, so then what you are saying is, we are going to do a comparative trial looking at antibody end points, but we don't even know what to make of the VZIG end points.

I mean, we can say that, if you use VZIG of a certain titer, and give it within an appropriate time, you are going to get a certain amount of efficacy and, if we get similar titers, then we can make the supposition that this stuff should work just as well.

I think that is what we were talking about when we said, when you want to compare it to VZIG, you can do that, but if you are looking for clinical end points, I think that is going to be very hard to do. There is just not enough disease around.

DR. ALLEN: I think those are very good points, and looking in particular at our opening presentations about what has happened to the demand for product over the last couple of years, the clinical situations demanding its use, apparently, aren't there nearly as frequently.

I suspect, therefore, that the disease outcomes are going to be much more difficult to assess because it is just not going to occur that frequently.

I think we are going to have to use some degree of surrogate markers looking at antibody levels and that sort of thing, perhaps as you said, in immunocompetent populations, although I have got some immediate questions that come up about the ethics of doing those kinds of studies.

I think this is going to have to be looked at very carefully, and I think we are going to have to accept some degree of surrogate markers, at least as an initial step, while we are trying to get clinical end points.

DR. LA RUSSA: Just one other point. To compound the problem even more, we are doing such a good job of vaccinating kids that your pool of susceptible kids that potentially you could use for these kinds of studies is decreasing as time goes on.

So, unless you are willing to accept as a pool of immunocompromised kids those that have previously received vaccine, you don't really have a pure susceptible population. It is going to be a very small number.

DR. DI MICHELE: Does that mean that we are using equivalency in terms of FAMA titers? Let's say a child get leukemia and we are looking at FAMA titers for immunity. Are we using vaccination and endogenous infection FAMA titers are equivalent, in terms of protection? Are you saying that this child is protected, or are you giving these kids VZIG?

DR. LA RUSSA: You should ask me that question in another year. We were just talking about this over lunch, that essentially we have got this partially immune population of kids that are aging into the age of leukemia, and we are going to have to watch very carefully.

I can say anecdotally that I haven't gotten a lot of calls from frantic oncologists saying I have got kids with leukemia who have been vaccinated and now they have disease. That, again, the problem there is that the burden of disease to be exposed to is much less, too.

DR. KATZ: A question I think is probably for the FDA. As I look at the incidence of varicella and the apparent decline in use of VZIG, I am just wondering if the IVIG manufacturers are, in some way, shape or form, clamoring for this indication, i.e., to do the requisite trials.

DR. SCOTT: I hadn't noticed any clamoring at all. That said, there have been maybe mild degrees of interest expressed when this problem became known.

DR. SEWARD: I just wanted to make a comment on the correlate issues. I mean, studies -- the vaccine trials, you know, the best correlate marker that has been described is an antibody level six weeks post-vaccination.

A year out, or two years out from that, there seems to be some marker set that measures something. It might be the cell mediated immune response.

So, you can't look at a child two to three years after vaccination and make any sense of that antibody titer in terms of protection, and we are not measuring kids six weeks post-vaccination out there in the community. So, we don't really have a correlate that is applicable to community use.

DR. ALLEN: Not seeing any other hands, I am going to ask another question of the FDA. Dr. Scott or Dr. Epstein, what about other manufacturers that might take on exactly the same process that has been used?

I mean, we are not talking about a process that necessarily has, you know, been found not to work, or to be inapplicable in current technology. Are there other manufacturers that could be invited or induced in some way to assume responsibility for creating a product, which might at least simplify the licensure requirements?

DR. SCOTT: In theory, it is possible to accomplish this kind of technology transfer. I think, in practice, for somebody to want to go into relatively small scale fractionation with virtually identical equipment and procedures, would be considered a fairly high undertaking, given the potential financial benefits of this kind of product.

I am just pointing out, there is a fairly high threshold that it wouldn't be impossible from a regulatory point of view at all.

DR. ALLEN: I mean, it certainly qualifies classically. It is not a drug. It is a biological, but it is an orphan biological situation.

There is a need for it. There are kids and adults that potentially are going to be harmed by the absence of the product. There is a national interest to have it available, it would seem to me. Payment for it in our current structure may be more difficult.

DR. AMBROSINO: I will make a relevant comment, I think. Our other product, cytogan, that is a larger market, and our partners there are Medimmune, and Medimmune is actually the distributor of that product, and are looking to transfer the exact same process to a contract manufacturer and, in fact, we are assisting in any way we can.

The trouble is -- and we are glad to give our batch records away, we are glad to say, here, make it. I want to be helpful here. It just isn't enough patients out there that don't have an alternative that anyone would do that, at least everybody we have talked to, that it would make sense, and that is our problem, but boy, we would be glad to do a tech transfer in terms of offering this to anyone.

DR. ALLEN: In some regards, that seems like that may not be the least costly option but it may be the simplest option, even though I think we would agree VZIG isn't an ideal biological.

If it were to be formulated from scratch today, it at least seems to have a reasonable degree of efficacy and utility that has not been supplanted either by antivirals or by the standard IVIG.

So, there seems to be a continued role for it, even though it is still very much an orphan biological at this point.

DR. SEWARD: My comment to the second question, following on from that, is that it remains to be proven whether IVIG could substitute. I don't think the data is there right now.

It may well be able to do that, but the current scientific data isn't strong enough to make the statement now that it does, and the same small numbers, difficultly with exposures in the immunocompromised, acyclovir, the data is in healthy children, and not enough data in the immunocompromised children, and they are the main target group for this product, I think.

DR. KATZ: As I recall the vaccine in healthy children publication, the antibody levels are lower after immunization than natural infection, which I guess is no surprise whatsoever.

The other concern I have, I actually, as I look at the data, and if I had to guess, I would say that IGIV will, in fact, be effective if we figure out a reasonable dose to use.

I think a lot of authoritative people not concerned with licensure are intimating that in the recommendations that come down, but what is going to happen to the ability to maintain anything like the antibody levels that we see now as the immunized population ages and becomes our donors.

DR. LA RUSSA: I think those are good points, and perhaps the issue then becomes one of how do you stimulate and pay for a clinical trial that would compare IVIG appropriately with VZIG in an appropriate population.

DR. HARVATH: The question I had would be to propose an alternative to a randomized trial, because I think a randomized trial is, in terms of what we are hearing in terms of sheer numbers of people who would even be eligible, it doesn't sound like it is a likely possibility.

What we have done, an alternative approach we have taken, at least at NHLBI, for orphan diseases or really rare conditions for which we are trying to facilitate clinical studies of therapies -- for example, populations such as thalacemia patients -- is to first think about a registry or a reporting of cases.

CDC would probably be a great place to start in terms of reported cases where you have taken various approaches to treat patients who have these complications from this infection, and then what approaches we are taking to treat those patients.

It is not anywhere near as gratifying as doing a prospectively designed trial, but if you set a registry up appropriately, and you know the kind of questions that you would like to answer, you can at least get closer to the type of information you need, especially in the situation where it is going to be very difficult to come up with sufficient numbers to conduct a prospectively designed clinical trial.

The other question I had is for the folks who work -- like Dr. LaRussa and Dr. Seward -- what types of cell mediated immune in vitro tests have been done along the way to evaluate the responsiveness to therapy.

For example, if someone has had an exposure to the virus, and then they are given passive immunization with VZIG, has anyone done studies subsequently to find out whether they do develop cell mediated immunity?

DR. LA RUSSA: I can make a couple of comments. First, to go back to the issue of the randomized trial, I think -- just before I forget this point -- if you were willing to accept equivalency with VZIG, you could take a situation like, let's say, health care workers, where most health care workers are screened with varicella, for varicella antibodies. So, you would at least find an ongoing population of susceptibles.

Then do a study where you gave half of them VZIG and half of them IVIG at the appropriate dose, or this other product, whatever it is, and show that you got similar antibody titers. You might accept that type of equivalency.

That might be the kind of trial that you could do, but it would only be in terms of looking at antibody titers, and not any kind of efficacy, and obviously you would have to look at safety, too, if you were going to do IVIG.

To answer your question about cell mediated immune responses, actually the best tests that we had is one that is no longer available.

There were a number of skin test antigens that were really wonderful for testing cell mediated immunity. The only problem with those is that they can also be immunogenic at the same time that you are testing.

We, in one small study, we saw antibody rises after skin test antigen testing. So, that clouds the water a little.

There are plenty of tests. There are in vitro lymphocyte stimulation, there are LE spot assay, there are interferon release, there is a lot of stuff. It just depends how much money the CDC is willing to spend. You could look at that.

To answer your question, though, with VZIG, people have looked for both infection rate, in terms of long-term persistence of antibody and cell mediated immunity, despite getting VZIG, and those things do happen. That is part of the problem. It doesn't prevent infection.

DR. KLEIN: Before we spend too much time talking about randomized trials, is there anyone here who believes we have enough product available to design a randomized trial, get it off the ground and completed? It sounds to me like there is not a prayer of doing that.

DR. SEWARD: Certainly not time, let alone if product is the problem. CDC, if we put an RFA out for the next fiscal year, we will be funding it next August, and the results will be in a year or two after that. We are out of this product by next year.

DR. KLEIN: I think we will look at something else then; right?

DR. SCOTT: From a practical standpoint, though, if you have a product under IND and you have an associated treatment IND for people who aren't eligible for the IND product under the IND study, there is a potential -- far less than ideal, but there is a possible short term solution there.

DR. LA RUSSA: I am just curious, from the FDA standpoint, how many patients in each group would you need to see in order to say that antibody titers were equivalent at 48 hours or one week? Would you be happy with 20 or 30 in a group, or would you need to see more than that?

DR. SCOTT: Something on the order of that number, and PK studies, for example, that were pivotal to licensure were done with the vaccinia immune globulins. You are looking at less than 100 people, and they had several different doses in each group.

DR. ALLEN: Let me just take a moment to point out that question number two is, please comment on whether the available scientific data support use of IVIG or acyclovir as a substitute for VZIG for prophylaxis of severe varicella zoster virus infection in any clinical settings.

We have skirted on some of these issues. Dr. LaRussa addressed it from his perspective in some of his concluding statements, but that question is open for discussion also.

DR. LA RUSSA: I think the answer has to be no, in the absence of further study.

DR. KATZ: If the word scientific was taken out of the question, would you change your answer?

DR. LA RUSSA: Well, no, I don't think I would. I think I would want to know how much antibody is in the different IVIG preparations, so that I could figure out the right amount to give.

I really want to know if I am causing other problems that we haven't talked about. I have seen the kids who get rapid infusions of IVIG and white out their lungs and do other things. So, I need to see some safety data.

If I am backed up against a wall and I don't have any VZIG, yes, I am going to do that, but that is purely non-scientific.

DR. SEWARD: I see a difference between supporting use of, or recommending use of. So, if scientific were taken out, I could say, yes. I mean, if you are up against a wall and you don't have anything, I think most clinicians are going to give IGIV or use acyclovir, because they don't want to sit there.

If the scientific data isn't available, I think everybody imagines these things are going to provide some benefit, but it is not strong enough scientific data now to say that it is going to be equivalent and should be recommended. So, I see a difference with those words.

DR. ALLEN: And I guess I would be a little happier if we actually had 2-A and 2-B, with 2-A being IGIV and 2-B being acyclovir.

I think they are quite separate issues. I mean, acyclovir as an antiviral has got certain very appropriate uses, but it is not a substitute in any way for the immune globulins, and I think you presented sufficient overall data, Dr. LaRussa, to indicate that each has got its own appropriate role in this, but there is certainly not going to ever be equivalence or used as substitutes for one another.

The issue with IVIG, I think, has been laid out separately in terms of identifying antibody levels, targeted antibody levels, appropriate dosage, and looking at safety and efficacy under different clinical situations, and there we need additional data.

DR. KUEHNERT: I think, going back again to a clinical standpoint, I think that if you look at question two and add to it, versus doing nothing and watchful waiting, I think you have a very different answer than if you are looking at a rigorous scientific data. So, it depends what your standpoint is, I think.

DR. SCOTT: I think it would be fair to say -- and Jay can correct me if I am wrong -- that the point of question two, really the underlying point is to ask, do we need VZIG.

I think that we have talked about this a lot, and what I have heard is that there are some circumstances still, even though you don't meet it very often, where it is felt that you need it, and that is what the clinicians think, and that seems to be supported also by the kinds of patients that we know are out there.

DR. KLEIN: It just seems to me, from hearing this discussion and trying to absorb all this information, that you need it until you can demonstrate that there is something else as good.

Right now you have a gold standard. It appears to be effective. There are loads of studies. They aren't all perfect but they support the use of this drug.

We don't have anything that says, given the absence of this drug, there is something equivalent. Maybe IVIG is going to be terrific if we figure out what dose, but we simply don't know, and we are not going to have a chance to find out before the supply runs out.

DR. DI MICHELE: The only thing I would add to Dr. Klein's statement, which I agree with, is that unfortunately the issue of need is a moving target, and one that we don't completely understand.

DR. ALLEN: To add onto that, the point that Dr. Katz and others have raised earlier is the fact that our donor population is changing also, in terms of the type and titer of antibody.

We will be switching over time from people whose immune response is caused by wild type virus infection to people who will have vaccine titer antibody, or vaccine antibody, and what we will need to do and how, under future circumstances, very carefully needs to be monitored over time.

It sounds to me like the IVIG, if that is to be the substitute pending further studies, that, again, we need to continue to assess that over time, because the IVIG of the future, with regard to this antibody, is not likely to be equivalent to what we have available today.

DR. LA RUSSA: Just one last comment. If you had said to me, here is the data that shows that IVIG is of equivalent immunogenicity, let's say, as VZIG, I can come up with -- I will give you the dose, and you will get the proper antibody titers, it is still going to be a much more difficult product for the clinician to use, and will essentially take what is a very short interaction with the health care system and turn it into a much longer one.

I guess I would say that, if I had a choice, and you asked me, should we continue to find a source of VZIG, I would say, that is my preference.

If that is not an option, I can live with IVIG with all the caveats that we have talked about, but that would certainly not be my preference.

DR. ALLEN: Dr. Marin, can I ask you a question? Has the ACIP addressed this question and the issue of the declining availability of VZIG in the future, in any of its deliberations?

DR. MARIN: This issue was discussed in the ACIP VZIG working group, and the decision was to postpone it for the August discussions, and to go to a recommendation for the end of October meeting of the ACIP.

So, we presented to the working group a review of available data on efficacy and effectiveness of IVIG, some data about antivirals used as post-exposure prophylaxis. Most of the discussions will be in the August meeting of the working group.

DR. SEWARD: I wouldn't anticipate, based on my experience with working groups and the data that you have all seen, that they are going to be having any different discussion than we are having here. Same data, same limitations, no other available product.

DR. AMBROSINO: May I add about the red book? Dr. Reynolds asked me to mention to you -- the chairman of the red book -- that they will have recommendations in the fall for alternative use, just so there will be recommendations out there.

They are hoping that ACIP and red book, as usual, will be harmonized. Sometimes that happens in the beginning and sometimes later.

DR. ALLEN: Dr. Epstein and Dr. Scott, I wonder if there shouldn't be communications with the ACIP and with the red book staff also, just to let them know about this discussion here and the FDA's concerns and issues in terms of approaching it.

DR. SCOTT: Thanks to the session, and also to the preceding telecoms, I think we have established ties through CDC to ACIP and we should connect with the red book folks as well.

DR. KLEIN: It just seems to me that, given the discussion that we heard and the limited amount of information, that you can always get an expert panel together and, given the inferior products, you will get a recommendation about how to use them until data is available.

It seems to me, from what I have heard, that you would like to look for an alternative source of manufacture, and it seems to me that that should be the number one thing to do.

Once you have found someone, whether it is inside this country or outside this country, who is willing to do so, then you should make it financially reasonable for them to produce it.

It also seems to me that we have talked a lot about the declining need in the United States, but from what I heard, with the immigration issues that we have, this need is not going to go away for a very, very long time.

So, we shouldn't assume that, with vaccination, that this is not going to be an issue in the United States in five years or ten years. It will be.

DR. ALLEN: I think that is a very good point, and in particular, if we go back to our early presentations on what has happened, yes, there has been a fairly dramatic decline over the last several years in terms of the need for the product.

Nonetheless, if you are looking at pediatric doses, you were still producing, what, 10,000 doses a year, and in adults the equivalent would be 2,000 a year.

That is a fair number of patients overall that have some need of the product. I understand that is what is being produced, may not be what is being administered and used.

Still, we are talking about something that is needed by thousands of people a year in this country alone, and I agree with Dr. Klein that my immediate take is that, while we do need to fund some additional studies, we do need to look at what will be happening over time, we do need some good comparisons, that trying to find an alternative source for VZIG at the present time is clearly the preferable way to go.

Again, one hesitates to bring some of these issues up to congress, which has the appropriations responsibility for the federal government, because they will tend to beat government people around the ears, claiming that they have created a crisis and didn't pay attention to this early enough. The issue somehow does need to be brought to other levels of the administration, and congress also.

DR. SCOTT: I just wanted to mention there are some incentives. Clearly on the numbers of people treated, this would qualify as an orphan product.

I say that, obviously, without a formal submission, and there are tax credits as well for the study, as well as study grants, which are not enormous, but it is more than nothing, perhaps. There is also the potential for cost recovery for an IND product like this.

DR. ALLEN: Dr. Holmberg, I am sure you have paid attention to the discussion also, and will take it back with regard to your committee responsibilities.

DR. HOLMBERG: I have a lot of concern about this, primarily because, when we talk about the supply of -- I think the information you gave us was that in January you would be running out of supply.

On the other hand, trying to use the IVIG as an alternative without the scientific data to support it, we are in the same situation that we are currently with IVIG, where we have anywhere from 40 to 100 percent of the hospital use being off label, which just exacerbates the problem.

So, we are aware of this, and we will be working closely with all the other agencies -- CDC and FDA along with this -- to try to work out of a problem, of a solution to this.

I think some of the issues that we have, and some of the suggestions that have already been made, as far as going outside the country, with a product that may be made in Canada with U.S. plasma, definitely in the United Kingdom with U.S. plasma being used over there, there is some great potential of expanding beyond our borders here.

I think I hear the message loud and clear, and I agree with Dr. Klein, that this is not going to go away. We have a growing immigration rate and we do have some real concerns here, to protect those people, to protect the American population.

DR. ALLEN: Dr. Epstein and Dr. Scott, have you received the discussion that you need? Do you want further clarification or explication in any area?

DR. EPSTEIN: I think it would be helpful to have a specific discussion about surrogate markers. Do committee members, either individually or collective, think that PK comparison with VZIG ideally, prospectively, and otherwise, retrospectively, would be a valid approach, plus or minus whatever review we can do of the Canadian clinical trial, because it has been pointed out that the product in Canada was, in fact, approved there based on a clinical trial.

I would also comment that, if we think PK is a suitable approach -- that is to say, antibody levels -- would it be suitable to do those studies in normal, healthy individuals, or do you really have to look for these rarer, susceptible populations to do PK studies, or could you simply look at the evolution of titers in healthy normals.

I think that is kind of the crux. I think we have heard enough about question two. The general sense appears to be that there is a need for a VZIG product and that, although clinicians might use whatever is available otherwise, they would certainly want the continued availability of VZIG, which is established. I am simply summarizing what I thought I heard. I think I haven't heard as clear an answer on question one, particularly 1-B, surrogates.

DR. DI MICHELE: I think there are two issues here. One of them is titers, but the other is clinical efficacy in the patients who need it most.

I just -- I am going to go back to what I said before, the VZIG pivotal trial for licensure that was done in the 1980s seemed to at least look at presence or absence of the worst systemic complications of disease, plus a pox count.

That, combined with something like titers, I think might be the best approach, if it is doable. Again, depending on what the FDA was willing to accept in terms of an equivalency trial.

I think that issue is not just has import when you ask us, what population do you want to study, because if you want to just look at PK, you can probably look at it in any population.

If you want to look at PK combined with efficacy, then I think you have to look at it in the most susceptible populations.

So, it just depends on the issue of whether you want a clinical end point, either compared to historical controls or in addition to the surrogate marker. I think that will determine what population you use.

DR. LA RUSSA: I guess what we could do in the short term is maybe design a very quick study that we could send around to pediatric oncologists and see how much varicella they are still seeing, to see whether it is even feasible to do what you are asking.

We have a pretty large pediatric oncology group at Columbia, and I am saying, I haven't gotten a call about a varicella case in the leukemic probably in the last year or so.

DR. DI MICHELE: That is because they are still getting VZIG.

DR. LA RUSSA: I don't think so, because we have to approve VZIG.

DR. SEWARD: I mean, varicella disease is 80 to 90 percent declined. So, you are not seeing it in schools and in day care centers and, if we do, it is modified mild disease, breakthrough in vaccinees, which is not as infectious.

So, I think the amount of varicella around is going to make it a lot more challenging to do the clinical efficacy study now in the United States. You could do it in Canada, although Canada is now vaccinating for varicella as well, but they don't have as fully implemented a program. You could do it in Europe, in the United Kingdom.

DR. LA RUSSA: The other thing I would say is, if you wanted to do just a PK study, I suppose you could do it in people that were seropositive, but that is really going to muck up the analysis stage, because then you are going to have to normalize for their pre-VZIG antibody titer.

I guess what I was proposing is that, let's say that you believe that five percent of the adult population is susceptible and, since health care workers in many cities have a disproportionate number of people from outside the country, who may have a higher rate of susceptibility, you may, in fact, end up with a pool of health care workers, susceptible health care workers that you could do a quick PK study on and answer at least the equivalency question. I really don't think you are going to be able to answer the clinical question.

DR. KATZ: I don't know about health care workers. I know that, at my hospital system, we require proof of immunity, history or proof of immunity, and we immunize if they can't provide one or the other. So, health care workers may be tough.

I have a question and that is, is using normals, immune or susceptible, appropriate? Are the highest risk people in any way more catabolic? Do we know anything about PK in these particularly sick kiddies and what not, that would be different from normals?

DR. LA RUSSA: My problem there, as I pointed out before, is that there are a lot more variables. The kids that you would like to give it to all get blood products. They get either acyclovir, sometimes gancyclovir prophylaxis, and there are lots of other things going on.

You will have to look at renal function and liver function and other things. I think it just becomes a much more complicated study. I agree, that that would be the best population to do it in, but I think it is problematic.

DR. ALLEN: I agree. For a baseline, I really would like to see a comparable trial between IVIG at several different doses, and VZIG in a well defined normal population, preferably kids.

It is probably not ethical, it can't be done very easily, but it would be nice to have that kind of baseline data.

The other variable that it doesn't begin to address in any way is cell mediated immunity, which is an important component of the response to this infection. At least that would begin to answer one initial set of questions with regard to the pharmacokinetics.

DR. LEW: I just want to make one comment, though. I know that, technically, we always like to first do trials on the healthy folks and then you move on down.

The truth is, this is going to be a product that really is for the immunocompromised child that we are really trying to target.

When you get the most severe, we are talking about bone marrow transplant kids. In a way, I have mixed feeling, that they are truly the target with all the caveats that you have, Phil, that yes, they have renal problems, they have every sort of problems, are on many different medications, but that is really the target group. I am curious as to whether -- it seems like that is the group we really do want to study.

DR. LA RUSSA: And again, I would agree with you. I just don't know what to do about their blood product use and the other things that are going to complicate the analysis.

I would be happy, if we had the time, the money, to get enough to sort out the variables. I would be very happy to do it in that population.

DR. DI MICHELE: On the other hand, the cancer patient isn't the only immunocompromised pediatric patient as well. There are transplant recipients, the renal disease population, and there are a few others.

DR. QUIROLO: I have one question about using IVIG as a treatment. Even if you did devise a study, you would have to know what the titer is in the IVIG you are giving and then you would have to depend on the manufacturer to tell you what the titer was in every dose of IVIG, which I don't know if they would be willing to do. It is expensive.

DR. ALLEN: That is certainly one other caveat with regard to the use of that product, and it is certainly one that wasn't there with VZIG because every lot was titered to within a very narrow range.

If IVIG is going to be used in the future, if there is an established efficacy and it is used as a routine in the future, you probably are going to have to know what the range is for each lot that is used.

It may be that certain lots should be set aside, if you will, for this particular use as opposed to other lots. I don't know.

DR. SEWARD: I am trying to ask the question whether immunological equivalency, as demonstrated just in the lab, and then safety data, in immunocompromised children, would be sufficient for licensing an orphan product.

DR. ALLEN: I think it does need to be addressed. I think that is a good point.

DR. LAAL: Is there information about correlates for protection, surrogate markers for protection, that we can get out of the studies that must have been done when the vaccine was licensed?

All that I am hearing about is the antibody part of the immune response, and I don't know enough about the literature, but when the vaccines were made, what kind of studies were done?

DR. LA RUSSA: The reason why we try to separate these two things out is because it is one thing to immunize someone with an antigen that stimulates both antibody and cell mediated immunity, but that is not really applicable to the question of prophylaxis, where you are relying purely on antibody to do the protection.

So, unfortunately, since those two arms of the immune system are so wound together that the data from the vaccine trials, frankly, is irrelevant to the question that you are asking.

DR. LAAL: Even if one was to look at the antibody responses in children who were protected versus the breakthrough children who were not so well protected.

DR. SEWARD: You can't separate the antibody responses from the cell mediated immune responses. I mean, they are highly correlated and interrelated.

DR. LA RUSSA: You know, in some ways, the antibody responses are really a reflection of a good cell mediated immune response and not a separate response.

Here you are saying we want to use antibodies, pure antibodies, as protection. So, the vaccine studies really don't help you. If anything, they confuse the situation.

DR. ALLEN: Other comments or discussion on this issue?

DR. SCOTT: I wanted to thank the committee, and I want to paraphrase some ideas that I heard into a possible approach.

If PK studies could be done in normal people that are not immune, and there was comparability shown between the current VZIG product and another VZIG product, that wouldn't answer the clinical question, but it could be considered reasonably likely, which is actually the wording of the CFR for accelerated approval to be connected, or connectable to efficacy in the immune compromised people.

Now, that kind of a study comes with a major caveat, that there is a post-marketing study as well, which could actually be some way of monitoring some of these immune deficient patients, or the first X number of patients that receive the product in a certain category.

That is just an example. I am not saying that is an imprimatur, but that is something that comes to my mind, and I wonder what the committee thinks about that kind of an approach.

DR. SEWARD: I think it is a good start.

DR. KLEIN: I would be very comfortable with that. I think, unfortunately, the good news is that, with the rate of disease, and with any kind of a product that is any good at all, it will probably take 100 years to demonstrate that you have more disease than your historical controls.

So, you are probably never going to find that out, but certainly this would be a reasonable approach with a post-marketing survey.

DR. SCOTT: I point out 1984, when the CDC looked at the distribution of this product. They had about 10,000 vials a year distributed, and the clinical trials were undertaken just a few years before that.

So, whether or not there are enough people out there to do a study, or to collect the data and do a post-marketing study, I think there is a possibility. We don't know how the current VZIG is being used. That is one of the hurdles, coming up with a design.

DR. KATZ: We keep supplies in my hospital, where I am responsible for this issue, and we outdate it all, two or three doses for a 70 kilo guy. We buy it once or twice a year -- not a 70 kilo guy, I apologize for my sexism, a 70 kilo person. We are outdating it. We haven't used any for three years.

DR. LA RUSSA: One thing you could do is make receipt of VZIG contingent upon completing the results of whatever study, go back to the way we used to distribute VZIG before it was a licensed product. That way you could get that information.

DR. ALLEN: Yes, it would be good if that kind of information were routinely available in many circumstances, but it is not, but that is a good suggestion.

Other comments or discussion? Okay, I want to thank the committee. I think this has been a difficult discussion, but very exciting.

I want to thank the special members who have joined us, and our presenters, who came in for their part of it. It has been very helpful. Thank you all, and that will close section two. We will go ahead and have the break now, and I would like to have people back and ready to start at 3:45, please.

[Brief recess.]

DR. FREAS: If I could have your attention, I would just like to acknowledge that we have two new members joining the table, and they have been appointed as temporary voting members.

The first, on the right-hand side of the table, in the middle of the table, if you would raise your hand, Dr. Jerrold Levy is professor of anesthesiology, cardiothoracic anesthesiology and critical care at Emory University Hospital.

On the other side of the table, if you would raise your hand, Dr. Michael Miller, professor, deputy chairman, department of plastic surgery, the University of Texas Anderson Cancer Center. Thank you both for joining us.

DR. ALLEN: Our third topic for the day is dextran-1 pretreatment for safe use of dextran 40 and dextran 70. We will have an introduction by Dr. Lawrence Landow of the FDA. Dr. Landow.

Agenda Item: Dextran 1 Pre-treatment for Safe Use of Dextran 40/70. Introduction and Background.

DR. LANDOW: I thought I would begin my presentation with my summary slide, so everyone is on the same page.

Dextran 40 and dextran 70 were originated in Sweden, but they were licensed in the United States in the 1950s and 1960s.

They, since that time, have been associated really with life threatening anaphylactoid reactions when given without hapten preadministration.

The hapten preadministration is dextran 1. It is commercially known as promit, and it has been approved in the United States since 1984.

The label for that product says it is indicated for the prophylaxis of serious problems in connection with the IV infusion of clinical dextran solutions.

So,t he problem before us, in summary, is that the current labeling for dextran products -- and I underline the word, current, because in the early 1980s and early 1990s, I have seen labels that do discuss promit and, for some reason we are not sure of, they have disappeared from the label. Current labeling for dextran products do not mention use of dextran 1 per-injection.

Just to get back to how these products originated, as I said, dextran 40 was approved in 1967. It has there indications, thrombo-embolic prophylaxis, volume resuscitation, and pump prime for cardiopulmonary bypass machines.

Dextran 70 was approved earlier, and the only indication for which it is approved is volume resuscitation. My own experience, and anecdotal experience of people in this country is that dextran is used primarily for thrombo-embolic prophylaxis by plastic surgeons, and they use them mostly for skin flaps and vascular surgeons, and I have seen them use it for carotid enterectomy.

In Europe, the situation is completely different. They use them quite often, from what I have read, for volume resuscitation. So, it is just a difference in clinical practice. I just wanted to point that out.

Here is a chronology of events. In the 1950s and 1960s, as these products started to be used more often, there were rare reports of severe hypotension, bronchospasm and even cardiac arrest.

Then, in the 1970s, dextran induced anaphylactoid reactions were discovered to be triggered by preformed circulating dextran reactive IgG antibodies.

These antibodies occur naturally or by the digestion of polysaccharide components of bacterial cell walls.

In a canine model, preadministration but not -- I repeat -- not simultaneous administration of a small hapten, dextran 1, blocked these IgG molecules from cross linking and it thereby prevented the symptoms of this anaphylactoid reaction.

This drug promit, dextran 1, was approved in Sweden, I believe, in 1983, and the next year was approved in this country on the 30th of October.

Just to give you some idea of the labeling, under the indication section it says, promit, dextran 1, is indicated for the prophylaxis of serious reactions in connection with the IV infusion of clinical dextran solutions.

Under clinical pharmacology it states that a retrospective 10-year review of severe reactions to dextran, after the prophylactic use of hapten inhibition, demonstrated a 35-fold reduction as compared to previous estimates. Previous estimates refers to historical controls in Sweden from 1970 to 1979 with very large sample sizes. We are talking about tens of thousands.

The warning statement said that, in a population of 70,000 patients, two severe adverse reactions were noted. The routine clinical use of promit to date has involved only one fatal reaction, in a patient with preexisting cardiac disease.

Dr. Ljungstrom, who is the author of several -- of almost all the papers, that we handed out to this committee, will speak on this topic after me.

So, the issue, once again, is that dextran 1 was approved decades after dextran 40 and dextran 70 products were approved and that, unlike the labeling in the late 1980s and early 1990s, current labeling did not mention the use of dextran 1 pre-injection for the prophylaxis of serious reactions.

This slide shows the adverse events that have been reported to the FDA for the period of 1969 to 2005. There have been 92 cases worldwide of dextran induced anaphylactoid reactions, two of which occurred this year, and there have been 15 fatalities. Domestically, there have been 66 cases of this, of which 10 died. So, it is still an ongoing concern to FDA.

So, how can we communicate the heightened risk that we believe is out there for clinicians who do not use dextran 1?

Well, obviously, the first thing we always think about is a dear health care professional letter. As this citation concludes, mailed warnings alone do not affect prescribing patterns.

Alternatively, a letter accompanied by substantial internet and media coverage, and a campaign to inform pharmacy dispensing organizations of the warning did result in a change in prescribing patterns.

I might add that an alternative to think of is having little notices in the journals, the surgery journals, the anesthesiology journals, that highlights a change in the labeling, or highlights the problems that can happen when you administer dextran products without dextran 1 preadministration.

Then, of course, there is the ultimate of black box warning. I have just copied some of the sentences from this FDA talk paper for depoprovera, and I have given the FDA web site location for this at the bottom.

Black box warnings are designed to highlight special problems, particularly those that are serious. They are also meant to provide physicians with important insights into how to prescribe a drug which may be associated with serious side effects in a way that maximizes its benefits and minimizes its risks.

So, the question for the committee, after you hear Dr. Ljungstrom, is to discuss what revisions to the product labeling for dextran 40 and dextran 70 would be most appropriate to address the risk of DIAR, and the relevance of pretreatment with dextran 1.

In particular, please comment, a, whether a class labeling change is warranted and, b, what other forms of risk communication FDA should consider to alert the medical community about the risks of dextran induced anaphylactoid reactions. Thank you.

DR. HARVATH: Just a couple of questions. I wondered, could you clarify, there is only one manufacturing source of dextran 1? Is that correct, there is just one company?

DR. LANDOW: Correct.

DR. HARVATH: Is the company a European company?

DR. LANDOW: It is a Swedish company.

DR. HARVATH: To your knowledge, are you aware of difficulties with investigators or investigators in the United States being able to get the product?

DR. LANDOW: To my knowledge?

DR. HARVATH: Yes.

DR. LANDOW: No.

DR. HARVATH: Then the final question is, have you heard of any adverse events with administration of dextran 1 to patients who are hypotensive, when it is administered?

DR. LANDOW: The adverse event reporting system, as you know, is a passive reporting system. That is part of the problem. It is estimated that, at best, we receive word of 10 percent of the SAEs, the serious adverse events, that occur.

Second of all, these adverse events reports usually are sparse in detail, particularly, did this subject, or did this patient, rather, get pre-injected with dextran 1.

Most of the time -- our pharmaco-epidemiologist can help me out on any of these individual reports -- the details are missing.

The third thing -- and this is probably the most important -- this is a very old drug, or these are very old drugs. If something happens adversely, it is unlikely that someone will pick it up as readily and report it to FDA as when it is a drug that is maybe one or two years old. So, all of these factors really lead to a serious under-estimation of the true incidence.

DR. HARVATH: So, it is possible that administration of dextran 1 could have more adverse events affiliated with it than what you reported here?

DR. LANDOW: It is possible, but highly unlikely. Dr. Ljungstrom is the world's expert on this. He has all the numbers, he has published these numbers.

When dextran 1 was approved, they did review the literature very carefully and came up with that conclusion that I mentioned to you, that there were only two that they could find.

DR. KUEHNERT: Maybe you said this and I missed it, but I just wondered what the denominator is. I mean, how much of this stuff is used in the United States? Is there a handle on that?

DR. LANDOW: I don't have a handle on that. Maybe Dr. Zinderman would know.

DR. ZINDERMAN: Craig Zinderman with CBER, office of biostatistics and epidemiology in FDA. Since it is a passive reporting system, we don't have the actual number of dextran administrations that are given over the time period of when those cases occurred. We only have spontaneous reports that are submitted to FDA.

MR. GARBER: Basil Barber(?), FDA. In terms of the safety of the dextran 1, I don't want to give the data that Dr. Ljungstrom is going to be talking about, but essentially he is going to be talking about studies where the dextran 1 was used, together with the dextran 40/70, compared to dextran 40/70 by itself, in terms of outcomes.

If the dextran 1 was the problem, then you would expect more adverse events with those cases than when we used the dextran 40/70 by itself, and I think the exact opposite is true. I think his data should speak for themselves, and you should be able to judge it from that.

DR. ALLEN: We will have a chance to ask some of these other questions at a later point in our discussion. Unless there are other clarification points now -- go ahead.

DR. LEVY: Can I make a comment? Dextran 1 is 1,000 molecular weight. Most 1,000 molecular weight antigens are not that unit. A drug is a 1,000 molecular weight. Unless they haptenize, they are usually not terribly antigenic. They don't usually have the size to be antigens, and 1,000 is usually the cut off based on drug, and drug haptenization.

So, to answer your question, it has never been studied. On the other hand, logically, if you design a hapten inhibitor, it would make sense to design it at the 1,000 molecular weight, just a perspective here.

MS. STEFANO: I am Tony Stefano. I had poked around really quickly, working on this dextran issue, and in answer to Dr. Harvath's question, there are several hospital sites and distribution sites that have alluded to some difficulties in obtaining promit.

DR. ALLEN: Okay, we will move on to our main speaker on this topic. Dr. Ljungstrom is associate professor of surgery at the Karolinska Institute in Sweden, and as was already pointed out by Dr. Landow, he is an author on virtually all of the background papers that we were provided, and we look forward to your overview. Thank you.

Agenda Item: Prevention of Adverse Reactions to Dextran.

DR. LJUNGSTROM: Mr. Chairman, members of the committee, ladies and gentlemen, I want to thank the committee for the invitation to prevent these data here.

It has forced me to reread my thesis of 22 years ago, and also other materials, and it wasn't that bad, I would say.

Part of this will be rather basic in the beginning, because actually the knowledge of dextran in the United States is today rather limited, which is strange, because a lot of the basic studies on dextran were made in the United States by military researchers at the end of the 1940s and the beginning of the 1950s, when there was a big interest in the United States for this blood replacement solution.

The history began in 1942, when this chemist, Bjorn Ingelman, was asked by a sugar company, what was the stuff that was occluding their pipes.

It was a white sticky substance, and he analyzed it and found it to be a well described polysaccharide, dextran.

So, he wanted to devise a test so he could tell the sugar company if there was sugar present in the solutions.

He took this substance, he hydrolyzed it to make it injectable, and he injected it into rabbits to immunize them. So, from the beginning, immunology was involved in this substance.

Much to his surprise, they didn't develop any antibodies at all. Then he drew the conclusion that it is not immunogenic, and it may serve a purpose as a corollary, and that was the start of the dextran story.

The dextrans are made from alpha-1 to 6 linked glucose residues, long chains with occasional side branches. It has been in clinical use since 1947, and it is manufactured by using sucrose, which is converted by this bacterium -- it is a streptococci, leuconostoc mesenferoides -- to a native dextran. This is then hydrolyzed and fractionated.

We thank the Americans for finding this strain, B-512, which is still used today, that was found in the beginning of the 1950s. It produces a dextran which is almost linear, with very few side branches, one in every 20 glucose residues.

To give you an idea of what the molecular weight distributions of the clinical dextrans are, this is a comparison of their various correlates. This is albumen, this is a gelatin preparation not used in the United States, no gelatins are here, as far as I know.

These are the two common dextran preparations, dextran 40 and dextran 70, and these are for comparison, the most common health preparations, which have a very side molecular range, both small and large molecules.

I think it is perhaps superficial to say, dextran 1947 and dextran 2005 is not the same. It was old at the time in a green beautiful mineral water bottle, now days in plastic.

As we will find out, dextran has now been over 50 years in clinical use, but the indications for dextran have changed over the years.

From the beginning it was only used for replacement of blood loss and plasma. Then, in the 1960s, it was discovered that it had thrombo-prophylactic properties and that became, in the 1970s, the main indication for use in Sweden, actually.

Later on, radiological improvements with dextran 40 became more and more common. I think it is fair today to regard dextrans as pharmacological agents, because they have many pharmacological effects.

On reprofusion syndrome, they lower the bad cholesterol, and a lot of other things that are specific to dextrose.

Actually, no colloid is an inert exponder. They all have some pharmacological effects. Some of these may be beneficial, some may be troublesome, and they all have adverse effects.

The most common one is undoubtedly fluid overload. The injudicious use of colloids can cause cardiac failure in elderly patients.

Renal function impairment can be induced both by starches and dextrans by elevating the colloid aquatic pressure enough that you have a renal shut down.

You can dilute down the coagulation factors with efficient colloids, so that the hemorrhagic state ensues. The starches can be loaded in the reticular endothelial system, and cause problems, and they all cause colloidic reactions.

As an example, this is a severe anaphylactic reaction to a colloid gelatin. The gelatins are the most common cause of allergic reaction to colloids, with the tremendous swelling of the face and/or the upper airways. I think they were very lucky to have the endotracheal tube here before it happened.

Now the question of anaphylactoid or anaphylactic reactions. Of course, anaphylactoid are those reactions that we cannot explain by finding an antibody. Then they are called anaphylactoid.

They may look similar, but the mechanisms may be quite diverse. Anaphylactic are allergic reactions involving either reaginic antibodies -- IgE -- or antibodies in other classes, IgG, IgA, and so on. Dextran reactions belong to this group.

The reactions to different colloids may look very much the same but have different mechanisms. They have some common features, in that, for example, the most severe reactions are always elicited by minute volumes. The quicker the reaction comes, the smaller the volume that starts it, the worse it can get.

This is, for example, a cardiac arrest caused by 30 mls of human serum albumen. Incidentally, the only two prospective large trials of various colloids -- the ring methma(?) trial and the laxin air(?) trial from the early 1990s, the two most severe reactions in each of the studies were caused by human serum albumens causing cardiac arrest, none by the other artificial correlates.

This is a severe reaction caused by hydroxin. It is a starch. This is a severe gelatin reaction, and the black bars represent histamine levels during this reaction. It is known that gelatin causes histamine liberation, and in some cases it is IgE dependent.

This is a severe reaction to dextran 70, less than 20 ml causing cardiac arrest. So, we have the allergic reactions now to dextran.

We have used always in our papers in this group dextran induced anaphylactoid/anaphylactic reactions because most exist, and in the severe ones dextran reactive antibodies are involved.

So, most, at least, of the mild reactions are anaphylactoid, and the people who have them have more of them and an allergic history than the general population.

In contrast, this is not true for those having severe reactions. They have a lot more of them with a history of allergy than the general population.

We know now that these are anaphylactic and are caused by these IgG antibodies of draw type,and the type of anaphylaxis is called type III or immune complex anaphylaxis.

I would like to point out that IgE, elevated IgE level, and histamine liberation has never been shown in dextran reactions.

It has been searched but never found. We have no indication. On the contrary, we have other indications. It was found by Dr. Haden in the 1970s that there was a connection between antibodies.

This has been denied by the manufacturers previously because they had only analyzed serum samples collected after the reactions. She went out and went to the blood banks. I am in great debt to the Swedish blood banks. They have done me many services.

There we can find serum samples from the cross matching, and collect those, and analyze dextran active antibodies and then in post-reaction samples.

Here you see the correlation between the degree of severity. Number four is the most severe type, and the titer here, all the severe and fatal ones are up here in this region. So, there is a clear correlation between this. It is not as good for IgM and IgA.

So, the severe reactions are caused in this way. IgG molecules and the dextran form immune complexes. The immune complexes activate platelets, leukocytes, the complement system via the classical pathway, which has been shown by reduction of factor C1Q and C4.

This then leads to vasoreactive mediators across the clinical symptoms. These mediators have not been identified, but are probably of prostaglandin nature.

In a series of monkey experiments with type III anaphylaxis it was shown that you could attenuate these reactions by using doses of indomethacin.

The reactions have been classified in five grades of severity. From the beginning it was four, but I broke out the fatal ones, to have them more clearly seen in the pictures.

They are ranging from the mildest type with skin symptoms only, mainly, moderate circulatory derangements, and these, from grade three and downwards, are severe reactions.

One wonders, then, what is the cause of the dextran reactive antibodies, because I have told you from the beginning dextran was not immunogenic.

That was hydrolyzed soluble dextran, but native dextran may be immunogenic. It is a multi-million dalton molecule. We have often dental plaques that contain dextrose in our mouth. That is one way.

Food additives are another way, and sugar -- because the bacterium, the niche that is sugar. So, sugar produced in hot climates, like places where you grow can sugar, are more often contaminated with dextran than other sugars.

The most likely explanation we think is that most of them represent cross reactive polysaccharides that people develop toward encapsulated bacteria, like the pneumococci, streptococci and so on.

When you are born, you have no antibodies. After a year you can start detecting antibodies, and so on. There are differences in titer between countries, and most of it is probably genetically determined, as is everything else.

I thank these two colleagues for most of this, what I have presented until now, the late Professor Wolfgang Richter and Dr. Harrier Hedin, who did almost all the basic research. Professor Richter even did the first animal experiments with hapten inhibition.

The hapten, then, is an old idea. The term was introduced already in 1921 by Karl Landsteiner, who defined it as an incomplete antigen which did not cause the formation of antibodies, but can bind to them.

Hapten inhibition was first tried against penicillin allergy rather early, and it failed, which is not so surprising, because the penicillin molecule is much more complex than the dextran molecule, and there are antibodies directed toward different parts of it, and the hapten couldn't protect against all these antibodies.

Luckily, the dextran molecule is very simple. This is a picture of a dextran molecule with a molecular weight of 40,000.

An American researcher in the beginning of the 1960s, by the name of Cabot, he did a lot of in vitro experiments with dextrose, and he showed that the antigenic determinant is approximately five glucose residues long.

He even did prove hapten inhibition in vitro by the addition of hapten to his serum samples. He showed that you could block antibodies and prevent the formation of aggregates.

So, the idea of hapten inhibition in dextran reaction is delightfully simple, to chop up the molecule in small parts and inject them first.

If the patient has antibodies of the IgG class, they will be blocked by the hapten, which combines to the combining sites of the IgG molecule. Then, when the clinical dextran is introduced, no immune complexes are formed, and no reaction occurs.

The dextran 1 molecule looks like this. This is the molecular distribution with high performance liquid chromatography.

You can see each individual saccharide of glucose, isomaltose, 3 isomaltose and so on, and you see that the majority are around five, the peak there.

So, we set out to prove this rather early in human trials. We based this on the animal trials performed by Professor Richter, and some trials performed in Germany as well.

So, in 1978 we started with this. Of course, looking back, it is a very crude method we used. We simply started a clinical trial with protocols and everything, but it was not randomized.

All hospitals wanting to participate in Sweden, Norway and Finland were engaged. Approximately 65 hospitals participated.

We started off with a dose of the hapten that was calculated at the desk of Professor Richter to be sufficient based on the antibody titers that we had seen in reactors before.

When we had close to 30,000 patients, we saw that we had, in fact, reduced perhaps the incidence, but not eliminated the reactions. We still had seven reactions.

So, we changed and started injection of twice the dose, three grams. Bingo, after 41,000 patients total pre-injected with three grams, we had only one severe reaction.

Almost simultaneously, or slightly after us, the Germans and the Swiss also launched trials of a similar nature, arriving at exactly the same conclusions.

So, in the fall of 1982, the hapten was registered in Sweden. In 1984, I was over in Boston giving talks about the hapten, and it was introduced in the United States a few months later. It was registered in slightly less than 20 countries at that time, during the 1980s.

Actually, Sweden is, in this aspect, the best country to study the incidence. For one thing, we use a lot of dextran. Secondly, Swedish doctors are much more compliant to authorities than American doctors, I must say. They do report.

In 1974, the reporting of severe adverse reactions was mandatory in law in our country. So, it has been reported very thoroughly in our country.

The degree of reporting is connected to how easily the connection between the drug and the reactions are understood by the physician, of course.

If it is difficult to understand it, it will be perhaps not reported, but these reactions virtually all occur in the OR, when the anesthetist is giving something, and something dramatically happens. The connection is rather obvious in most cases.

We wanted to check how this worked and, of the three years, we made one post-marketing surveillance, and then I made another one when hapten had been used in our country for 10 years.

I could compare those results with a study from 1975 to 1979. During those years, some 650,000 units of clinical dextran had been distributed from pharmacies to hospitals.

We had 145 severe reactions. Twenty-three of these were fatal in these five years. So, I had the blessings of the Swedish equivalent to the FDA very much when we launched these trials, I must say, because they were worried.

From the delivery figures of 650,000 units, you could say that that is equivalent to approximately 300,000 patients being given dextran, because most of the indications were for thromboprophylaxis, and they used two units of dextran 70, which was the dominating substance.

During the 10 years after we launched the hapten, 1.2 million units of hapten have been distributed in Sweden, and we found 17 severe reactions reported to the company or to the authority. Only one was fatal.

So, that is one in 70,000 patients, and that is one in 2,000 patients. This is the explanation for the 35-fold reduction in incidence.

I was also asked by Dr. Landow about the 90-fold reduction in fatal reactions. That is derived from the 23 out of .3 million against one in 1.2 million. That is a 92-fold reduction.

I must first say that, as indicated already, there is never a good thing that doesn't have anything bad with it. As was pointed out, some of the patients react to dextran 1. The dominating symptom is skin symptoms. Most of these patients also have allergic history as common dextran.

Some patients react with circulatory symptoms, but without skin symptoms. We think that this may be related to the rapid injection of 20 ml of a 15 percent hyperaquatic solution in the patient.

I think by now some eight or nine million doses of dextran 1 have been manufactured and distributed, and we have had one fatal reaction to the hapten. So, there is nothing compared to what you could have expected in dextran with the patients.

For the purpose of this meeting, I have gone through the next 12 years, from 1993 onward, to see what has happened in our country since I wrote that last paper, because I have sort of followed the dextran over the years.

In the 1990s and until now, the marketing has changed twice between different countries. I have sort of piggy backed on the dextran and followed it, and asked, send all reports of adverse reactions to me. I will classify them and we will analyze it.

So, I have followed this all the time, and we have had only 15 severe reactions in these 12 years for approximately one million patients, compared to those 145 there, which is one in 67,000 patients. So, it has continued to be successful in our country.

The reason why it has not been so successful in the United States, I don't know. It was from the beginning sold by Pharmacea, the company that developed the clinical dextran, and they sold clinical dextran at that time and they had certainly in the package insert that you should use it.

Then they were other distributors of dextran who didn't think this was essential. In a way, it sort of scares -- they are afraid it will scare the doctors from using the substances, that you must have this precaution before you give the dextran.

So, from what I heard before I left from the company now distributing promit in Sweden, they haven't sold promit in the United States for some years. No one has bought it. So, that is the problem.

I have another way of -- there is another way of looking at it also to see the effectiveness from another viewpoint.

I just showed the titers. We found, in some of those who reacted despite the use of the hapten, titers that we had never seen before in the pre-reaction samples.

The worst one was a patient who lived across the street from our hospital. His titer was one to one-hundred thirty four millionths.

This means that, if you took 10 ml of his serum, poured it in an Olympic sized swimming pool and stirred well, that water would still aggregate erythrocytes coated with dextran.

He survived, which I am very proud of, I think, because he would never have survived without the promit injection.

Here are some references I want to give, and Dr. Landow, some of the publications that he can use in the future. This is the hospital where I have the privilege to work for 37 years.

Thank you for your attention. I am willing to try to answer any questions, only I want to point out one thing. My hearing is poor. So, speak up, really. Second, I am not an immunologist. I am a vascular surgeon. So, my ability to answer questions on immunology are somewhat limited, but I will do my best.

DR. ALLEN: Thank you very much. Dr. Lew?

DR. LEW: The manufacturing process, has it changed from the 1970s to 2004? You are comparing to historic controls in 1975 and now it is 2005. Is the manufacturing process exactly the same? Is the purity exactly the same?

DR. LJUNGSTROM: Yes, the purity of the clinical dextrose was the same only during the 1970s. The big changes in the manufacturing were made during the beginning of the 1950s, when they introduced the new type of leukonoptric bacterium, and also by introduction of a specific leuconostoc test, to make sure that there were not bacteria residues in the preparation. So, from the beginning of the 1970s it has been the same, actually.

DR. KATZ: You might have said this and I missed it. I am trying to get a feeling for why you use so much of this in Europe. What kind of patients are the patients that are getting this in Europe?

DR. LJUNGSTROM: I am a vascular surgeon. I use a lot of reomaculates(?) for vascular patients. The Swedish anesthesiologists like dextran because it is much more effective than a solution of other things in the preparation of patients for surgery in connection with regional anesthesia. They are much more stable. It is used a lot in our country still for this purpose.

Thromboprophylaxis was the main indication during the 1970s. They, of course, have been surpassed by the low molecular weight heperins, which are more effective in preventing thrombosis than dextrans. Still, dextrans are pretty good in preventing fatal pulmonary embolism.

DR. HARVATH: In the million patients that you described in Sweden, in which you have been following these adverse events, were all of those patients in the hospital at the time they received the dextran, and was it in a controlled environment of either a surgical suite or hospital ward?

DR. LJUNGSTROM: We don't have private practices in our country doing major surgery or operations where dextrans would be indicated.

A few places might use it for hemodilution of patients with polycythemia in connection with blood letting and so on, but I have seen, over the years, something like a handful of reactions occurring in our country outside the controlled hospital environment.

DR. HARVATH: The other question is, do you have experience in Sweden using this combination of products in patients who have had severe trauma and blood loss?

DR. LJUNGSTROM: Yes, of course. A lot of patients have obviously received this in connection with that. My personal view has always been, when I have been given this question by anesthetists and trauma surgeons, that if the patient is in poor condition, skip the promit, give the volume. That is the most important thing.

On the other hand, Sweden is a very peaceful country that has not been at war since 1814, and we have very safe driving. So, our level of trauma is negligible compared to what you see in many American cities.

DR. WHITTAKER: Could you tell me the cost of a dose of promit?

DR. LJUNGSTROM: That is always adjusted in the countries where it is sold, I understand, for competition with other products.

The price of the clinical dextran will be the same as, for example, as for a starch or a gelatin, if that is the most common drug in that country. It varies across countries and across the world, what kind of color anesthetists and surgeons prefer.

In South America, in Argentina, when I was there, I found much to my surprise they were crazy about the gelatin, and they were more expensive than the starch.

DR. MILLER: How does the incidence of adverse reactions with dextran compare with other colloids, like albumen or hetistarch.

DR. LJUNGSTROM: Good question, because that is largely not known. The first bid comparative trial of colloids was published in the 1970s, before the hapten, and it is somewhat misleading, because it contains a lot of dextran 40 patients, many of whom were given a series of infusions for vascular disease, stroke, such things.

If you give a patient one bottle of dextran and nothing bad happens, the next day, the chances that something will happen are virtually nil. Thus, if you calculate the incidence in relation to bottle(?), this will be very misleading.

In Sweden, where we don't use this rigorous scheme of hemodilution for such patients, the incidence in relation to bottles was approximately half that of dextran 70 to dextran 40.

Then you have the Laxanaire trial from the beginning of the 1990s. Just as someone said here, they don't know if the patients have had the hapten or not. So, that is really a problem. You cannot evaluate how it would have been if they had used the hapten altogether.

What I have to say is, the incidence of severe reactions in our country, with the regular use of this, is of severe reactions to dextran is not higher than it is, for example, for the starches.

DR. GORDON: David Gordon, National Heart, Lung and Blood Institute. As I understand the data that you presented, it all comes from basically adverse event reporting, spontaneous adverse event reporting.

Given the side effect profile that you listed for promit, which is, I guess the serious ones would be hypotension and bradycardia, and given the fact that dextran or the dextran promit combination would be administered to a lot of patients who are undergoing -- who have severe volume depletion or are undergoing surgery or soon, how would you envision that you would detect deaths that are due to promit or side effects?

How do you know promit isn't making them worse, because the side effect profile -- how would a physician spontaneously reporting an adverse event recognize that some exacerbation of a condition is actually due to the promit? Would you have any way of ascertaining that?

DR. LJUNGSTROM: Let me put it like this. I have recovered a lot of the international reports, from the international registry, where different countries register the adverse reactions.

In these they are always linked together. So, it is reported as a reaction to promit, and dextran 40 and promit, and dextran 70 and promit.

Of course, if the patient reacts to the promit, in most cases, they will not receive dextran 70 or dextran 40. During the trials, there were several brave anesthetists who, after the patients had bradycardia and then were okay, they started the clinical dextran. None of these patients developed a reaction, interestingly enough.

DR. GORDON: There has never been a randomized study of this one.

DR. LJUNGSTROM: No. We didn't start the study as randomized because we feared the -- we knew the level of incidence, how it was. We would need such tremendous trials, we thought we could never manage that trial. So, it was a double documented clinical trial, but not randomized.

DR. GORDON: There is nothing where you randomized, say, one county of Sweden to do it one way and one county to do it another way, so you would have a lot of cases.

DR. LJUNGSTROM: No.

DR. ALLEN: Other questions or comments? You will be here, I think, for the rest of our discussions of the questions?

DR. LJUNGSTROM: Yes.

DR. ALLEN: Okay, at this point we will move to our open public hearing.

Agenda Item: Open Public Hearing.

DR. ALLEN: I have got a list of two speakers. I do need to read through the public hearing announcement for general matters meetings.

Both the Food and Drug Administration and the public believe in a transparent process for information gathering and decision making.

To ensure such transparency, at the open public hearing session of the advisory committee meeting, FDA believes that it is important to understand the context of an individual's presentation.

For this reason, FDA encourages you, the open public hearing speaker, at the beginning of your written or oral statement, to advise the committee of any financial relationship that you may have with any company or any group that is likely to be impacted by the topic of this meeting.

For example, the financial information may include the company's or a group's payment of your travel, lodging or other expenses in connection with your attendance at the meeting.

Likewise, the FDA encourages you, at the beginning of your statement, to advise the committee if you do not have any such financial relationships.

If you choose not to address this issue of financial relationships at the beginning of your statement, it will not preclude you from speaking.

Our first speaker for this afternoon is Dr. Eileen Bulger, University of Washington, and I believe there is a handout that she has provided also. Dr. Bulger.

DR. BULGER: Good afternoon. My name is Eileen Bulger. I am an associate professor of surgery from the University of Washington.

I am a clinical investigator studying the effects of hypertonic resuscitation for trauma patients who are in hypervolemic shock.

I am here today to speak specifically about the risk of severe dextran-induced anaphylactic reactions in this patient population receiving a hypertonic saline dextran solution. I have no financial conflicts of interest with any of the companies or products being discussed today.

Hypertonic saline dextran is a 7.5 percent saline, 6 percent dextran 70 solution. It is given as an initial 250 cc bolus to patients in hypervolemic shock after acute injury.

It is currently approved for use in 14 European countries under the trade name, Rescueflow, which is produced by Biophausia in Sweden, and this is the product that we are studying in our clinical trials.

It is approved for use in these countries without the pre-medication with promit. There have been eight previous clinical trials, primarily in the United States, for which a meta analysis suggested significant benefit in this patient population with an improved odds ratio of survival of 1.47 and, for patients with concomitant traumatic brain injury, a two-fold increase in survival.

The potential advantages of hypertonic saline dextran resuscitation is that it provides a more rapid restoration of profusion with a small volume.

It improves cerebral profusion while decreasing intracranial pressure, which may be the mechanism by which it is particularly beneficial for patients with traumatic brain injury.

A large body of preclinical data suggests that it significantly alters the immunoinflammatory response after injury and, therefore, could decrease the risk of subsequent inflammatory organ injury, such as acute respiratory distress syndrome, and could reduce the risk of nosocomial infection by enhancing T cell function.

I am the principal investigator of an NIH funded clinical trial that has been underway at the University of Washington for the phase II trial in hypotensive blunt trauma patients administered hypertonic saline dextran in the pre-hospital setting.

The primary end point for this trial is the rate of ARDS within 28 days. We are looking at this as an immunomodulator.

Our current enrollment is 205 patients and, despite the fact that there have been on adverse drug related reactions in these patients and no evidence of anaphylactoid reactions, we were placed on clinical hold last week with the understanding that further discussion needed to be had as to whether promit pre-medication should be required in the trial.

I am also co-investigator for the resuscitations outcomes consortium, which is a multi-center clinical trials network that has just been funded also by the NIH, that is proposing a phase III trials that will look at two cohorts of patients, one with hypovolemic shock with a primary end point of 28 day survival, and a cohort with severe traumatic brain injury looking at neurologic outcome in six months. This trial is under IND review.

Just for your background, the Resuscitation Outcomes Consortium is a multi-center network that includes 10 clinical centers in the United States and Canada, and is funded by the NIH, the Canadian Health Research Institutes, and the Departments of Defense for the United States and Canada.

There have been several limitations to the prior reports of dextran use anaphylactic reactions that you have heard today, particularly when you are trying to apply them to this patient population.

As has been stated, the majority of the patients in the previous trials were in elective surgery situations and were, therefore, not hypovolemic.

They were a significantly older patient population with a mean age of 60 in the trials reported by Dr. Ljungstrom, and the highest rate of seroreactions was for patients undergoing regional anesthesia. The mechanism for that is not clear, but is certainly not an issue for trauma patients.

As has been mentioned, the data relies on comparison to historical controls from the 1970s, and there is no randomized control trial data available for this patient population.

We wanted to try to estimate what the risk would be in trauma patients receiving hypertonic saline dextran. So, we started by looking at what the experience has been.

Overall, there have been 900 patients enrolled in clinical trials, again, primarily in the United States, who have had no reports of dextran induced anaphylactic reactions. This is patients receiving hypertonic saline dextran in hypovolemic shock.

There have been 20,100 patients treated in Europe, primarily in Sweden, in that region, that the company that produces Rescueflow has data for and, again, there have been no reports of dextran induced anaphylactic reaction in these patients.

That gives an incidence of zero for 21,000 which, if you project it for 100,000 patients, which is what all the other numbers are based on -- I am trying to allow you to compare them -- it has to be less than five per 100,000.

The other way to look at the incidence in trauma patients is to look at the experience with hypertonic hetistarch, which has been used widely in trauma patients, primarily in Europe as well, and the studies are out of Austria.

The experience for hetistarch has been reported to have a two-fold higher rate of anaphylactic reactions than dextran. This projects out to an experience of four to eight per 100,000.

So, this is a take home slide for me, and the question is, how does the risk in trauma patients receiving hypertonic saline dextran compare, without promit pre-medication, compare to the risks with promit pre-medication in the elective surgery population receiving isotonic dextran solutions.

As you can see here, these ranges -- these are the ranges reported by Dr. Ljungstrom's series. The 1.4 series if the post-marketing surveillance series reported in 1993, and the three is the original clinical trial. It is not statistically different from the zero to four range that we would calculate for trauma patients.

Some of the problems in using historical controls have been pointed out previously, but as Dr. Ljungstrom's reports say, they range from 25 to 50 per 100,000 depending on the time period, in the 1970s, that he compares his data to.

The study that he referred to by Ring et al reported a much lower incidence of eight per 100,000. Again, he indicated that he thought there were some problems with that study.

Nonetheless, depending on which historical controls you use to compare the data to, the advantages of promit may look a little bit different.

To put all the numbers in context, the annual risk of anaphylaxis in the community, from a population based study in Wisconsin, and that listed such things as food allergies and insect bites and so forth, is 21 per 100,000.

There are two theories in the literature as to why trauma patients may be protected from dextran induced anaphylactic reactions. Again, these are theories. Nobody knows the exact mechanism.

Trauma patients in hypovolemic shock have high circulating levels of catacholamines, which are used to treat anaphylaxis. So, it could be protective.

It is suggested that the rapid infusion of hypertonic saline dextran may result in an excess of antigen in the blood that could also prevent the formation of immune complex, as much as dextran 1 is designed to do.

There are limitations to the use of promit, as has been alluded to a little bit in the earlier discussion. The side effects reported by Dr. Ljungstrom in the post-marketing surveillance rate was one per 100,000 but, if you go back to the original trial, where you would assume patients were more closely monitored for side effects than in post-marketing surveillance, it was 57 per 100,000.

Half of these were skin reactions, which were minor, but the other half involved some degree of hypotension, bradycardia, with hypotension. If you are giving this to a patient who is already hypotensive, this could be a significant problem.

Several studies suggest that hypertonic saline dextran is most effective as the first fluid given. Therefore, it is normally given in the pre-hospital or battlefield setting.

In this circumstance, you have to consider the feasibility of adding the pre-medication step, particularly if it is not necessary, because it may delay the medic from other critical interventions.

Finally, the immunomodulatory effects of promit are unknown, and its main mechanism of effect may be by modulating the inflammatory response. It could also be effectiveness, and all the previous studies with HSD have not included promit pre-medication.

So, in summary, trauma patients who receive hypertonic saline dextran appear to be at a much lower risk of severe dextran induced anaphylactic reactions during previous reports in elective surgery populations with isotonic dextran.

To date, there have been no reports of severe dextran induced anaphylactic reactions in 21,000 patients receiving hypertonic saline dextran.

There is no statistical difference between the estimated risk of severe dextran induced anaphylactic reactions for trauma patients receiving HSD, and the projected risk for promit pre-treatment before dextran infusion.

We ask the committee to consider whether promit pre-medication should be required in this circumstance. Thank you.

DR. ALLEN: Committee questions for clarification from Dr. Bulger?

DR. KATZ: I am a little concerned about your risk of severe DIAR in trauma patients. You cite 900 patients in clinical trials and 20,100 treated in Europe. I wonder, the 900 patients in clinical trials, I presume we have decent data regarding adverse reactions. Edify me on the 20,100 treated in Europe?

DR. BULGER: So, the 20,100 patients treated in Europe, again, the longest approval has been in the Norwegian countries where, as Dr. Ljungstrom alluded to, the serious events reporting system is quite good.

So, that is what you are relying on, post-marketing reporting, which relies on reporting of adverse events. You are relying on reporting of adverse events for interpretation of that 20,000 patients as well.

DR. KATZ: I don't know if Norway is the same as Sweden or not, but I wonder if FDA's statisticians or anybody else's have done some confidence intervals around a variety of ends to give us an idea of how precise we are. I mean, zero of 900 is a lot different than zero of 20,100, and I am not sure where the truth lies.

DR. WISE: My name is Robert Wise, with FDA's Center for Biologics Office of Epidemiology and Biostatistics -- or vice versa, biostatistics and epidemiology.

In general, if you have no observations, a broad rule of thumb is that the upper 95 percent confidence interval is there probably would be no actual occurrences in a third of the number of subjects observed.

So, you would have 95 percent confidence in roughly no cases in a third of the actual rate of anaphylaxis sort of serious adverse events, would be zero in 300. That is based on the 900 with presumably consecutive careful ascertainment of adverse events in a clinical trial setting.

I would be very cautious about inferring or having confidence in absence of observation of anything in the post-marketing spontaneous reporting setting.

I am not familiar with the Norwegian setting. The ascertainment fraction may be better than what it is in the United States, but generally, ascertainment of adverse event reporting through spontaneous reporting post-licensure passive surveillance is widely variable and not reliable for numerical estimations.

DR. BISWAS: Can I just clarify, I think Dr. Ljungstrom was also asked the same question and I think he clarified it.

I think the number of adverse events cited in patients receiving the promit or the dextran 1, the adverse events had occurred when the patient received both the dextran 1 and the dextran 47. Is that correct? If that is true, how do you know which of the products caused the adverse event. That is the first question.

DR. BULGER: Well, in his original paper where the rate is 100,000 -- and Dr. Ljungstrom can correct me if this is wrong -- but he reports it as side effects to the promit. I assume that those were reactions that were observed after the promit was administered.

DR. LJUNGSTROM: As I said, in some rare instances, anesthetists gave the clinical dextran after the patients had bradycardia after the injection and, in all these cases, no reaction of typical DIAR occurred.

On the other hand, if the injection was done and nothing happened, they started the clinical dextran in the ordinary way.

Most of these reactions to dextran 1 come rather rapidly, during injection or immediately after the injection. So, it is possible to differentiate between them.

I would say it has happened in recent years, one patient, for example, she got itching while the promit was injected, but she didn't tell the nurse, and then they started the clinical dextran and then it got even worse. That was a typical thing with the skin reaction. We have never, with the promit, seen reactions of the type that you see with clinical dextran, with skin reactions, bronchospasm, cardiac arrest and so on, nothing of that type. They are different.

May I add that what you are giving is not exactly the same substance, because you have the dextran in a different environment.

You have it in the hypertonic saline, which might very well have some influence on this. Something between 10 and 25 percent of the population have elevated titers of dextran reactive antibodies, but most of them don't know it. They don't know it and they don't react to dextran, with or without the hapten.

So, there needs to be something more under the circumstances than you infuse the dextran to start the reaction, and what that is, we don't know.

The reporting in Norway is quite the same as in Sweden, whereas the reporting in the United States of dextran reactions clearly is very scanty, because we -- Professor Richter analyzed antibody titers from blood donor samples from six countries -- the United States, Japan, Italy, Germany, Sweden and Norway.

In three of these countries, dextran reactions are reported frequently -- Sweden, Norway and Germany. What countries did have the highest titers? The United States, Italy and Germany. The Japanese had very low titers. So, their very low report of incidence was true.

So, the incidence of reports that we find in a country reflects much more the reporting quality of that country than it reflects the immunological status in that country.

DR. BISWAS: Can I ask another question? You point out that there is a difference from your data, or the data that you present, between patients who are receiving a treatment and had trauma, compared to elective surgery.

Considering that patients with trauma, a lot of them are in shock, and if you are talking about the DIAR as being manifested, one of the major manifestations being shock, how do you deal with that issue?

It seems to me that it would be harder to detect the patient going into shock getting this product, who is already in a shock-like state.

DR. BULGER: In reading Dr. Ljungstrom's excellent reports, it is clear that these are not subtle reactions. They are striking episodes of clear anaphylaxis, where the patient gets very swollen. It is not just hypotension alone that these patients manifest.

Our paramedics are trained, as were, I think, the medics in previous trials, to look for anaphylaxis reactions, which they are used to seeing for bee stings and so forth, and to report those as serious adverse events, as are ER physicians and so forth.

DR. KUEHNERT: Dr. Ljungstrom touched on that we don't know rates of anaphylactic reactions to other classes, and colloids and gelatins and starches. I wondered if you could add some insight into that, in addition to what you have in your chart, as far as how others, such as albumen, compare, as far as rates.

DR. BULGER: There is one reference from 2004 that tried to compare this, sort of on a meta analysis basis, by looking at the literature, among the various colloids.

Albumen is the baseline. So, albumen had the lowest risk. Dextran was about two-fold higher risk for anaphylaxis than albumen. Hetistarch or hextan was, again, two-fold higher than dextran, so four-fold higher than albumen, and then gelatin was the worst. Gelatin was off the chart.

DR. KUEHNERT: I just wanted to ask FDA, are there warning labels on these other colloids?

DR. LANDOW: I deal with a few of the starch solutions, and I have to be honest with you, I don't believe so, but I would have to look.

DR. MILLER: I wonder if we could get Dr. Ljungstrom's opinion about the idea that there is something unique about the trauma patients, and giving this hypotonic saline dextran solution, that is different than the types of patients that he reported on, who were getting elective surgery. Does he think that is a reasonable notion, given his expertise in this area.

DR. LJUNGSTROM: As I said, trauma is not a big issue in our country, although patients are reported from the 1970s that had severe dextran reactions. I recall only one patient who was in shock when their reaction -- it was an outpatient.

It was not in traumatic shock, but was in sort of septic shock when the reaction came. I couldn't find anyone reported as having a severe dextran reaction who was in shock when the dextran was given.

On the other hand, it was believed that you should start the dextran infusion when the patient was being operated, because surgery would start catecholamine levels to rise, and then they would be protected.

So, that was spread as the truth among the anesthetists and, consequently, virtually all the patients who died during the 1970s of dextran reactions were on the table when they were having the dextran and died.

As I said, the typical patient who died was an elderly gentleman with spinal anesthesia operated for his prostate. There, we think that regional anesthesia may have some influence on the poor outcome, because if you have a high regional anesthesia, you will block a lot of the adrenal response to what is happening. Of course, the weaker sex also.

That is what I can say. I have never been stopped by hapten to give dextran to a patient in shock. We have never practiced to use it in the emergency room, I would say.

So, I am not at all against what you are saying regarding the use of this special trauma solution, which I think is useful, too.

DR. LEVY: There are really, I think, two issues here. The concept of using this dextran hypertonic solution is using it for life saving resuscitation of hypovolemic shock and shock in general, which is a different indication than the current use in the United States, and I think Dr. Miller might like to comment.

Use in plastic surgery and in vascular surgery, as Dr. Landow is pointed out, it is used prophylactically to basically produce platelet dysfunction.

Especially, imagine a large atheromatous surface being operated on, creating a very pro-thrombotic effect, and in vascular surgery, because of the microvascular consideration of keeping the vascular open.

It is used more as a therapeutic adjunct in 2005 in that setting, versus as a life setting therapeutic maneuver for hypovolemic shock.

This is used electively. This is used life saving. I really think that it is not used in the United States in 2005 as a colloid volume expander for years, and I think that we are talking about a lot of important issues.

The reality is that, in this situation, you have the ability to prophylax with promit, because it is used as a therapeutic adjunct, not anything else. Here it is being used to save lives as a hypovolemic shock, resuscitative solution.

I think they are two separate indications, quite frankly. We have lumped them together, but I think we need to split them apart. I think you would perhaps agree with that as well. Dr. Miller, did you want to comment about its use in plastic surgery?

DR. ALLEN: Let me just interrupt here. We have still got one more speaker. We are really getting into the general discussion now.

Dr. Miller, please respond, and Dr. Katz, is it a question to our speaker here? If not, let's cut this discussion, get our last speaker, and then go into the general discussion more broadly.

DR. MILLER: Most people doing microvascular surgery have gotten away from using dextran or any antiplatelet agents. So, it is not commonly used. I agree with you completely. It is a totally different indication than trauma.

DR. ALLEN: Any other questions for Dr. Bulger specifically? If not, we will then move on, and our speakers will stay here and be part of our discussion subsequently.

Our next speaker in the open public hearing session is Colonel Holcomb, United States Army. He is trauma consultant to the army surgeon general.

COLONEL HOLCOMB: Good afternoon, coming to good evening. Colonel John Holcomb, I am an active duty trauma surgeon, associate professor of surgery at USHUS, co-chair of the resuscitation outcomes consortium, and commander of the U.S. Army Institute of Surgical Research at Fort Sam Houston, Texas. It is my pleasure to be here today.

I am here today on behalf of the United States Army Medical Research and Materiel Command, to express our support for the proposed ROC trauma trial with hypertonic saline dextran.

The army has been deeply involved in the developing research priorities of the ROC, and we felt this effort is critical to optimizing care on the current battlefield.

The current trial has a control group with an expected mortality of 40 percent, and that is a study of the most severely injured civilian trauma patients that have any chance of survival with optimal treatment. The results of this trial will translate almost immediately to the battlefield.

As a developer of the DOD trauma training program in the civilian centers, with previous combat surgery experience, six deployments into Iraq, I can tell you that personally, professionally, and representing the military, we are extremely interested in this discussion today and its impact on what we do in the battlefield.

This type of fluid will further the DOD's resuscitation strategy of minimizing weight. This is critical at a time when our combat medics literally carry fluid into battle on their backs, and decreasing any amount of volume is important to their survival and to their casualties' survival.

Recognizing this critical difference between military and civilian pre-hospital care, over the last six years, the DOD has adopted a comprehensive strategy of treatment of combat casualties.

We call this strategy tactical combat casualty care. It is published in the pre-hospital trauma life support manual, endorsed by the American College of Surgeons Committee on Trauma.

The current resuscitation algorithm recommends hextan, a fluid solution we discussed already, a hetistarch solution, mixed up in a balanced salt fluid.

That is our current recommended fluid of choice for combat medics to carry into the battlefield. It is 500 ccs, instead of a liter like most ambulances carry.

The current resuscitation algorithm is not exactly perfect. We would like to improve it. We would like a smaller and lighter fluid that carries more bang for the buck than hextan. Thus, our strong and long interest in HSD.

Only casualties that are hypotensive are resuscitated with this special algorithm, and it is a very logistically sound, practical approach to resuscitation on the battlefield.

Based on my experience as an army officer, clinician and researcher, I have come to appreciate the army's strong commitment to HSD over the last 15 years, as it has wound its way through the approval process.

After hemorrhage control, fluid resuscitation is the most basic strategy for treatment of trauma patients. However, the optimal fluid for this purpose has yet to be identified.

Of the various fluids under investigation, none has received as much attention as hypertonic saline dextran, as evidenced by the hundreds of publications in the scientific literature.

Without a doubt, ladies and gentlemen, HSD is safe. It is an effective volume expander and, because of its significant logistical advantage -- again, 250 ccs per bag -- and proven track record, it is of great interest to us.

A summary of the preclinical studies indicates that HSD enhanced hemodynamic stability, corrected metabolic disturbances, decreased the inflammatory reaction, and restored tissue profusions at volumes one tenth to one twelfth of that required to elicit a similar response from a liter of lactate ariners(?).

Meta analysis, as Dr. Bulger has already presented, of human trials suggested improved survival for all hypotensive patients, those with significant surgical procedures, those that were profoundly hypotensive, and those with head injuries, and specifically those with penetrating injury requiring surgery.

I have personally analyzed most of the 1,200 combat deaths in this current war, gone to the FIP, and reviewed the autopsies.

We have taken those apart and looked at the potentially preventable causes of death. There are about 200 soldiers.

Those exact conditions that result from the meta analysis are the ones that are in that list of 200 potentially preventable deaths.

The dextrans have had over 60 years of clinical use with well defined toxicologies. A compilation of preclinical and clinical studies of HSD have been appropriately designed to identify potential adverse effects, in addition to their efficacy.

With over 900 trauma patients treated with hypertonic saline alone, or in combination with dextran, in the United States trials alone, none of these theoretical adverse events have ever been described. I think that is an important point, despite the close scrutiny of the investigators.

In addition, as we previously discussed -- and this is from the same kind of data that Dr. Ljungstrom presents with the self reporting and, as he said, in a very much more compliant system than our system of physicians that are somewhat resistant to authority, over 20,000 trauma patients have been treated with HSD with no significant adverse effects ever reported in trauma patients.

As discussed previously, the army currently recommends hextan for fluid resuscitation on the battlefield.

It is recognized that hetistarch containing fluids, like the dextrans, that are associated with rare anaphylactoid like reactions.

Data from the European experience with hypertonic hetistarch, all reported from the elective surgery experience, have found the incidence of such reactions to be extremely low. It is estimated it is eight to 16 per 100,000. Dr. Bulger has completely reviewed this subject with the data.

The literature would suggest that the incidence related to dextran is half that of hetistarch. However, there are no data that we can find anywhere that relates a reaction in any trauma patient in any place in the world.

As clinicians, we all routinely balance risk and benefit every day, in all of our treatments to everybody. Not infrequently, we accept higher rates than have just been previously described in some detail.

We understand the variability of promit may reduce the already low elective surgery rate, although it is still very unclear whether there is any benefit in trauma patients.

Furthermore, as Dr. Bulger stated, the use of promit may compromise the ability of civilian paramedics, and especially military medics on the battlefield or in the streets of the United States to give the life saving hypertonic saline dextran.

It may actually induce its own significant adverse effects of hypotension in a patient population in the ROC trial designed to have a 40 percent mortality in the control group.

As promit is only effective as a pre-treatment, with a short period of time between giving the dextran, the therapeutic window is not effective when given concurrently.

I feel this use to be extraordinarily difficult, if not unacceptable, on the battlefield. Proposing to pre-treat combat trauma patients in the midst of a fire fight, for a reaction that has never occurred in a trauma patient, is difficult to envision.

The army remains strongly supportive of the proposed HSD trauma trial. The proposed study is based on greater than 20 years of promit's preclinical and clinical work by the resuscitation thought leaders in trauma in the United States and around the world.

For the very first time in the United States, we propose to study the airway breathing, circulation paradigm that we have always heard, but there is no data to support.

We have now proposed a well designed, multi-institutional, actually elegantly designed trial of the circulation for those ABCs.

I think, number one, that is a very good thing, just in and of itself, to actually study something that we do routinely, and put some data next to it for the first time, but especially because the results of that trial, once analyzed and reported, will be immediately transferred to the battlefield. The DOD eagerly awaits the results of the trial.

Considering the severity of the injuries, environment, and the very real logistical constraints of combat casualty care, we do not feel that promit would significantly improve our risk to benefit ratio in the treatment of combat casualties. In fact, this addition would likely delay care for American casualties that require immediate resuscitation.

Ladies and gentlemen, I return to Iraq in a little under 30 days. I am going to carry a low volume resuscitation fluid with me when I go, along with me when I go, along with a tourniquet and several other devices.

I would just ask you to think of this conundrum that we are laying out in front of you. We are talking about a drug that has a complication effect, that is not readily available in the United States, to treat a reaction that has never been reported.

The results of your decision has immediate benefit, not only for the ongoing NIH supported trauma trial of Dr. Bulger in Seattle, but for the ROC resuscitation trial, and for the battlefield. I would be happy to take your questions.

DR. KLEIN: You have obviously given this a lot of thought and I appreciate your comments. Do you think a black box warning would compromise the trial or the use or, if we went one step further, a black box warning, for example, for elective surgery would compromise your trial or your use in the battlefield?

COLONEL HOLCOMB: That is a good question. I think a black box letter would have significant impact on our ability to do the trials on clinical hold, the ROC trial. It would also have the effect, as I alluded to, on what we do on the battlefield for colloid solutions.

That speaks to trauma, and that is what I prepared and talked about. I think the discussion about elective surgery is a little bit different, and I do think there probably is an incidence in that effect, and you can use a drug to pre-treat elective surgery patients. I think that is actually an interesting discussion.

DR. ALLEN: I guess my question is, the solution that was used in this instance in these clinical trials that are underway or proposed, the hypertonic saline dextran, I assume it is a different product than the dextran 40 or 70. Is that correct?

DR. LANDOW: Dextran is a component of HSD.

DR. ALLEN: Well, it is a component of it, but I mean, if we were to recommend to the FDA a black box warning for situations in which pre-treatment was possible, it is not clear in my mind that it would necessarily apply to this product that is currently being studied in the clinical trials.

DR. BULGER: It is a 7.5 percent saline, 6 percent dextran 70 solution. So, six percent of the solution is made up of dextran 70.

DR. ALLEN: Did you get that supplied by a commercial manufacturer? I mean, you don't make that up in your hospital or research center.

DR. BULGER: That is correct. We purchase it from the Biophausia, which is a company in Sweden that produces it, markets it in Europe. How your warning would apply to the clinical trial, I would ask Dr. Landow, since he is aware of the IND.

DR. LANDOW: Could I just comment about the dextran 1 solution? I hope everyone is aware on the committee we are talking about a 20 cc syringe that is given essentially IV push over 20 to 30 seconds. I just want to make that clear.

DR. KATZ: So, you are doing -- Dr. Bulger, you are doing the trial now that is a couple hundred patients, as I understood it.

I don't know how the power calculations were done. The larger trial, I presume, is powered to detect an improvement in survival or neurologic outcome that, if I am reading the meta analysis correctly, is approximately 50 percent versus the worst risk that was alleged in the elective surgery patients of one in 2,000.

I think that probably, if the power calculations have passed muster at IRB, I don't think it is reasonable, with that estimated benefit, to hang up your trial based on those old numbers, given that, however uncomfortable I am with the rates of adverse events in trauma patients, the upper confidence interval is far less than the potential benefit that has passed muster of an IRB. I think I would certainly be uncomfortable with hanging up the trials.

DR. ALLEN: Do you have a question for Colonel Holcomb?

MR. DUBEK: No, I have a comment based on some of the issues that have been raised.

DR. ALLEN: What I would like to do is close out the open public hearing, and then move on to the general discussion phase. So, are there any other critical questions for Colonel Holcomb? He will be here. We will certainly involve him in the discussions in just a minute.

Thank you very much, Colonel. Is there anybody else that wants to speak during the open public session? We will go ahead and let you make a comment.

MR. DUBEK: I am Michael Dubek from the U.S. Army Institute of Surgical Research, and I have no conflict of interest in this discussion.

I just want to reiterate what has kind of been talked about. As Dr. Ljungstrom has said that the dextran in 1947 is different than it is today, primarily because of refinement and the molecular weight fractions of the product, in that same way, HSD is different than dextran 70.

I have been involved in preclinical studies with both Macradex, Reomacradex and HSD for the last 17 years, and I can tell you they are all different and they have different effects on the animals.

DR. ALLEN: Okay, I will now officially close the open public hearing session. We are going to move into the open committee discussion.

Agenda Item: Committee Discussion and Recommendations.

DR. ALLEN: Dr. Bulger or Colonel Holcomb, if you would please clarify for me, Dr. Bulger, you said that the clinical trial that you are doing, the phase II clinical trial at the University of Washington has been placed on clinical hold. You were notified about that last week or very recently. What was the reason you were given for the clinical hold?

DR. BULGER: I was notified by telephone last week to put this study on clinical hold and not enroll any further patients pending discussion of a plan for promit pre-medication.

DR. ALLEN: And that notification came from the NIH or the FDA?

DR. BULGER: From Dr. Landow.

DR. ALLEn: Thank you. What is the current status of the resuscitation outcomes consortium trial, the ROC trial?

DR. BULGER: It has been reviewed by the NIH protocol review committee and approved, by the NIH data safety monitoring board and approved, but it is now under IND review at CBER.

DR. ALLEN: It would seem to me, based on the testimony that we heard, that there is strong reason why that should be moved forward as expeditiously as possible. All right, thank you very much. Other questions or general discussion?

DR. HARVATH: I think a question for us, I know for a number of us at the NHLBI because we have discussed this issue recently, is even if you were to take a well controlled clinical environment situation, such as Dr. Ljungstrom has revealed in his country, I have been led to believe that we have a difficult time obtaining promit, even in some of the hospitals in this country.

So, I wonder how feasible it would be, in the well controlled surgical suite environment throughout this country, to implement the recommendation that we are being asked to comment on.

It would really help me personally to know about the availability, since there is only one manufacturer of the drug, and the company is in Europe.

DR. LANDOW: I can't speak to the availability. Someone referred to a web site of a company. I can't comment on that.

DR. STEFANO: It is actually the American Hospital Pharmacy web site that I obtained the information from.

MR. GARBER: I think the availability question is obviously an important question. I am not sure we can settle it here. There is some proprietary information that we have that we can't divulge anything about it.

What I would suggest is that, if that is regarded as an issue or is an issue, that the companies involved, or the people doing the trials, need to make direct contact, and the FDA, I think, is willing to be a third party in that contact, to make sure that this will be available.

This has to be feasible. You don't want to ask for something and then find out that the product is not available. It may be a problem, but I think we need to be able to solve it, and the way to go forward with it is to have those kinds of conversations.

DR. EPSTEIN: Just to comment that we have a free market and, to some extent, the availability of promit in the United States has been limited because the demand has been limited, but part of why the demand is limited is that there is no labeling, nor directed training on the need for dextran 1.

So, it is a bit of a circularity problem, and our expectation would be that, if there were alerts in labeling, that more likely than not, the suppliers would respond to demand, as they are interested in selling the product. They have not withdrawn it from the U.S. market.

So, I think there is a little bit of a vicious circle going on, and it is easily broken if demand goes up, but I am not speaking specifically about manufacturers' intentions, because I can't.

DR. BULGER: Well, immediately after being placed on clinical hold, I had my investigational pharmacist try to contact this company in Sweden, as he couldn't find any U.S. source for the drug either.

The company in Sweden is on its midsummer vacation. So, we couldn't get anybody to talk to about this specific issue, as to what their availability is or what the cost is. It is one small company in Sweden that manufactures this product.

I don't think the decision should be made on availability, though. I feel strongly in our data that there is not a significant benefit to the use of promit in the trauma studies, and I would like the committee to clearly weigh in on that.

DR. KUEHNERT: I just wondered if there could be some clarification on what came to light recently that stopped the trial? I don't quite understand that.

DR. LANDOW: We had been planning to discuss prophylaxis of dextran administration with promit for months.

DR. KUEHNERT: Was it like some sudden data that comes to light? It is just the data that has been presented? I just want to make sure we are not missing something.

DR. LANDOW: We became aware -- I can't tell you how, but we became aware that the labeling of dextran solutions lacked any mention of promit administration ahead of time, which they had done in the early 1990s.

DR. ALLEN: Doesn't the FDA have to approve all labeling changes?

DR. LANDOW: Yes, and somehow it fell through the cracks. It is an old drug, and when one company bought out another company and submitted their labels, we didn't check to see that it had dextran 1 mentioned. Dextran 1 has been around since 1984.

DR. KUEHNERT: Is there any data at all on how much dextran 40 or 70 is used in the United States? I know not a lot of dextran 1 is used, but I just wonder if it is not used much because the primary colloid isn't used, that it would be used to pretreat.

DR. LANDOW: It is used less and less, as Dr. Ljungstrom said, because there are other agents out there that do the same job, if not better, but there was a report in a plastic surgery journal in 2002, and that is how I got started on this, of someone who did not give promit 1, and that is when we decided to investigate this a little more fully.

DR. EPSTEIN: I am concerned that the discussion of the ROC trial has somewhat sidelined the issue that FDA wishes to bring before the committee today, which is about the product labels for dextran 40 and dextran 70.

Now, we understand that the predominant current use of those products is in elective surgery. I think it is fair, if the committee wishes to comment separately, about the various uncertainties in the trauma trial, but that is an issue apart from what we are really asking you right now.

We are asking you whether, as a routine matter, dextran 40 and dextran 70 should bear labeling on the relevance of pre-treatment with dextran 1.

I think what we have heard today is that there may be special issues in trauma, and Dr. Ljungstrom told us that his data base really did not deal very much with trauma.

So, it is a new question, but it is not the question we are bringing to the committee. I think we have also learned that there is the possibility that the presence of hypertonic saline may be a mitigating factor.

I think that the burden falls to the company to show us why that is true, and animal studies could be done. We could have a dialogue about that, and get over that issue.

Again, I think that we have to separate what is being asked here from what the ROC representatives have put in front of you.

I understand the disquiet of the trials being put on hold, but the way the FDA has looked at it is, if we believe that dextran may present an added risk that can be mitigated, the question in our mind is why shouldn't it be mitigated.

Now, if it can be mitigated in another way, that is fine, too, but where does the burden lie? I think the burden lies on the sponsor, to show us that this risk is mitigated, and it can be done.

The other point that I would just emphasize is that the rapid infusion of 20 ml of promit has been argued to be an undue burden and to make field use impractical.

I think it just depends how the administration kit is designed. A minute can be integral. We are talking about 20 more seconds and an added carrying volume of 20 ml plus a container. It is not entirely clear to me that that precludes all use, if we think that is the reasonable thing to do.

I think that the question about the ROC trial and use in trauma really comes down to the evidence that the risks of clinical dextran have been mitigated in that setting.

I think that, if we can see a good argument other than what I would consider to be unfortunately weak statistical arguments, that we can deal with it.

Again, I just would remind the committee that, at its core, that is not the question in front of the committee.

If the committee would like to comment on how to approach use in trauma, okay, but we are asking you whether there should be a label on dextran 40 and dextran 70 that has only the approved indications in elective surgery.

DR. ALLEN: Thank you for the clarification.

MS. SUTTEE: Allison Suttee(?) NHLBI. As mentioned, we are the sponsor of both the surgical trial in Seattle as well as the Resuscitation Outcomes Consortium.

We appreciate the very reasoned discussion of making a very separate and thoughtful estimation of the use of HSD separate from dextran 40 and dextran 70.

For that very same reason of the separateness, and as the sponsor of trials that have already been vetted by NHLBI, approved PRCs -- protocol review committees -- and data safety monitoring boards, we are puzzled, frankly, by the hold on the clinical trials which is using, as mentioned, a different solution.

We are also puzzled about the timing, given that we also reviewed the data and the references, and find nothing but rather old observational data using historical controls, a situation that we would rarely use in making a clinical judgement.

The NIH and the NHLBI, of course, take their safety issues very, very seriously, and that is why our PRCs and DSMBs are composed of thought leaders from all disciplines in these cases, because they are talking about preclinical trials where you have PRCs and DSMBs that are composed with leaders in the fields of emergency medicine, anesthesia, surgery, et cetera, and have considered these issues carefully as well.

I agree that these may be separate questions before the committee, but they have not been dealt with separately in terms of putting the trials on hold.

DR. ALLEN: Can I just ask you a question, please? Could you stay at the microphone? Was there, to your knowledge, consideration of the question of dextran 1 pre-infusion during any of these clinical trial proposals when they were being reviewed?

DR. SUTTEE: I have to admit that it was not specifically prospectively discussed, but it was brought to our data safety monitoring board when these issues began to come to light, and the DSMB was comfortable with the trials proceeding.

DR. ALLEN: Dr. Landow, I would like to ask you to come back now and formally give the committee the questions again.

Agenda Item: FDA Perspective and Questions for the Committee.

DR. LANDOW: It is right there. You can read it from wherever you want. I didn't realize it was back up on the board

DR. KLEIN: Mr. Chair, are we finished with general discussion?

DR. ALLEN: We can have general discussion at any time. Dr. Klein, did you want to ask an additional question?

DR. KLEIN: I just wanted to comment because I appreciate Jay's position, and clearly at least this part of the committee wants to address the question that he wants to have addressed.

I see the trauma trial as different from the issue of trauma. Just as we looked at albumen at our last meeting, and looked at the data available and would not comment on the toxicity in burns because there was no data, what we are doing now is looking at, agreed, older data, uncontrolled data, but based in a totally different clinical situation.

There is no question that trauma is different. It is different immunologically. From a blood transfusion standpoint, you see microchimerism after blood transfusion in trauma patients.

You don't see it in surgical patients, breast cancer patients who have been operated on. Clearly, there is something immunologically different.

I don't know if that directly impacts here, but I think the data we are going to be analyzing, or have analyzed in order to answer the questions, don't deal with trauma.

For that matter, the labeling currently, in the United States for the use of this drug, don't deal with trauma either.

I think we do need to separate these, if only with a subsequent comment, Jay, but they are different and the data we are evaluating do not deal with trauma.

DR. ALLEN: Thank you for that comment. I absolutely agree with yo. First of all, the current trial that is underway is a phase II trial. The other proposed ROC trial is a phase III trial.

HSD is not the same, in my view, as dextran 40 and dextran 70. Trauma patients may be a very different group in a number of ways.

Certainly there are situations that are different. My personal feelings would be to separate the two issues totally at this point, and to review them differently. I would hope that the clinical trials with HSD would be allowed to move forward, and I think the committee should spend its time focused on the dextran 40 and dextran 70 question. Dr. Landow, would you run through this question for the committee, again, briefly, please?

DR. LANDOW: What revisions to the product labeling for dextran 40 and dextran 70 would be most appropriate to address the risk of dextran-induced anaphylactoid reactions, and the relevance of pretreatment with dextran 1.

In particular, please comment whether a class labeling change is warranted and, b, what are the forms of risk communication that FDA should consider to alert the medical community about the risk of DIAR.

DR. ALLEN: Let me ask you a question first. Can you briefly summarize for the committee -- because we have got some people who have not served on the committee before, they are here as temporary members, but I know that some of the details escape some of the rest of us sometimes, too. Tell us again what is involved in a class labeling change.

DR. LANDOW: There would be some type of statement added to all dextran products, a warning, stating that promit should be given immediately before administration of this product, 20 ccs, IV push, something to that effect. That is one level.

Then there is a higher level, obviously, is a black box warning to the same effect, referring them to a discussion in the warning section of why this would be important.

DR. ALLEN: In general, once a product has been approved for marketing by the FDA and labeling has occurred, what is the FDA's authority to go back and request a change, versus the manufacturer needing to come in and request a change with reporting data?

DR. STEFANO: Karen Stefano, assistant to the director for labeling policy. Basically, at any point in time, the FDA can notify the company, much like what is going on in the arena of the antidepressants and the like.

At any point in time where there is a safety signal, the FDA can go to each company and present them with a question at hand, and give them the opportunity, if they have data on file that would suggest variances in what we are seeing, since it is very difficult, based on our spontaneous reports, quite often, to find out specifically what the drug is or what other concomitant drugs or whatever are being used.

So, yes, at any point in time, FDA does have the authority to request it. In fact, the regulations that talk about the letters that go out to physicians, the dear health care provider letters, are really specific to FDA having to do things a certain way, where the companies may.

Quite often we end up working very closely together to ensure that the message gets out that is accurate.

DR. ALLEN: Thank you. Okay, general questions?

Agenda Item: Further Committee Discussions and Recommendations.

DR. SCHREIBER: I would like to ask a question. In the handout that we got it said that one company currently labels, or mentions, dextran 1. What do they say?

DR. LANDOW: That should have said one company used to. That was Pharmacea, a Swedish company, and they had a statement in their label stating that dextran should always be given immediately before, 20 milliliters of dextran 1 should always be given immediately before infusion of the solution.

Subsequently, Pharmacea no longer makes this. So, the other company that brought out the product did not put it in their label and we did not catch it.

DR. KATZ: I have a question for FDA. Since trauma is not an approved indication for this drug, I am presuming that whatever language we may or may not recommend for the label and the improved indications isn't going to mention trauma, may not mention trauma.

DR. LANDOW: Can I just have slide number two of my presentation? Can you just go back? Actually, both have been approved for volume resuscitation.

DR. ALLEN: All right, discussions pertinent to the questions we are being asked.

DR. HARVATH: Just to make the comment that the promit data have not been developed in the setting of volume resuscitation. So, whatever labeling change is made, it is going to have to be very, very carefully crafted.

DR. ALLEN: The way the question, part A, is asked, technically if Dr. Freas wanted to go around and say whether a class labeling change is warranted, we could answer that yes, no, or abstain. That doesn't provide much guidance to the FDA.

I am going to, at this point, suggest that we not do a formal vote on it, but that people be able to express their opinions about the kind of change, if any, that they believe might be warranted, and the caveats that they would put on that. I suggest we do that first, and then discuss section B.

DR. LANDOW: Can I just add one small point? In one of Dr. Ljungstrom's papers, he notes that three subjects in his studies died after receiving one half to one milliliter of dextran without dextran 1 pre-administration.

DR. ALLEN: I think that would be consistent with what often happens with an anaphylactic type of response. You say it was a patient living across the street from the hospital or near the hospital that had those extraordinarily high antibody levels? I would believe that is certainly possible. Discussion.

DR. DI MICHELE: One question, actually, for Dr. Landow. Among the fatalities that have been reported in the United States, do you know the circumstances under which the fatalities occurred? Were they elective surgery, or was it under circumstances of volume expansion or not?

DR.LANDOW: I think I will let the epidemiology answer that.

DR. ZINDERMAN: The vast majority of the spontaneous reports that we had from the United States, those 66 cases that Dr. Landow presented, are in the circumstances associated with a surgery, either antithrombotic prophylaxis was listed as the indication, or improved vascular microsurgical indication associated with some impending surgery. I believe there are only one or two reports that described volume replacement.

DR. DI MICHELE: But there are one or two reports.

MR. ZINDERMAN: Not among the fatalities.

DR. ALLEN: Dr. Miller?

DR. MILLER: I think a labeling change is warranted. I have been aware of dextran possibly causing allergic reactions, but in all the years, I have never been aware that there was any way to prevent that. I think a labeling change is warranted.

I don't think it has to cloud the issue of the trauma, because we are talking about dextran 40 and dextran 70.

The labels on those products can be changed. I don't know why that needs to affect other dextran products, as long as we don't label those products in similar fashion. I think it is a different fashion.

I think people need to know that there is a way to prevent a catastrophic complication with these two products that are, in my experience, given electively.

DR. ALLEN: Would you go to the extent of recommending a black box warning on the package insert, the label so to speak?

DR. MILLER: I guess I don't know enough what the implications of that are, to be able to comment on that.

DR. KUEHNERT: I guess what I am a little hung up about is where it says class labeling change. As it is written, then it would require labeling of all the dextrans, is what I heard, and I would be concerned about that, because that is not supported by the data.

DR. LANDOW: All the dextran 40 and dextran 70 products.

DR. KUEHNERT: What about the HSD?

DR. ALLEN: That was the public session. That is not on the table right now.

DR. KUEHNERT: So, that is not included as a dextran product.

DR. ALLEN: It is a different product, as Jay is saying.

DR. KUEHNERT: So, we are just talking about dextran 40 and dextran 70.

DR. ALLEN: Yes, that is what this question is.

DR. LEVY: Is there a level of risk of incidence of anaphylaxis that spurs a black box? You look at a drug like protamine. Protamine incidence of anaphylaxis is one in 1,500 versus maybe one percent in the NPH diabetics for sensitization. This is data we published in the 1980s. So, that is one in 1,500. It doesn't have a black box.

You look at other agents, for instance, the neuromuscular blocking agents, maybe one in 5,000 to one in 25,000.

You look at this, the incidence of anaphylaxis is relatively low compared to other perioperative environmental and other antigens.

I am just a little bit confused. I think that clearly you have got a therapy that products hapten inhibition and reduces the risk based on older data, but at what level of incidence does a black box appear? That is a question I want to ask the committee.

DR. STEFANO: It is not the incidence that necessarily drives whether it rises to the level of a box or not. It is the severity and how preventible it is.

For example, there are all sorts of takes on that theme as well, that when you are considering labeling like this you can go from the black box being the most notable, to a black box that appears not in the front of the labeling but at the top of the warning section.

Then you could also have just a bolded statement within the warning statement that addresses it. So, there are a number of places just within the warning, if you would, that can describe its use.

It is also true, if this is something to consider, then not unlike other treatments that are out there, that one is used with another, all, even promit, would have to carry the same kind of labeling.

DR. ALLEN: Dr. Levy, I would suggest that the committee or committee members make a general statement with regard to, yes, we feel it should be a very prominent warning or it should be a warning -- in other words, we can talk relatively about it based on the information.

This really is an issue that the FDA is going to decide, regardless of exactly what the committee says on it. So, we don't have to come up with a specific answer. I think we should give a general guidance about how strongly we feel to the FDA.

DR. DOPPELT: Not to make this too confusing, I understand that we are calling the HSD a somewhat different product even though it has dextran in it. This is only applying to dextran 40 and 70. Are there other products with dextran that we haven't discussed, other preparations that would somehow fall between HSD and these products?

DR. LANDOW: There may be, but what we want from you right now is dextran 40 and dextran 70. That is all we want you to consider.

MS. BAKER: Could the content of the wording of the labeling change be specific about the dextrans that we are discussing as well as the use, trauma versus elective surgery?

DR. ALLEN: I think that is a very good question, and that certainly would be my recommendation that we talk about in elective settings or something like that, that there be a general discussion and that, particularly within an elective use, it would be strongly recommended that dextran 1 be used, something to that extent.

I think the FDA will take the general discussion that we have given. My general sense based on all I have heard, including the material at the open session, would be at this point, and especially for HSD solution, would be to exempt the trauma and this kind of special setting, and to refer primarily to the elective use of the dextrans and make a fairly strong recommendation in that kind of a setting.

DR. LANDOW: Can I just comment about the two indications on the label, for each of those products, there is volume resuscitation. It is not HSD, but it is dextran 40 and dextran 70 that can be used for volume resuscitation.

DR. ALLEN: I appreciate that. Nonetheless, that is not what is in clinical trial that has been put on hold now.

You can certainly have volume expansion within a hospital setting as well as indications other than trauma. I think my suggestion would be to make a fairly strong warning, but still leave it an option to the prescribing physician to decide exactly whether or not he is going to use the dextran 1.

I would certainly think that, under most circumstances, that would be highly advisable, and if you are using dextran 40 or dextran 70 for volume expansion, regardless of the setting, I have heard enough data today to suggest to me that it is in the patient's best interest, generally, to use dextran 1 first.

I think the question is out on HSD, because it seems to me that that may be a separate product, and it may be not so much the product difference as the setting difference.

I don't know. I can't tease the two apart based on the information, but I would think the wording could deal with that adequately.

DR. KATZ: On part A, I think if we believe the Swedish data from before dextran 1, a one in 2,000 risk of three, four or five severity anaphylactic, anaphylactoid reaction, that very, very clearly there needs to be substantial warning.

I don't think it is too hard to craft language that says observations in the elective use of this product for surgical procedures suggests. It is what it is.

If the FDA felt compelled to put in something about, we don't know about volume resuscitation or shock from trauma. That would be wonderful, but one in 2,000, and fairly reliable data, I think clearly requires that.

I think, beyond just changing the label, which some people read and some people don't, that the kind of other approach -- I think it was the internet and other communications that were cited -- I think that needs to be done, and would trust that the clinical trialists would be able to write up their results in a fashion that trauma surgeons would be able to understand.

DR. KUEHNERT: I guess my concern is about the two different settings. They are really quite different issues. So, if you have an elective surgery situation, the physician looks at the label, oh, we need dextran 1 with it, make sure it is in supply, order it if it is not, postpone the elective surgery, fine.

If you are in a situation for volume resuscitation in a trauma situation or other situation which is not elective, you don't have that luxury.

My concern is that there might be some confusion here, on the part of the clinician, on trying to get the dextran 1, make sure it is used appropriately, and that may harm patient care. That is what I would be concerned about.

DR. ALLEN: Certainly, in this instance, failure to provide volume expansion with the best available agent is much worse.

DR. KUEHNERT: I am not talking about the trial. I am talking about a clinical -- the way it is used.

DR. LANDOW: Just real quickly, I spent my career as a trauma anesthesiologist. There is nothing mystical about dextran. If you don't use dextran, there are many other things that you can use that are as effective.

DR. MILLER: It would seem in a label you could simply say something like, except in cases of life threatening volume requirements, that you must use dextran 1. I mean, something like that. Just put a little phrase to except those situations, but I think I am convinced enough that, in an elective situation, patients should be protected from a disaster.

DR. KLEIN: I agree with Lou Katz. I would rather see it phrased as to what the data say. I think we all wish we had more data and we wish they were controlled, but I think it would be relatively easy to craft labeling language that would say something to the effect that, there have been reports of reduced allergic reactions, or anaphylactic or anaphylactoid reactions when used as we have heard described in certain settings. One could also add, I suppose, that there are no data in trauma.

That way, the obligation to quote the data as they are quoted are there, without extending them so far as to make interpretations that are not really supported by any of the data.

Certainly all of us who practice medicine have read enough labels that, gee, you see headaches and nausea and lord knows what on virtually every drug there, when you know that the data are pretty weak that there is a causal association.

So, I think it is not an unreasonable thing to put that in here, but I think I would quote the data as they are.

MS. STEFANO: We are actually moving to try to change the way the adverse reaction section is handled, specifically because it has become a repository for a whole host of information that is often not terribly useful.

In response to your question, though, about being very data specific, one of the things that we did, in fact, talk about is that, while reporting in to FDA is not mandatory, reporting an adverse reaction back to the firm, the firm is quite often the more knowledgeable, the more -- in terms of what kind of information has been reported to them, either by literature or by actual reports.

So, yes, it is not unreasonable to go back to each manufacturer of the dextran 40s or 70s or promit, even, and ask them for what they have, and try to come up with something far more concrete than just referring back to some old data.

DR. ALLEN: Other discussion on point A? I think we have expressed some clear positions. All right, point B is what other forms of risk communication FDA should consider to alert the medical community about the risk of DIAR, whether they should hire airplanes and drop leaflets, post it on the internet, send a letter to every dear physicians, and I would be interested in data on what percentage of those get read by the physician. Other suggestions for the FDA on that?

DR. KLEIN: I think it would be foolish just to sort of sneak it in, the same way that it got sneaked out the last time.

I would recommend simply sending a letter as described there but, once again, have it be a data specific letter.

I mean, physicians are supposed to be trained to evaluate what the data are. So, tell them what the data are, and you can still say you are putting a labeling change in based on this, and here are the data.

DR. ALLEN: My other suggestion would perhaps be to get to the appropriate medical specialty societies, and make them aware of the change and suggest that they put it into educational programs or whatever.

DR. LEVY: Because this is dispensed by pharmacies, usually in hospitals, that if you work with the pharmacists, too, they are very good at distributing that data, since this is not an OTC drug or whatever. I think that is a good way, to focus on them, as well as the multitude of other mechanisms you describe.

DR. ALLEN: Thank you. I think that is a good suggestion and perhaps also the Center for Medicare and Medicaid Services. I don't know if there is a reimbursement problem with the use of the dextrans, but certainly to make them aware that they don't want to disapprove the use of dextran 1 in association with dextran 40 and 70.

DR. KUEHNERT: I think a letter is indicated here. I think it is probably more likely to be read by a physician than a label, although I agree the pharmacist issue is a good one.

I wonder if there is any level of adverse event reporting that is higher than the usual -- I am concerned about hearing this today that it is passive reporting. Is there any way to make it more active for this particular colloid?

DR. ALLEN: The whole issue of post-marketing surveillance and adverse event reporting is a whole separate issue that is very important.

DR. KUEHNERT: If that could be encouraged in the letter, I would recommend it.

DR. ALLEN: I think that is a good point.

MS. BAKER: May I also recommend that you consider alerting the certified nurse anesthetists, their professional society.

DR. ALLEN: Thank you. I think that is a good suggestion.

DR. KATZ: That was my question. Who gives the stuff? I mean, I haven't seen much of it used, but I am hearing that I think it is anesthesiologists, or is it the plastic surgeon before the person goes to the OR, or a nurse on the floor?

DR. LEVY: It will be given by an anesthesiologist. It is usually immediate before a surgical procedure, or I think a nurse anethsetist is a good suggestion, too, and there are PAs, the PA Society, too, that gives anesthesia. So, those are three things to consider.

The only problem is, is there also going to be work to get promit available, since it is not really available?

I mean, we are making all of these -- I don't want to get back tracked, but these are interesting suggestions, but there is no promit available.

So, will there be recommendations made -- I mean, you are making recommendations on a molecule that is not currently available.

DR.ALLEN: It is licensed, however, and once the vacation period is over -- you know, I take my hat off to many of the countries in Europe that have a much more sensible approach to summer vacation than we do in this country.

I am sure the firm will be back in business before the labeling change is completed. You know, I think the issue of getting the information to the pharmacy and therapeutics committees in hospitals, I mean, there are a variety of ways.

I think we have made some very good suggestions. Just notifying physicians with a dear doctor letter is not going to be adequate, but I think we have addressed a number of the ways in which this can be addressed.

DR. DOPPELT: I was going to add as a procedural point, in the operating room, this material could be given by a number of people, including PAs, anesthesiologists, et cetera, but it is not going to be sort of stocked in the OR shelf. It is going to come as a specific request from the pharmacy.

So, that seems to be the final common pathway, and they are usually very good about telling people, putting labels, calling the physician before they release it. I think that is the target.

DR. ALLEN: What is it, the American Society of Hospital Pharmacists, I mean, there are groups that need to be specifically notified about this in addition.

MS. STEFANO: I believe American Hospital Pharmacy has a note about their difficulty in obtaining dextran 1, and they also make reference to the use of it prior to.

I went on some of the academic hospital web sites to look at treatment guidelines, and several of them actually did have that information already.

DR. ALLEN: Okay, other points on B? If not, I am going to declare discussion on this topic at an end, and I get to bang the gavel, and we are going to adjourn 20 minutes ahead of schedule.

[Whereupon, at 6:10 p.m., the meeting was recessed, to reconvene the following day, Friday, July 22, 2005.]