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: </