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 acut