Thursday, August 16, 2007


This transcript has not been edited or corrected, but appears as received from the commercial transcribing service.  Accordingly, the Food and Drug Administration makes no representation as to its accuracy.


      This meeting came to order at 8:00 a.m. in the Doubletree Hotel and Executive Meeting Center, 8120 Wisconsin Avenue, Bethesda, Maryland.  Dr. Frederick Siegal, M.D., presiding.





















           T-A-B-L-E O-F C-O-N-T-E-N-T-S



Statement of Conflict                            4


Opening Remarks                                 10


Committee Updates


      Summary of May 10-11 Meeting of DHHS      11

      Advisory committee on Blood Safety and



      Summary of April 25-26 Workshop on Immune 20

      Globulins for Primary Immune Deficiency



      Summary of August 15 Workshop on          28

      Licensure of Apheresis Blood Products


Informational Presentations: WHO Biological Standards


      Summary of January 29-30 WHO meeting      34


      Potency and Safety Standards for Plasma   52



      Joint FDA/WHO Minimum Potency Standards   72

      for Certain Blood Grouping Reagents


Topic I Response to the Office of Blood Research

  and Review Office Level Site Visit


      Introduction                              79


      Office Response                          100


Open Committee Discussion                      132


Topic II Measles Antibody Levels in U.S. Immune

  Globulin Products


      Introduction                             151


      Current Epidemiology of Measles in U.S.  172


      Measles Infections and Estimated         195

      Protective Titers


           T-A-B-L-E O-F C-O-N-T-E-N-T-S


Topic II cont'd.


Measles Antibody Titers in Plasma Donors       219


Measles Antibody Levels over Time in Licensed 236

  Immune Globulin Products and Patients with

  Primary Immune Deficiency Diseases

      (Baxter Healthcare and CSL Behring)


Open Public Hearing                            253


Open Committee Discussion                      261



                                         8:05 a.m.

            EXECUTIVE SECRETARY JEHN:  Let's go ahead and get started.  Mr. Chairperson, Members of the Committee, invited guests, temporary voting members and public participants, I would like to welcome all of you to this 90th meeting of the Blood Products Advisory Committee.  I'm Donald Jehn, the Executive Secretary for this meeting.

            This meeting will be completely open to the public.  At this time, I would like introduce the individuals seated at the head table for today.  To my immediate left is our BPAC Chairperson Dr. Frederick Siegal, Medical Director of Comprehensive HIV Center, St. Vincent's Catholic Medical Centers, New York.

            To my right and going down the table is Dr. James Allen, Medical Advisor, American Social Health Association; Dr. Mark Ballow, Chief Division of Allergy and Immunology, SUNY New York and Women's and Children's Hospital of Buffalo; Dr. Richard Colvin, Clinical Assistant in Medicine, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital East; Dr. Henry Cryer, Chief of Trauma and Clinical Care at UCLA; Dr. Adrian Di Bisceglie, Chief of Hepatology, St. Louis University School of Medicine; Dr. Willarda Edwards, President and Chief Operating Officer of Sickle Cell Disease Association of America; Dr. Maureen Finnegan, Associate Professor, Department of Orthopedic Surgery, University of Texas Southwestern Medical Center; Dr. Simone Glynn, Branch Chief Transfusion and Medicine and Therapeutics Branch, NHLBI.

            And then on my left side going down, Dr. Keith Quirolo, Clinical Director, Apheresis Program, Department of Hematology, Children's Hospital at Oakland; Dr. George Schreiber, Vice President of Health Studies, Westat; Dr. Irma Szymanski, Professor of Pathology, Emerita, University of Massachusetts Medical Center; Dr. Donna Whittaker, Chief Department of Clinical Support Services, U.S. Army Medical Department Center and School, Fort Sam, Houston; and Ms. Judith Baker, our Consumer Rep located at UCLA; and, finally, our Industry Rep, Dr. Louis Katz, Executive Vice President, Medical Affairs, Mississippi Valley Regional Blood Center.

            Committee members not in attendance are Drs. Cooner, Kulkarni, Manno and Quinn.  Dr. Allen is at the table for the discussion of the response of the Office of Blood, Research and Review Office Level Site Visit for Research.  I would like to thank all of you for attending this meeting.

            Now if I could have Dr. Goodman.  We have four retiring members after this meeting and we would like to recognize them.  Dr. Szymanski. 


            EXECUTIVE SECRETARY JEHN:  Dr. Donna Whittaker.


            EXECUTIVE SECRETARY JEHN:  Dr. Keith Quirolo.


            DR. WHITTAKER:  And Dr. George Schreiber.


            EXECUTIVE SECRETARY JEHN:  We thank them all.  Thanks very much.

            Okay.  Before we start the meeting, I do have a conflict of interest statement to read.  It's rather lengthy, so please bear with me.

            The Food and Drug Administration, FDA, is convening today's meeting of the Blood Products Advisory Committee under the authority of the Federal Advisory Committee Act, FACA, of 1972.  With the exception of the Industry Representative, all participants of the Committee are special government employees, SGEs, or regular federal employees from other agencies and are subject to the Federal Conflict of Interest laws and regulations.

            The following information on the status of this advisory committee's compliance with Federal Ethics and Conflict of Interest laws including, but not limited to, 18 USC Section 208 and 21 USC Section 355(n)(4) is being provided to participants in today's meeting and to the public.  FDA has determined that participants of this advisory committee are in compliance with Federal Ethics and Conflict of Interest Laws including, but not limited to, 18 USC Section 208 and 21 USC 355 (n)(4).  Under 18 USC 208 applicable to all government agencies and 21 USC 355(n)(4) applicable to certain FDA committees, 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 a particular individual's services outweighs his or her potential financial conflict of interest, Section 208, and where participation is necessary to afford essential expertise, Section 355.

            Members of the Committee 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 employers, spouse or minor child related to the discussion of (1) FDA's response to the Officer of Blood Research and Review Office Site Visit held on July 22, 2005 and (2) measles antibody levels in U.S. immune globulin products.  These interests may include investments, consulting, expert witness testimony, contracts, grants, CRADAs, teaching, speaking, writing, patents and royalties and primary employment.

            Today's agenda also includes several updates.  In accordance with 18 USC Section 208(b)(3), waivers were granted to Dr. Mark Ballow and Dr. Melvin Berger for the discussion of topic two on Measles Antibody Levels in U.S. Globulin Products.  A copy of the written waiver may be obtained by submitting a written request to the Agency's Freedom of Information Office, Room 12A-30 of the Parklawn Building.

            With regard to the FDA's guest speakers for Topic two, 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 presentation and/or comments made.  Dr. Donald Baker is employed by Baxter Healthcare Corporation.  Dr. Baker has financial interests in his employer.  Dr. William Moss is employed by Johns Hopkins Bloomberg's School of Public Health as an Associate Professor in the Departments of Epidemiology, International Health  and Molecular Microbiology and Immunology.  Dr. Jane Seward is employed by CDC as a Deputy Director, Division of Viral Disease, National Center of Immunization, Respiratory Diseases.  Dr. Toby Simon is representing Plasma Protein Therapeutics Association.  He is employed by ZLB Plasma as the Corporate Medical Director.  Dr. Simon has a financial interest in his employer.  Dr. Othmar Zenker is employed by CSL Behring.  As guests, they will not participate in the Committee deliberations.  Nor will they vote.

            In addition, there may be regulated industry and other outside organizations' speakers making presentations.  These speakers may have financial interests associated with their employer and with other regulated firms.  The FDA asks in the interest of fairness that they 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.

            Dr. Louis Katz is serving as the Industry Representative acting on behalf of all related industry and is employed by the Mississippi Valley Regional Blood Center.  Industry Representatives are not special government employees and do not vote.

            This conflict of interest statement will be available for review at the registration table.  We would like to remind members that if the discussions involve any other products or firms not already on the agenda for which an FDA participant has a personal or imputed financial interest, the participants need to exclude themselves from such involvement and their exclusion will be noted for the record.  The FDA encourages all other participants to advise the Committee of any financial relationships that you may have with any sponsor, products, direct competitors and firms that could be affected by the discussions.

            Before I turn the microphone over to the Chair, I would like to request that everybody take a moment and check to make sure they have their cell phones and pagers set to silent or turned off.  Thank you.  Dr. Siegal, I'll turn it over to you.

            CHAIRMAN SIEGAL:  Thank you, Don.  I would like to welcome you all to this glorious summer meeting of the Blood Products Advisory Committee. Fortunately, we don't have a lot of controversial topics, but we have a fair amount to cover.  I particularly want to welcome back Jim Allen, an old friend from the AIDS wars.  Can you not hear me?  Well, it's not really important anyway.


            CHAIRMAN SIEGAL:  But Jim was, of course, my predecessor on this committee and we've known one another since about 1981 maybe.

            Our first set of topics are the Committee updates and we're going to start with Jerry Holmberg who is going to review and summarize the meeting of the DHHS Advisory Committee on Blood Safety and Availability.  Jerry.

            DR. HOLMBERG:  While we are waiting to get that up on the screen, I'll just give you a little disclosure.  I do have financial interests in my company, the Federal Government, and that financial interest is not only receiving a salary, but paying taxes.


            DR. HOLMBERG:  And if anybody would like to know, I have had my annual financial review with the Ethics Office.

            What I would like to do today is to give you an update on the Advisory Committee on Blood Safety and Availability and the Office of Blood Safety and Availability and also primarily give you a summary of the May 10 and 11, 2007 meeting.

            First of all, I would like to note that we have some staff changes.  The biggest staff change that I would like to mention that is not on the slide here is that Dr. Aquinobi, the Assistant Secretary for Health, has resigned from the Administration and that  resignation is as effective as of September 3rd.  In my office, we do have Lt. Commander Rich Henry who has moved up to the Deputy Director position and we have a new Public Health Officer, LTjg Jennifer Lunney who is our Senior Health Preparedness Advisor.

            At the May 10th and 11th meeting, Dr. Aquinobi asked the committee to review several commonalities between transfusion and transplantation safety.  The reason for that is in October the charter for the Advisory Committee on Blood Safety and Availability was modified to include interests or concerns of transfusion and transplantation safety.  This sort of opens up the scope of issues that we can deal with at the committee and Dr. Aquinobi was looking to see are there areas of commonality.

            So the first question was is there a process, an opportunity, to lay out a process for transfusion and transplantation safety for the future and the committee overwhelmingly said that, yes, there is a need to develop a process to enhance the quality and improvement in transfusion medicine and transplantation medicine.

            Is there scientific evidence to support a need for a master strategy?  In this particular area, the committee really struggled as far as finding scientific evidence, but based on surveillance evidence there is a limited reports of infectious disease transmission and therefore, substantiate the need for a master strategy and you can read on there as far as the differences in the risk/benefit profiles between transfusion tissue and transplantation recipients but that all these patients have the potential for acquiring life-threatening infections if an infectious disease screening is flawed or emerging or unknown diseases evolve unchecked over time.

            So another question that was asked was what should be the scope of a master strategy and the number one issue that came out was a recipient outcome surveillance or a biovigilance system to identify all donors using common identification numbers linked to biological products that are uniquely identified; mandatory adverse event reporting process for tissues, organs and blood therapy through appropriate mechanisms to designated public health authorities and to recipients and donors and timely and efficiently trace all biological products to the clinical user, recipient, and donor and to recognize transmissible events resulting in adverse outcomes including infectious agents, malignancies and toxins; also to build communication and education networks to disseminate data to users; to develop informatics to support surveillance, process, involvement, improvement and evidence-based research; and to include other strategic plan elements as needed such as donor recruitment, donor screening, research coordination and emergency preparedness.

            What are the areas of commonality of blood products, cohort progenitor cells and bone marrow tissues and organs?  Key elements in common with transfusion required for ensuring high quality include donor recruitment; donor screening; and, of course, eligibility; collection; infectious disease testing; transportation; storage; processing; labeling; traceability; good manufacturing practices; good tissue practices.  I would also say probably good transplantation practices; outcome analysis; adverse event reporting.  And in addition, there needs to be a way to evaluate the differences between the different transfusion and transplantation products, modalities.

            How best should this be done with the stakeholders and how do we begin?  The recommendation was that HHS should convene a forum of stakeholders to include public health agencies, accrediting agencies, manufacturers, clinicians, consumers and endusers and HHS should be responsible for implementing a master strategy with appropriate resources based on input from stakeholders.

            And what are the resources needed and what are the estimated costs?  The committee really do not get to that area and had a difficult time trying to put a price tag on what this would mean.

            Let me just go back to that slide there.  As an outcome of the recommendations, Dr. Aquinobi has sent a letter to Dr. Bracey who is the Chairman of the Advisory Committee on Blood Safety and Availability.  In that letter, he does recognize the recommendations and the answers to the questions and also reassures Dr. Bracey that the Department has already moved forward in various aspects on bioviligence and we have already put resources towards those bioviligence endeavors through not only the recipient side but also through the donor side of surveillance and also CDC is supporting a collaborative effort with the TTSN for tissues and transplantation.

            Our next meeting is next week.  The two issues that we're primarily looking at ethical considerations and risk benefits for ensuring transfusion and transplantation safety during focal periods of shortages.  Those focal periods of shortages could be seasonal shortages, preparation for pandemic, disasters both manmade or natural and then also to review and discuss the elasticity of the blood supply to support transfusion and transplantation safety as well as strategies and barriers to those strategies.

            And that's all I have.  If there are any questions, I'll be happy to entertain those.

            CHAIRMAN SIEGAL:  Questions from the Committee?

            DR. FINNEGAN:  One of my questions and I realize I'm a little bit naive about what the infrastructure for IT is within this environment, but would you consider having IT infrastructure as one of the stakeholders?  Because it would seem to me if you had a good IT infrastructure, that the cost long term would be much less.

            DR. HOLMBERG:  Absolutely.  We have already initiated some of those discussions primarily using some of the infrastructure that is already in place within the Federal Government and outside the Federal Government.  Also within the Department of Health and Human Services is a health information technology office that is personally -- that reports directly to Secretary Leavitt.  They've done case studies analysis for electronic health records and also for laboratory surveillance.

            So we're moving in that direction, but, yes, definitely in our stakeholder meetings, we will consider IT so that there are stakeholders, there are placeholders, I should say, for future systems that are developed that we can mine the data down into.

            The other thing that I want to emphasize there is that we are really looking at this as a quality system in such a way that this will be a system to develop or to get data that we can analysis in hopes of being able to share it throughout the entire community and not to be punitive against a stakeholder.  So it's trying to be very open in the way we collect the data and for that reason, we have already involved many of the stakeholders such as the AABB and the UNIS and the various -- the American Association of Tissue Banks.  Yes.  Dr. Ballow.

            DR. BALLOW:  So is this to include all fractionated blood banks as well?

            DR. HOLMBERG:  Well, we do have them --

            DR. BALLOW:  Coagulation products, IV, IG, etc.?

            DR. HOLMBERG:  We do have them as one of the stakeholders and we have not had the meeting yet, but they are on the list to participate.

            The other thing I want to draw the attention to is that we do have a federal registry notice out that came out on July 30th seeking nominations to the Advisory Committee on Blood Safety and Availability.  I would like to take this opportunity to draw your attention to that and to remind people that nominations are due by August 31st.

Thank you.

            DR. SZYMANSKI:  I had one more question.  I notice an interesting word "malignancy" and how are you going to screen for that?  In donors or in the recipients?  Is that something new that is not being done now when you screen donors?

            DR. HOLMBERG:  I didn't understand the word that you were referring to.

            DR. SZYMANSKI:  You said you are going to not only worry about infectious diseases, but transmission or something with malignancy and I was wondering.  Do you have any other approaches than what are used right now when you screen donors for blood donation?

            DR. HOLMBERG:  As far as blood donations, we do not have a mechanism to be able to track that.  However, in the organ community they do have the adverse event reporting and that does get passed back to UNIS.  But it's open.  We're the point right now of just developing this and, of course, as we move forward in bioviligence, I'm sure there will be other avenues that we want to investigate.  I think that what he want to do is to not only look at what we know today but also to look towards the future and to be able to look beyond the horizon for anything that may potentially affect the blood organ or tissue products.

            CHAIRMAN SIEGAL:  Are there any other questions for Dr. Holmberg?  Okay.  If not, Jerry, thank you.  The next speaker will be Jennifer Scharpf who is going to review the FDA workshop from last April on immune globulins for primary immune deficiency disease referencing antibody specificity, potency and testing.  Dr. Scharpf.

            DR. SCHARPF:  Thank you, Dr. Siegal, and good morning.  This morning I will provide the Committee on the FDA's workshop on immune globulins for primary immune deficiency diseases and the workshop was officially titled "Immune Globulins for Primary Immune Deficiency Diseases; Antibody Specificity, Potency and Testing."  And the workshop was held on April 25 through 26 of this year at the National Institutes of Health.  FDA is grateful to The Immune Deficiency Foundation, The Plasma Protein Therapeutic Association and Dr. Holmberg and the Office of the Secretary, Office of Public Health and Science at HHS for their sponsorship of the workshop.  And we thank the sponsors not only for their financial support but also their scientific contributions to the program.  Additionally, I would like to recognize Dr. Dorothy Scott for her role as organizer and chair of the program.

            The goals of the workshop were fourfold:  (1) to assess the current potency testing of immune globulins.  The potency tests currently required are for antibodies to measles, polio and diphtheria and at the workshop, we wished to examine the potential for potency tests for antibodies against pathogens most commonly associated with infection in PIDD patients; (2) to list antibodies needed to protect primary immune deficient patients from infections; (3) to identify candidate antibody specificities for potency testing of immune globulins for treatment of PIDD; and, finally, on the second day, our goal was to address approaches to diminishing measles antibody levels in currently licensed products.

            So on the first day of the workshop, our goal was to identify the most clinically relevant antibody specificities for PIDD patients.  Epidemiology and surveillance data was reviewed and there was a description of patient registries in Europe and the United States.  The registries which are supported by the European Society for Immunodeficiencies and, the United States, Immunodeficiency Network, have the potential to gather long-term perspective clinical data on these patients.  We then reviewed data on antibody levels in currently licensed products and both of these datasets were taken to then address the question of which antibody specificities would be useful and relevant to measure with respect to clinical importance and to assure lot to lot manufacturing consistency.

            The first question we addressed to the panel of experts and the workshop audience was which pathogens are of greatest concern in immune globulin treated and untreated patients.  And to address this question, data on infectious diseases and PIDD, both patients with humeral and cellular immunodeficiencies was presented by clinicians.

            The workshop participants identified Strep pneumococcus and Haemophiles influenzae as the most important bacterial infections for this patient population.  Several viral infections were also mentioned as pathogens of concern including Epstein-Barr Virus, Cytomegalovirus, echoviruses, Varicella Zoster, adenovirus and Coxsackie.

            Representatives from the FDA, the Paul-Ehrlich-Institut in Germany and two IGIV fractionaters then presented data on antibody levels in currently licensed products.  The presentations revealed that multiple antibody specificities have been studied, trends in antibody levels over time, across products and variations with the plasma source whether recovered or source were observed and regarding emerging diseases, West Nile Virus antibody titers, have been measured in U.S. products, although as one would expect both seasonal and locational variations are observed.

            So at the end of the first day of the workshop, it was proposed that pilot testing of immune globulins for Strep pneumonia and H. influenza should be conducted and we believe this type of study is feasible since assays have been validated for the specificities in serum and who reference labs already exist to which samples could be sent for testing.

            In the proposed studies, manufacturers would voluntarily send blinded samples to their reference lab for testing antibody levels to determine the feasibility, antibody levels and function, and several manufacturers have expressed their willingness to send samples.  And finally, we would like to measure the trough titer level antibodies to these bacterial pathogens in patients receiving the product to determine the relationship between in vitro potency and in vivo levels.  And we anticipate that by working with manufacturers, samples from clinical studies would be available for this type of testing.

            On the second day of the workshop, we discussed the current lot release tests for measles antibodies and measles antibody levels are a standard lot release measure of potency in the United States products and this was a historically important specificity due to measles epidemics.  There has been declining antibody levels observed in products over the past several years and this is attributed to the decline of titers in the donor population.

            The regulatory impact of declining measles titers is that the product could fail the lot release specification and the specific lots must be rejected and rejection of lots could lead to an obvious negative impact on the availability of the product for the primary immune deficient patients.

            Presentations at the workshop revealed data on the measles epidemiology in the United States,  decreasing measles titers in the donor population, immune globulin products and primary immune deficient patients and the estimated protective level of antibody in these patients.  I won't expand on these presentations since the data will be presented to the Committee later this afternoon.

            Following those presentations, we asked the following questions to the expert panel and the audience:  is measles infection of current clinical concern for primary immune deficient patients, how much measles antibody is needed to attenuate or prevent measles in this patient population; what is the potential clinical impact of diminishing anti-measles titers in immune globulin products; and finally, what are the possible approaches to address the decline of anti-measles antibodies in immune globulins with respect to clinical efficacy in prevention of measles infection as well as with respect to utility of a test for lot-to-lot consistency.

            So the possible approaches identified by the discussants at the workshop included: (1) gathering relevant data relating product titers to patient trough levels and estimated protective levels and (2) the option that CBER can potentially change the recommendation on antibody potency, however, this change in level must be scientifically and clinically justifiable and this is the issue that will be before the Committee today.

            So in summary, the next steps identified at the workshop are to (1) design and implement testing protocols to assess levels of antibodies in immune globulins to H. Influenza and Strep pneumonia pathogens commonly associated with infection in primary immunodeficient patients and the study will evaluate the feasibility of using these specificities as potency tests; (2) implement a study to measure measles antibody trough levels by neutralization assays in patients to better ascertain the relationship between product dose and trough level; and finally, CBER will deliberate on solutions to address the diminishing measles antibodies titers and immune globulins weighing, of course, the scientific, clinical and supply considerations.

            And finally, information is available on the CBER website including the transcript and all of the workshop presentations.  Thank you for your attention.

            CHAIRMAN SIEGAL:  Thank you, Dr. Scharpf.  Are there questions from the Committee?  I actually do have a question which is that since we will discuss this later but is it feasible to change the licensure requirements entirely so that measles antibody which may not really be relevant is simply not part of the criteria for approval of the product.

            DR. SCHARPF:  I think we can look at examining changing the titer and that's what we will present later this afternoon to the Committee.

            CHAIRMAN SIEGAL:  Because it certainly would be more relevant to look at representative pneumococcal antibody titers for the PIDD population.

            DR. SCHARPF:  And that was some of the conclusions of the workshop.

            CHAIRMAN SIEGAL:  Anybody else?

            DR. GOLDING:  Yes, I'll just help to answer that question.  I mean we are looking very actively at changing this, the relevant titers, and what Jennifer mentioned is that we're looking at H. influenzae and also at Strep pneumoniae as being much more important and relevant pathogens.  But I don't think we have any plans in the near future to drop measles because as you will hear later, we still think this is a pathogen we need to worry about even though it's much rarer these days.  But also in terms of consistency of lot-to-lot testing, it's important to have tests in place that have the history and the ability to show differences between batches.

            CHAIRMAN SIEGAL:  Okay.  Let's move on.  Finally, Lore Fields from FDA is going to summarize the FDA workshop just yesterday on licensure of apheresis blood products.

            MS. FIELDS:  Good morning.  Yesterday we had a workshop on the licensure of aphersis blood products at Lister Hill Auditorium at NIH.

            In keeping with the vision of CBER to protect and improve public health and to approve safe and effective blood products, we planned a workshop to help educate industry on how we approve apheresis submissions at the Blood and Plasma branch.  We estimate that currently appropriately 40 percent of the submissions coming into the Blood and Plasma branch are on apheresis products.  We did have 175 places available yesterday for the workshop and we did fill the entire auditorium.

            The goals and objectives for the workshop were to educate industry on the licensure process for apheresis platelets, red blood cells and plasma for transfusion.  We wanted to discuss the managed review process as it applies to the Blood and Plasma branch, discuss and review the required documents needed for submission, review the comparability protocol and what is required to obtain one and review the requirements for an apheresis instrument.  Additionally, we asked speakers from industry to give examples on how they successfully submit their FDA's licensure submissions. We also asked Dr. Katz from the Mississippi Valley Regional Blood Center to talk on his recently published paper, "Frequent Platelet Apheresis Does Not Clinically Significantly Decrease the Platelet Counts in Donors" by Dr. Katz, et al.

            The workshop was developed and cosponsored by CBER, the Department of Health and Human Services, AABB and America's Blood Centers and we would like to thank AABB, ABC and HHS for their contributions to the workshop.

            During the workshop, we had several presentations.  I'm going to go over just very brief overviews of what was discussed.  Dr. Goodman did open the workshop for us.

            Dr. Williams provided an informative presentation on the statutes and regulations that we use to do licensure submissions.  Dr. Williams also covered licensing, changes to an approved application, alternative procedures and how managed review is applied to the Blood and Plasma branch.

            Ms. Ciaraldi did a comprehensive presentation that described how we perform reviews.  This presentation included the documents, regulations, guidance and operators' manuals references that we frequently use when we are doing our reviews.

            Ms. Nesbitt did a top ten pitfalls with submissions presentation and what we did with this was he got together in the Blood and Plasma branch and we came up with the top ten reasons that we find errors in submissions and she went through them.  Hopefully, the blood centers will then be able to apply this to their submissions before they send them in and it will facilitate the process of getting licensure done in  a timely manner.

            The next two presentations were given by representatives of the American Red Cross and Blood Systems.  We are always being asked for examples of acceptable submissions.  So we asked these two blood centers to provide the attendees with an overview of their processes.

            Steve Kassapian who is the Director of Regulatory Affairs at American Red Cross reviewed his processes and included some of the examples and forms that his group has put together over the last couple of years that they use to facilitate their process.

            Ms. Kathleen Hopping from BSI reviewed how they have standardized their platelet Apheresis licensure process.  She also provided the attendees with timetables on how the process improvement has reduced the time of the licensure or the approval for licensure at their blood centers.

            I went over a brief review of the current guidance for platelet Apheresis and the 2005 draft guidance.

            We did have an unexpected presentation yesterday that is unfortunately not on your slides.  A direct final rule was actually displayed yesterday as well.  So we had a surprise presentation by Ms. Elizabeth Callahan who is the Acting Director of the Division of Blood Applications and in this is the changes that will allow a storage period of seven days for platelet Apheresis and also the increase for the minimum pH from 6.0 to 6.2 for platelet Apheresis quality control.

            Dr. Katz put on a presentation based on the comments to the 2005 draft guidance.  His group did a study to determine what the impact is on platelet counts and donation intervals.  This is the data that was previously presented to you in March of 2006.  The paper was recently published and so we asked him to present the data to the attendees.

            The failure investigation presentations covered the regulations behind the investigations by Ms. Hoi-may Wong and also one example of how a structured investigation process is working at a major blood center.

            Ms. Faye Kugele described how the ARC has standardized their failure investigation processes and how the standardized procedures have improved their investigation of failed products.

            We did something a little different at our workshop and one of the things is we spent a lot of time talking to the regulatory people at the blood centers, but they never actually see our faces.  So we spent about 30 minutes at our afternoon break kind of introducing ourselves to them so they had a face to go with the person that they talked to.

            The Device Manufacturers Forum was an opportunity for the manufacturers to provide the attendees with pertinent information from their operators' manuals, package inserts and other documents that should be included with their submission.  They also provided updates on recent changes on their cleared devices and this was done by Merilyn Wiler from Gambro, Dr. Orton from Fenwal and Sue Finneran from Haemonetics.

            The final session was a question and answer sessions.  Questions were actually provided to a docket in advance and we discussed the answers as our final session.  There were 17 questions submitted and discussed.

            Overall, we received excellent feedback on the workshop.  The Regulatory Affairs staff from the blood centers who attended said they learned a lot and they were provided an excellent resource to help them with their next submission to CBER.

            The workshop planning committees contains six people from industry: Celso Bianco, Sue Finneran from Haemonetics, Joe Giglio from AABB, Steve Kassapian from American Red Cross, Dr. Orton from Fenwal and Merilyn Wiler from Gambro BCT.  In addition, there were seven people from FDA on the planning workshop.  Thank you.

            CHAIRMAN SIEGAL:  Thank you.  Are there questions from the Committee or anybody else?

            (No response.)

            CHAIRMAN SIEGAL:  All right.  Thank you very much.  In view of that, let's go onto the Informational Presentations on WHO Biological Standards.  The first presentation will be by Paul Mied from FDA talking about the WHO meeting and Collaborating Centers for Biological Standards and Standardization to Support the Development of WHO Biological Reference Preparations for Blood Safety-related in vitro Diagnostic Tests.  Dr. Mied.

            DR. MIED:  Thank you, Dr. Siegal.

            This morning I would like to present a summary of the January 29th and 30th WHO meeting with the WHO Collaborating Centers for Biological Standards and Standardization.  Now this two day meeting was held at CBER in Bethesda and the three WHO Collaborating Centers for Biological Standards and Standardization that participated in the meeting were NIBSC in the U.K., PEI in Germany and CBER.

            The meeting was convened by WHO, specifically the Quality Assurance and Safety Blood Products and Related Biologicals Team and the Department of Medicines, Policies and Standards of the World Health Organization.  The objective of the meeting was to foster cooperation among the WHO Collaborating Centers in the development of WHO international biological reference preparations for the control of in vitro diagnostic tests related to blood safety.

            Now the WHO is establishing a five year strategic plan to prioritize development of these reagents.  These biological reference preparations are used for the validation, quality control, assessment of comparability and regulation on a global basis of blood safety related in vitro diagnostic tests.  This contributes to a harmonized regulation of blood and blood products.  Specifically, these reagents are used to provide an indication of the analytical sensitivity of in vitro diagnostic test kits.

            Now the meeting, the two day meeting, covered the following agents which have an impact on blood safety:  HAV, HBV, HCV, Parvo B19, HTLV 1 and 2, CMV, West Nile Virus, Dengue Virus, HHVA, prion agents, bacteria and the causative agents of syphilis, malaria, Chagas and Leishmaniasis.  The existing established WHO biological reference preparations were discussed at length along with several new proposals for development of international standards and reference panels and the priority projects identified were, first of all, the replacement of four existing WHO biological reference preparations and I'll briefly describe for you some of these highest priorities.

            One of the highest priorities identified was a proposed second international reference preparation for anti HBS immunoglobulin to replace the first international reference preparation that was established back in 1977 and it's now close to exhaustion.  NIBSC will be the coordinator of the WHO collaboration study to demonstrate the usefulness of candidate materials for use with a wide range of assay kits and the report of the WHO collaborative study is expected to be submitted to the Expert Committee on Biological Standardization or ECBS in October 2008.

            For HCV RNA, there is an ongoing collaborative study that NIBSC is coordinating that was begun in 2006 to replace the second international standard of HCV RNA with the proposed third international standard.  Two lyophilized candidate materials generate from anti HCV-negative window period genotype 1A donations have been distributed to 32 laboratories covering the main commercially-available NAT tests for HCV RNA.  It's expected that the proposal for the establishment of this standard will be submitted at the meeting of the ECBS in October 2007.

            The first international standard for Parvo B19 DNA which was established in 2000 will be nearly exhausted by 2009.  A small collaborative study was proposed by NIBSC to demonstrate the comparable potency of a freeze-dried candidate replacement material to this standard.  NIBSC will present an update of discussions from the SoGAT meetings to the ECBS in 2007 and the Collaborative Centers agreed to submit the report of the WHO collaborative study to the ECBS in 2008 for establishment of the second international standard.

            Now there was some discussion at the meeting that what was really needed is a genotype reference panel for Parvo B19 DNA and a consensus was reached to identify source plasma materials of genotypes 2 and 3 and to present an update to the ECBS about that in 2007.  Regulators want to be sure that all three genotypes 1, 2 and 3 with two subgroups are detected by various NAT assays worldwide for the testing of plasma pools and that appropriate plasma standards are available to validate those NAT tests.  There will be future discussion about the establishment of a Parvo B19 genotype reference panel.

            The current anti syphilitic reference here and the first international standard was established way back in 1957 and it has assigned unitage and it's used by reference laboratories, diagnostic labs and manufacturers of diagnostic immunoassays.  NIBSC is the coordinator of an WHO international collaborative study that is already underway to evaluate two freeze-dried plasma pool preparations, one representing active syphilis IGG and IGM and the other latent syphilis for IGG that had been selected as replaced candidates for this first international standard for T. palladum particle agglutination tests and cardiolipin assays and various immunoassays.  The data are currently being analyzed and the study report will be submitted to the ECBS meeting in October.

            Now a second set, as a second set, of priority projects, there was agreement among the collaborating centers that several new WHO biological reference preparations are needed.  First of all, an HIV-1 genotype panel is needed to assess the impact of new HIV variants on test sensitivity.

            The first international reference panel for HIV-1 RNA genotypes was established by the ECBS in 2003.  Now this was a set of ten HIV-1 genotypes A, B, C and D, CRF 01AE, F and G, AGGH and Group N and Group O.  But CBER and NIBSC will be collaborating to identify representatives of the less common subtypes such as G, H, J and K and a range of circulating recombinant forms such as CRF 01AE and CRF 02AG to be used in a panel that's an extension of this reference panel and CBER and NIBSC will develop a plan and hold a discussion at a WHO workshop and report on the WHO collaborative study to ECBS in 2009.

            For an HIV-2 RNA standard, CBER and NIBSC are collaborating to exchange information on available candidate HIV-2 strains.  These are cultured subtypes A and B and there will be a discussion of a plan at a WHO workshop and a report of the WHO collaborative study to ECBS in 2009.

            The proposed second anti HIV international reference panel will be an extension of the established first panel for anti HIV-1/2 antibodies.  This first panel was a six member panel established by the ECBS in 2006 and it consists of subtypes A, B, C, CRF 01AE, Group O and HIV-2.  This panel is needed for the control of the HIV EIA tests, rapid tests and combo antigen antibody tests.  Samples from CBER comprised of different HIV-1 and HIV-2 subtypes from different geographical regions will be provided as candidate materials.  The project proposal is to be submitted to ECBS for endorsement by 2008.

            Eight different genotypes are known for HBV, A to H, representing different subtypes related  to A determinant of HBsAG.  The current WHO biological reference preparations for HBsAG and HBV DNA both generated from genotype A2, subtype ADW2 represent only one percent of worldwide HBV infected population.  So there is a need for the development of HBV genotype reference panels to evaluate surface antigen tests and HBV DNA NAT tests in terms of their ability to detect those other genotypes or subtypes prevalent in the regions where the tests are on the market.

            The aim here is to develop two genotype panels, one for HBsAG tests and one for NAT assays and PEI is coordinating efforts to collect plasma units worldwide that represent these different genotypes and is conducting a feasibility study to characterize and assess candidate panel members and by September 2007, PEI will develop protocol for the collaborative study to investigate the impact of the different genotypes on the sensitivity of surface antigen and NAT tests.  The report of the collaborative study will be submitted to ECBS in 2008.

            The standardization of anti Hepatis-B core testing using WHO international standard and the assessment of the sensitivity of anti-core assays is important to ensure the detection of true low level reactive samples.  PEI in cooperation with NIBSC and CBER is evaluating for the international collaborative study the candidate material which is a low anti-core positive without any other detectable HBb markers.

            After the international collaboration study the statistical analysis will be done at PEI by March 2008 and they'll submit the study report to ECBS in 2008.

            An anti HCV reference panel containing antibodies directed against single HCV antigens is needed for the quality control of anti-HCV tests.  This would be a reference panel for each of the four  major antibodies detectable by commercial anti-HCV test kits, anti-core and antibodies to the nonstructural proteins NS3, NS4, NS5.  Now Chiron offered to help by preparing mono-specific anti-HCV antibodies and these are from pooled HCV Genotype 1A positive plasma units with high titers against each of the four Reba-3 antigens.  A feasibility was conducted by the WHO collaborating centers using these candidate materials.  But because of the limited quantity of these materials that was available, this panel was considered useful for regulatory authorities to determine the potencies of the tests rather than to be used for the control of batch consistency by manufacturers.  PEI will finalize the analysis of all data from the feasibility study and will present the progress report to the ECBS in October 2007 and the WHO collaborative study will start in 2008.

            As you know, there is now mandatory screening for antibodies to HTLV-1 and -2 in many countries around the world.  These agents pose significant risks to the blood supply in specific areas such as Africa, South America, the Caribbean and Japan.  CBER proposed that an anti HTLV-1/2 reference panel be developed because the current lack of reference panels hinders the ability to evaluate new tests which have improved sensitivity and to assure that they are detecting the antigenic variance.  Some HTLV-2 subtypes, we know, may escape detection by currently available technology.

            The collaborating centers felt that for the development of a reference panel the candidate material should include samples from HTLV infected individuals, from areas where HTLV-1 and -2 are endemic including special samples that represent the HTLV-2 subtypes and CBER will coordinate the feasibility study by collecting and testing samples from these diverse geographical areas.

            For Plasmodium, there is a need for an antibody reference panel to define the sensitivity and specificity of serology assays to detect malaria infection.  The panel would be useful for the validation of EIA test kits and to compare the efficacy of commercial test kits by regulatory agencies and by the user.  Additionally, these antibody standard preparations would be a useful tool for assays to measure safety and efficacy in the development of malaria vaccines.

            It was decided that the panel should include sera from individuals who were exposed to only one species of Plasmodium and should cover the recognition of all species of Plasmodium.  NIBSC will send samples from positive donors to CBER to determine their reactivity to different mono-specific recombinant antigens and CBER and NIBSC will select a pilot panel of sera and develop a protocol for the collaborative study that would be reported to the ECBS.

            Several countries in Latin America representing the highest endemic region for Chagas disease, the U.S. and Spain, have implemented testing of the blood donors for antibodies to T. cruzi.  However, serological tests are of variable sensitivity and there is no global reference material.  Reference preparations are needed for both screening and clinical diagnosis.  Although variability in the antibody response throughout the endemic range does not appear to be a large problem, there is enough concern in the field that a reference panel of reactive sera should have representatives of multiple geographical areas.

            CBER proposed the development of an international reference panel for anti T. cruzi antibodies and WHO will form a working group that will discuss issues related to the development of this WHO anti T. cruzi panel including the need for the establishment for the panel of reactive sera representing multiple geographical areas.  Now at the WHO Chagas meeting in July, it was agreed that the panel would include antibody-positive plasma units from Mexico, Columbia, Bolivia and Brazil.

            Now in addition to these priorities, there were several other biological reference preparations that were proposed that need further discussion by the collaborating centers, an HIV-2 RNA genotype panel, an HCV genotype panel, as I mentioned earlier, a Parvo virus B19 genotype panel, an anti CMV standard, a West Nile Virus RNA preparation or a Pan panel for arthropod born flavivirus RNA, an HCV core antigen preparation, anti-HHV8 and HHV8 DNA preparations, TSE blood preparations, a blood-borne bacteria panel and anti Leishmania panel.  So there will be additional discussion among the WHO collaborating centers in future meetings about those various panels.

            Now there were some additional agreements among the WHO collaborating centers such as a need for collection and exchange of epidemiological information which has an impact on blood safety.  It was agreed that the established WHO biological reference preparations and those to be developed in the future are suitable to cover new technologies such as microarray and nano particle assays for the detection of infectious agents.

            They recognized a need for improved collaboration among WHO collaborating centers and with the WHO.  Annual face-to-face meetings and teleconferences are necessary to monitor progress on all of these priority projects I talked about and there is a need to establish a network of WHO collaborating centers for IVD-related biological standardization representing all WHO regions to ensure complimentary and focused expertise at the global level.

            So what's the plan of action?  Well, the priority projects to establish WHO biological reference preparations, to support international regulations for blood and blood products safety.  We'll form a five year in vitro diagnostic strategic plan and this plan will be submitted to the ECBS for endorsement in October 2007.

            Thank you for your attention.

            CHAIRMAN SIEGAL:  Thank you, Dr. Mied.  Are there questions?

            DR. DI BISCEGLIE:  I have a question please.  With regard to the standard for HCR RNA, you said that the standard that was being reworked was for genotype 1.  Are there other existing standards for other genotypes and, if not, why not, I guess?

            DR. MIED:  I think they're very hard to get.  I know that what they have has been generated from a genotype 1A donation or several genotype 1A donations.

            DR. DI BISCEGLIE:  The issue being this that I think it's well known that the genotype may affect the sensitivity of assays to detect HCV RNA.

            DR. MIED:  Yes.

            DR. DI BISCEGLIE:  And, for example, genotypes 3 and 4 are emerging in Europe at the moment.  We haven't seen that in this country yet.  But can we be reassured about the sensitivity of NAT assays to detect these other genotypes if we don't have standards?

            DR. MIED:  Yes.  That's one thing we really -- Mei-ying, go ahead.

            DR. YU:  I would like to comment about this.  Usually, the primers and the approach should be situated in the very conserved region.  So whatever you are detecting you should detect all genotypes at least for HCV.  I mean, yes, I understand there are mutants and there are some nearly evolved isolates, but in essence for HCV NAT, they are selected.  But I understand your issue.

            DR. DI BISCEGLIE:  No, I understand that and I think those of us with longer memories will recall that the very first assay that was developed for measurement of HCR RNA was found within a few months to have very discrepant ability to detect various genotypes despite the primer selection.  So I am somewhat concerned about this.

            DR. MIED:  Yes, it is a concern.  But I think that the assays that are licensed for use in the United States for screening, the NAT assays, some limited numbers of the different genotypes have been tested and there hasn't seemed to be a problem because of conserved region in the primers and probes that are used.  But it remains to be seen, you know, on a global basis with other HCV NAT tests how well they detect these other genotypes.

            DR. DI BISCEGLIE:  Sorry to be persistent.  I accept that.  I did see, for example, there was a plan to develop an HBV genotype panel for similar reasons.  I would have thought the reasons to develop an HCV RNA standard of different genotypes would be more compelling than that for HBV DNA and at this stage, I'll just -- I won't comment anymore.

            DR. YU:  May I just add one more thing?  Actually, NIBAC has HCV genotype panels that there is a panel that contained all six genotypes of HCV and you can obtain that from NIBAC and again, during that collaborative studies, there were using the primers and, of course, those all six genotypes were calibrated against the first international standard of HCV and again, in that study, yes, there are some.  They are less sensitive, one of the genotypes and so forth.  But again, primers and probes should be situated in the conserved regions in order to get the maximum sensitivity.

            CHAIRMAN SIEGAL:  Dr. Katz.

            DR. KATZ:  Yes.  Paul, on your next to the last slide, you had the very tantalizing category, blood-borne bacteria.  Would you enlighten me?

            DR. MIED:  The blood-borne bacteria were discussed.  I think that PEI has six different standards that they're willing to contribute to a feasibility study.  The need here, of course, is for methods and platelet bacteria screening and also pathogen reduction of cellular blood components.  These standards, bacterial standards, could be of value in evaluating those methods.  So a feasibility study is needed to see if there are standards, if there are strains that PEI has will be useful in that regard.

            DR. KATZ:  So this is some, I presume, relatively arbitrary clinical samples from blood or platelet contamination spiked into something?

            DR. MIED:  I'm not sure what they actually are.  I don't know.  I'll have to check on that.

            CHAIRMAN SIEGAL:  Dr. Epstein.

            DR. EPSTEIN:  I could just comment on that.  The Paul-Erhlich-Institut, Miesha Kneubbling, has actually published on this.  They have developed a candidate panel.  The source of the isolates, of course, is from clinical cases, but the isolates are selected for very reproducible growth conditions and resistance to serum killing so that they can then be spiked into samples that others wish to study and then the presumption is then you have a level playing field for assessing the capability of detect assays and obviously they are designed to span a range of bacterial groups and types.  So that's the underlying concept because right now, if a manufacturer wants to validate a bacterial detection assay you simply have to engage in a conversation on where they get their isolates and which ones they choose instead of having any kind of standard array.

            DR. MIED:  Yes.  The PEI standards were prepared from different blood-borne bacteria.  They're offering six defined stable and shippable bacterial standards, Staph epidermidis, Staph aureus, Staph pyogenes, Klebsiella pneumoniae, E. coli and B. cereus for a feasibility study.

            MS. BAKER:  Thank you for the presentation.  I know that the World Federation of Hemophilia has held near annual meetings about blood safety, the next being in September, I believe, in Montreal.  Are you aware of any efforts to communicate this information, the summary, with the World Federation of Hemophilia or other similar international consortia?

            DR. MIED:  No, I'm not aware of those efforts.

            MS. BAKER:  Okay.

            DR. MIED:  There may be some on the part of WHO.  I don't know what the plans are there.

            MS. BAKER:  Thank you.

            DR. COLVIN:  I just want to go back to the hepatis C issue again in that from a infectious disease point of view it seems to me that we could almost treat the different HVC genotypes as almost different infectious agents because they act so differently and, yes, there are obviously conserved sequences.

            But I agree with Dr. Di Bisceglie that we may not be looking at the same thing.  Yes, in some panels, they may work.  But especially if we're setting an international standard, it seems that we should look at each one individually.

            DR. EPSTEIN:  Let me just say that this is an issue that has been recognized by the WHO and there have been consultations and certainly it's open for additional discussion and we go to this meeting.  We're members of the panel.  We hear you.  We can pursue this further.  But the bottom line here is whether the reagents that are available do or don't work as generalizable standards and that can be determined at the laboratory level.

            And as it's been said, each of these reagents is evaluated in a large collaboration of multiple laboratories.  So we will get the right answers through the studies and the question is how do we approach the problem up front.  But, yes, we can bring this discussion to Geneva.

            DR. MIED:  The plasma samples that NIBSC has, they've procured HCV genotypes 2 through 6 specifically, 2B, 3A, 4A, 5 and 6A.  These were calibrated against the first international standard for HCV RNA in a collaborative study and they have been set at 1,000 International Units per mil for each genotype.  The problem is that the expression of these genotypes 2 through 6 in International Units should be taken with caution due to the genetic variability of the virus and the fact that the calibration had been made against the International Standard representing the genotype 1A.

            So it was agreed that this panel didn't have the status of the WHO international reference panel, but it is suitable for use in NAT assay validation.  So we'll just have to see.  We need scientific studies to assess the global variation of HCV and evaluate the impact of these variants on the sensitivity of various NAT tests around the world.

            CHAIRMAN SIEGAL:  Thank you, Dr. Mied.  Next we'll hear from Dr. Mei-ying Yu from FDA on the potency and safety standards for plasma derivatives.

            DR. YU:  My talk will be potency and safety standards for plasma derivatives.  The outline of my talk, first I will briefly give the introduction and then I will describe the available potency standards for clotting factors, potency and safety standards for immune globulin and albumin products, safety standards for in process control and finally standards under development.

            The Division of Hematology in CBER FDA has the primary responsibility for the scientific evaluation of manufactured biological products derived from blood or plasma and their analogs from recombinant DNA technology.  To ensure their safety and effectiveness, DH personnel have actively participated in developing and establishing CBER FDA/WHO global potency and safety standards through close collaboration with WHO collaborative centers, EDQM and industry.

            Now the global potency standard means that it's not only a WHO standard but also is European Pharmacopeia standard as well as CBER standard.  So CBER FDA standards are available to IND sponsors of licensed manufacturers.  These standards are for setting minimum potency requirements or maximum limits of final container products and it's for lot release testing of final container products and it's for in-process control testing as well.

            So the next few slides will be the potency standards for clotting factors.  The first one is Factor 9 potency standards.  These are for Factor 9 products like Factor 9 Complex, Coagulation Factor 9, Coagulation Factor 9 that's recombinant.  Now this standard is called WHO 3rd International Standard for Factor 8 Concentrates, but it's also European Pharmacopeia standard and as well a CBER standard.  So this standard is a global standard.

            It has an assigned unitage, 10.7 IU/vial.  This is based on the international collaborative studies.  It was formulated from a Coagulation Factor 9 product that is manufactured by using monoclonal antibody chromatography.  It was available since 1996.  Now there is a need to develop a new replacing standard because of the low inventory.

            This one is a potency standard for Factor 8 products.  The Factor 8 product assays are antihemophilic factor and the recombinant antihemophilic factor.  The standard is CBER Mega 2 from European Pharmacopeia Biological Reference Preparation Batch 3 for Factor 8.

            Again, based on the international studies, the assigned unitage is 11.4 per vial.  This is based on a one stage clotting assay.  If it's based on the chromogenic assay the unitage has been assigned as 8.6 IU/vial.  It was formulated from a plasma-derived high purity Factor 8 preparation provided by CBER and CBER/FDA.

            This standard was available since 2001 and this is after the potency calibration against four Factor 8 concentration standards.  That's there were Mega 1 from European Pharmacopeia BRP Batch 2, WHO Fifth International Standard and Sixth International Standard in a collaborative study.

            This is a potency standard for von Willebrand Factor.  The product assays, antihemophilic factor, von Willebrand Factor Complex (Human).  This standard is the first international standard for von Willebrand Factor Concentrate and the unitage has been assigned as 9.4 IU von Willebrand Factor.  This is based on the Ristocetin co-factor assay.  It contains 9.4 von Willebrand Factor per ampoule.

            It was formulated from a von Willebrand concentrate product by NIBAC, and it has been available since November 2001 after potency calibration against the WHO Fourth International Standard for Factor 8 von Willebrand plasma in a collaborative study.

            This one is a potency standard for Thrombin-containing products.  The product assays are  Fibrogen sealant and bovine thrombin.  This standard is WHO Second International Standard for Thrombin and also it's called CBER Lot K.  The unitage is 110 IU Human Thrombin per ampoule.  It was formulated from a human plasma derived thrombin by NIBSC.  It has been available since 2003 after potency calibration against a First International Standard for Alpha Thrombin and the U.S. Standard Thrombin Lot J in a collaborative study.

            The next few slides I will show you this potency and safety standards for immune globulins and albumin.  CBER referenced immune globulin for measles and poliomyelitis antibody levels.  This standard is to be used for setting the minimum requirement for measles and polio antibodies and the product assays are all the immune globulin products.  Here I listed immune globulin, immune globulin intravenous, immune globulin subcutaneous and so that this standard is called CBER Lot 176.  It was 2 mL fill per vial and stored liquid frozen.

            It was formulated from one immune globulin lot as 16.5 percent IGG solution in 1991 and made available since 1992 after a collaborative study with IG and IGIV manufacturers.  It was calibrated against Lot 175.  Again, it's for the purpose of meeting potency requirements of product lots for anti-measles and anti-polio levels when compared at the same IGG concentration.  So the requirement for anti-measles antibody levels is not less than 0.6 times the level of the Lot 176 when determined by hemagglutination inhibition or by neutralization.  And the requirement for a polio antibody level is not less than 0.28 for Type 1, 0.25 for Type 2, or 0.20 for Type 3.  Again, it's by neutralization assay.

            Now this standard will be discussed further.  It will be mentioned in this afternoon's session.

            And now this standard, Lot 176, was recently calibrated against the Second International Standard for Anti-Measles Serum (Human).   So the consensus titer was 42 IU anti-measles per mL of the Lot 176 and the data has been published by Audet, Suzette et al. in Journal of Infectious Disease, 2006.  Again, this 42 IU anti-measles per mL is based on a neutralization assay.

            It was calibrated -- Lot 176 also was calibrated against the first WHO international reference preparation for anti-HAV and also the CBER reference, Hepatitis B Immune Globulin Lot 2 for use as a reference for anti-HBs and anti-HAV level in immune globulin.  So it was determined to contain 2 IU anti-HBs or 95 IU of anti HAV per mL of this particular lot.  And again, in this collaborative study, all immune globulin manufacturers participated.

            Now there is a need to develop a replacement standard, Lot 177, because of low inventory.  A candidate 10 percent IGIV preparation is now available and is kindly provided by Baxter Bioscience.

            CBER Reference Hepatitis B Immune Globulin for Anti-HBs Potency Assay is used to assay products such as hepatitis B immune globulin or hepatitis B immune globulin intravenous.  The current lot is Lot 2.  It contains 220 IU of anti-HBs per mL.  Again, this standard is stored liquid frozen and it was formulated from an HBIG product which was a 17 and a 3 percent of IGG solution and made available in 1977 and, in fact, this product was also further diluted and freeze dried for establishing the first international reference preparation for anti-HBs immune globulin that Dr. Paul Mied just mentioned earlier.

            And there is a need to develop the second international standard for anti-HBs immune globulin and also that will serve as a CBER Lot 3 as well in collaboration with NIBSC and Paul-Ehrlich-Institut because of depleted supplies of the First International Standard and CBER Lot 2.  Now a candidate HBIG preparation is available and it is kindly provided by Nabi.

            CBER Reference Prekallikrein Activator, this is a safety standard and the product's assays are albumin product IGIV, IGSC and some specific IGIVs. This standard is called, current standard is CBER Lot 3.  It contains 100 IU PKA per mL and it's a liquid frozen preparation.  It was formulated from a highly purified PKA.  It actually contained 26 nanogram per mL Beta Factor 12A in a 5 percent albumin solution.  It was calibrated against Lot 2 in 1987 and found to be equivalent.  So Lot 2 and Lot 3 have equivalent potency.  Lot 2 was calibrated against the First International Standard for PKA and it was calibrated and the unitage assigned was 100 IU per mL.

            Now we have a maximum PKA level in plasma protein fraction.  So the upper limit is no more than 35.7 percent of Lot 3.  So that means not more than 35.7 IU per mL of the PKA.

            Again, since this reference material was prepared, was made available very early, now the inventory is very low.  So we need to replace CBER Lot 3 and we have recommended to use Second International standard for PKA, and that is 29 IU per ampoule.

            Global potency standard for anti-D immune globulin, this standard is used to assay Rhi(d), Rho(d)IG, or Rho(d)IGIV.  These are anti-D immune globulin products.  The standard is WHO Second International Standard, but it's also a European Pharmacopeia first BRP or CBER Lot 4.  The assigned unitage is 285 IU per ampoule and when reconstituted, it's 285 IU per mL.  It was formulated in NIBSC from two Rho(d)IG products licensed in the U.S., one acquired by the FDA and the other kindly provided by Talecris and formerly, Bayer Corporation.

            And this standard was calibrated against the WHO first international reference preparation for anti-D immune globulin and along with two other reserve candidate preparations that is by European Pharmacopeia and also CBER Lot 3 in a collaborative study co-sponsored by NIBSC, EDQM and CBER FDA.  It was established and available since 2003.

            Now the standard dose for use in preventing hemolytic disease of the new bone, this is by the FDA, should be not less than 15 IU per dose or equivalent to 300 microgram per dose.  Now the detail of the study please reference to Susan Foab's paper in Vox Sanguinis 2003 or in Pharmacopeia -- I mean Pharmeuropa Bio 2003.

            International reference reagents for anti-D to standardize hemagglutination testing, now this is a safety standard obviously and the product to be assay is IGIV, IGSC, and some specific IGIV.  It was after the collaborative study the WHO recognized this as international reference reagents and it's to standard hemagglutination testing.

            This standard was formulated by NIBSC by spiking an anti-D free 5 percent IGIV kindly provided by Bio Products Laboratory with the WHO Second International Standard for anti-D immunoglobulin and the spike, the total amount that had been spiked, was 0.475 IU anti-D per mL and the negative, it's just 5 percent IGIV and we call this the positive -- there is a positive international reference reagent as well as the negative international reference reagent.  The positive international reagent is also called CBER Lot 1A and so forth.  So anyway, these international reference reagents are kindly shared with CBER by NIBSC.  Again, all papers are published in Vox Sanguinis 2005.  This is by Susan Thorpe, et al.

            Briefly in that international collaborative study, the sample assay were those positive and negative international -- those are positive and negative reference reagents along with four IGIV samples with varying levels of anti-D by a proposed reference method which is a so-called direct hemagglutination test.  So the direct hemagglutination test was carried out by 19 of the 20 laboratories.

            But then six of the 20 labs also assay these materials with an in-house indirect anti-globulin test that's called IAGTs.  And based on the collaborative study by the direct method, the positive reference reagents has a nominal titer of 8.  However, with those indirect methods in the collaborative study, it shows that it has in fact about six of the laboratories, only one of them show up that has the same titer as the direct method.  Some of them could not even detect any titer at all.  So anyway, indirect method shows why inter-laboratory variability and less sensitivity.

            So there is a need for using positive international reference reagents to define the maximum level of anti-D in immunoglobulin products and to ensure sufficient sensitivity of hemagglutination testing.

            Now the results were presented to the European at the Group 6B meeting and it was recommended by the Group 6B to revise the appropriate monograph and to include the specification and to use the direct test.  CBER also adopted the same limit and the direct test after CBER's preliminary findings that only one of nearly 140 lots of the all-licensed immunoglobulin products failed the proposed specification.

            Now since the international reference reagents, the stocks are limited.  So larger fills were carried out by NIBSC and this larger fill is called reference preparation and this is for anti-D immunoglobulin.  And because it's larger fill, more vials were available.  So it's going to be -- it's being used to control the level of anti-D in Europe as well as in the U.S. for all the licensed immunoglobulin products.

            Now the reference, so it's this reference.  These reference preparations are called European Pharmacopeia BRP Batch 1 or CBER Lot 1B.  That's for positive reference standard and the negative, there`s also a negative standard.  Now the positive standard, as I say, is very similar to the previous one.  It also was spiked with 0.0475 IU of the anti-D per mL and based on the collaborative study in which all U.S. manufacturers also participated in using the direct methods and that has the nominal titer of 8 as well and I already mentioned that.

            So the standards were shared with EDQM and CBER and, as I mentioned already, that it was calibrated against international reference reagents with the proposed direct method and found to be nondistinguishable, at least, this is for the positive reference reagents.  So now, the maximum anti-D titer for five percent IGG for lot release is not more than the level in positive reference preparation by a direct method.

            The next few slides will be the safety standards for in-process control.  First is CBER Papovirus B19 DNA standard.  Now this standard later on was sequenced and found to be genotype 1 of B19.  This standard is to be used, it's used for validating in-process powers B19, not methods, for plasma for further manufacturing as analytical procedures which are viewed and approved under biologic licensing applications called BLAs and all their supplements for plasma derivatives and this is based on the September 1999 BPAC recommendation.

            This B19 standard is to use for screening plasma minipool to exclude B19 DNA positive donation  is used as a standard and it's to monitor the level of B19 DNA in manufacturing pools destined for plasma derivatives to ensure that the level does not exceed 104 IU/mL which is the FDA's proposed limit.

            Now this standard has a unitage of 106 IU or genome equivalent of B19 DNA per mL and it's 1 mL per vial.  And it was formulated from a window period plasma unit and diluted with a cryo-poor-anti-B19 negative plasma pool and it was provided as one of the candidate preparation for the WHO collaborative study to establish an international standard for B19 DNA.  And the results of that collaborative study is shown in this slide and it's freeze-dried preparation by NIBSC and CC is the CBER reference preparation, and since AA was recognized as a WHO First International Standard for B19 DNA in October 2000 and the unitage was assigned as actually it's 5 X 105 IU per vial.  But when reconstituted, it's 106 IU per mL and based  on because from the collaborative study AA, BB, CC are indistinguishable statistically.  So CC has international units of 106 IU/mL.

            And now because AA soon will be depleted, the proposed Second International Standard will be BB preparation and it will be NIBSC who will soon carry out the collaborative study to make sure that BB can used as a second international standard for B19 NAT.

            Another in-process control is CBER hepatitis A virus RNA standard.  This is used for validating in-process HAV nucleic acid testing method for plasma for further manufacturing and it's for minipools and meant to screen minipools and for manufacturing pools.  And these are since -- HAV NAT is considered as -- is validated as an analytical procedure which are reviewed and approved under BLAs  or supplements for plasma derivatives.  Now this is based on the recommendation of the June 2000 BPAC.

            The standards contain 6 X 103 IU or 104 genome equivalent of HAV RNA and again it's a 1 mL fill.  It was formulated from a window period plasma unit and diluted with with a cryo-poor, anti-HAV negative plasma pool and again this standard was provided as one of the candidate preparation for the WHO collaborative study to establish the international standard for HAV RNA.

            And the data is shown in this slide.  There are quite few preparations, candidate preparations, and EE is the CBER preparation and so forth and then AA that is a freeze-dried preparation was then later on based on the collaborative study it was recognized as the WHO First International Standard that contained 5 X 104 IU/mL or 105 IU/mL when reconstituted and it was established in the -- recognized as the WHO First International Standard in February of 2003.  So AA was 105 IU/mL.  So EE when calibrated against AA it was 3.79 which means 6,000 IU/mL.  Now again, all these studies are being published for B19 as well as HAV NAT is referred to J. Saldanha's paper in Vox Sanguinis.

            Now the next few slides will describe the potency and safety standards under development.  First is the WHO Second International Standard for anti-HBs immunoglobulin CBER Lot 3 in collaboration with Dr. Morag Ferguson of NIBSC.  Dr. Paul Mied already mentioned about this.  Now I already mentioned that a candidate five percent HBIG preparation is available and kindly provided by Nabi Biopharmaceuticals.

            And the second is CBER Reference Immune Globulin Lot 177.  Again, a candidate 10 percent IGIB preparation is available and is kindly provided by Baxter Bioscience.

            The third standard under development is Global Reference Preparations for Anti-A and Anti-B Hemagglutinins to control the levels in immune globulin products and to standardize hemagglutination testing in collaboration with Dr. Susan Thorpe of NIBSC and Dr. Marie-Emmanuelle Behr-Gross of EDQM.  Now again, a candidate negative five percent IGIV preparation derived from type AB plasma donation is available kindly provided by Baxter BioScience.  And Dr. Susan Thorpe is formulating a candidate positive IGIV preparation.

            Last one.  The Papovirus B19 Genotype Panel containing all three B19 genotypes in collaboration with Dr. Sally Baylis of NIBSC.  There is a need to detect all B19 strains which are recently classified into three genotypes because of genetic diversity by B19 NAT and the higher titer window period donation of both genotypes 2 and 3 are available kindly provided by Baxter BioScience and Talecris Biotherapeutics to NIBSC and CBER.  Negative plasma donations totaling 20 liters not detectable by all kinds of NAT procedures is kindly provided by NGI and so we will have to formulate a negative plasma pool and then that would be used as a negative member as well and also as a diluent for high viral stocks.

            The last one that I would like to mention is the WHO Fourth International Standard for Factor IX Concentrate.  This is in collaboration with Dr. Elaine Gray of NIBSC.

            Now the very last slide, this is the conclusion.  So DH personnel in CBER/FDA will continue active collaborations and participation in developing biological standards when needed and in testing candidate material in collaboration with WHO collaborative centers, EDQM, and industry to ensure the safety and effectiveness of plasma-derived products and their analogs.

            Thank you for your attention.

            CHAIRMAN SIEGAL:  Okay.  Thank you, Dr. Yu.  Are there any questions?  If not, anybody?  Yes.

            DR. SZYMANSKI:  I'm asking for clarification.  Your slide which says "Reference Preparation to Control the Level of Anti-D in Immune Globulin Products" you say you are titering the anti-D by direct method.

            DR. YU:  Yes.

            DR. SZYMANSKI:  What do you mean with that?  Do you mean that there is IGM anti-D there?

            DR. YU:  No.  This is an IGG anti-D.

            DR. SZYMANSKI:  Okay.  So what is the direct method?

            DR. YU:  Yes, it's by preparing treated red blood cells.  So you don't really need a second --

            DR. SZYMANSKI:  Thank you.

            DR. SCHREIBER:  I have one naive question.  I was noticing in your slides that Lot 176 is 16.5 IGG.  The standard that you're proposing is 10 percent IGG, and it looks like from the presentation we're going to see later that the most common preparation out there is five percent IGG.  How do you decide what the concentration is when you're deciding on your standard, and why wouldn't the standard be more attune to what the most common preparation on the market appears to be?

            DR. YU:  Actually, it's very common.  IGIV is prepared as 10 percent IGIV, as a ten percent formulation.  In fact, many of the five percent IGIV I know when it was infused that you usually like to reconstitute two ten percent IGIV and then use clinically.

            Now again, why back in 1991, that's the only product available.  It's intramuscular immunoglobulin which is a 16.5 percent IGG concentration and you are right.  Nowadays it's five percent or ten percent IGIV.  There are more such preparations and we can dilute the ten percent to five percent if needed.  But it's ten percent.  Actually, I would like to say the assays, when you compare it, you have to assay under the same IGG concentration anyway and it's available, donated by the manufacturer.

            DR. SCHREIBER:  Well, I had just noticed that on your slides some of your standards that you are proposing are five percent, in five percent and some are ten.

            DR. YU:  Yes, you are correct.

            DR. GOLDING:  Can I just -- I think for clarification when the assays are done, they dilute it down to one percent so that the standard and the product are both at one percent.  So when the assay is done, they have the same concentration in terms of immunoglobulins.  So I think there's a way of taking that into account.

            DR. YU:  Besides 16.5 percent IGG really cannot freeze well.  We were surprised that it lasts for so long since the 1991 until now.

            CHAIRMAN SIEGAL:  All right.  Well, we should probably move along because we are way over time unfortunately.

            Dr. Kochman, please, is going to talk about minimum potency standards for certain blood grouping reagents.

            DR. KOCHMAN:  This is just a brief summary to clarify what minimum potency standards are available for some of the blood grouping reagents that CBER regulates.  The list that has been available up until very recently includes Anti-A, Anti-B.  There are two Anti-Ds listed here.  The second one should actually say Anti-CD although it is intended as a standard for Anti-D.  Two standards for Anti-C, one for Anti-c, two standards for Anti-E, one for Anti-e, one standard for the Anti-IgG portion of any anti-human globulin reagent and one standard for the Anti-C3d portion of any anti-human globulin reagent and interestingly, you can sort of get a sense for what order these were prepared in by their lot numbers because the lot numbers were pretty much assigned sequentially.

            These were all manufactured in the early 1970s.  So they're getting quite old.  They are all polyclonal material, and we've always recognized that they were all potentially biohazardous.

            Why would we want new standards?  There has been a lot of question as to whether or not they're actually relevant to current reagents since most of these reagents in particular are available in monoclonal form.  We also recognized diminishing stocks both here at FDA and in WHO.

            The European Union's In Vitro Diagnostics Medical Device Directive No. 98/79/EC was recently implemented, and you may ask if it's European Union directive why should FDA care.  There are two reasons we care.  One is that many of our licensed manufacturers wish to be able to manufacture a product for distribution in Europe, and they would like to not have to worry about juggling different sets of standards, and we also have a number of foreign manufacturers who are expressing interest in becoming licensed so that they can distribute product here in the United States.  So it's best for both worlds if we can come to some sort of agreement on these things.

            And, lastly, and most unfortunately, some of the CBER standards have been found to be reactive for some of the tests for hepatitis.  This isn't totally unexpected because at the time the tests for HCV were implemented, they found that a number of source plasma donors with blood grouping reagent antibodies or even other entities of interest in use for controls in the reagent industry were found to be  reactive in some of the tests for HCV.  So while we weren't surprised, we weren't real happy about it either.

            Why did you choose to collaborate?  As I mentioned just before, to encourage international harmonization.  Maybe more importantly, to elicit input from a larger pool of experts in the area.  The collaborating centers included NIBSC, the International Blood Group Reference Laboratory in Bristol, CLB, CBER, and WHO, and this was helpful because it allowed us to replace both the FDA and WHO standards at the same time.

            For materials and methods, I should preface this by saying a method, a very specific method, was developed, put down on paper, and provided to all centers who chose to participate, and there were standardized worksheets for them to report their instructions on.  We recognize that hemagglutination testing is extremely variable.  So we wanted to standardize as much of the process as we could.

            Part of that standardization was to include only potency testing.  We didn't want to know specificity or avidity or anything like that.  We just wanted to focus on potency testing.  This was done with serial two-fold dilution titrations again in a hemagglutination test and most importantly in manual tube tests.  We recognize that reagents can be used in various other forms these days, but the manual tube test needed to be the baseline on which we standardized things.

            The participants were asked to test as many commercial reagents and/or reference standards as were available to them and the result was that there were 45 low protein anti-D reagents in the study.  There were only ten high protein anti-D reagents in the study, 22 anti-As and 23 anti-Bs, and we did not ask them to distinguish whether these reagents were monoclonal or polyclonal.  We normally were able to figure that out though.

            The anti-D study was done first.  There were 20 laboratories in 13 countries that participated.  U.S. licensed manufacturers did participate.  Those included the American Red Cross's Diagnostics Manufacturing Division, Gamma Biologicals, Immucor, Medion, Millipore, which was formerly Serologicals, and Ortho Clinical Diagnostics.

            The anti-A and -B studies were done later.  The participants were fewer.  We had only 17 in nine countries, perhaps because they found out it was so much work.  Again, the same licensed manufacturers participated in these studies.  So the good thing is that all of the currently licensed manufacturers at the time of the study were participating in it.  As we expected the results were very widespread in variability.  Endpoint titer results varied by between four and eight tubes and the endpoint titer across the laboratories for both the standards and the reagents.  There were only few outliers, predominantly a few that were extremely low titers and a few that were extremely high titers.  So very few datapoints were believed to be incorrect.

            But because of the extreme variability and the huge number of tests involved, it was an extremely complex analysis of the data that would have been far too complicated to go into here.  So if you really, really care, the results of the analyses are published in these two articles in Vox Sanguinis.  I believe the Committee received copies of both of these.

            The conclusions from the studies were that for Anti-D reagents, the Anti-D standard which is now designated as 99/836 for manufacturers who are making a low protein Anti-D reagent, they are to reconstitute the standard because it's provided freeze dried.  They are to reconstitute it as described in the insert that comes with it and then prepare a 1:3 dilution.  This standard replaces FDA's standard Anti-CD and as I said before, this is actually a standard for Anti-D.  It just happens to also contain Anti-C, number 9.

            For high protein Anti-D reagents, the manufacturers are to again reconstitute it according to the directions provided and then make a 1:8 dilution, and this replaces FDA standard Anti-D 4A1.  The difference in dilution is not anticipated to be a significant problem.  The high protein reagents are rapidly disappearing from the market in favor of the low protein monoclonal antibodies and so in reality, most of the products will be at that higher potency level.

            The Anti-A standard 03/188 results in a 1:8 dilution after reconstitution and this replaces the FDA's Anti-A Standard 6A.  The Anti-B Standard 03/164 is used at a 1:4 dilution after reconstitution and replaces FDA Anti-B 7A1.  I would like to point out that these are minimum potency standards and that is the only thing they're good for.  Manufacturers can make their products a little bit stronger, significantly stronger, if they choose to, but they have to balance that increased potency with the other written standards for specificity, avidity, and other characteristics.

            The reason that we go with a minimum potency standard rather than sort of a what the market would love to see standard is that we want to make sure that reagents are not going to waste or that they aren't so strong that they start causing difficulty in differentiating some of the blood groups from each other as frequently happens with the monoclonals.  It was less common with polyclonal antisera that you were confused as to the true status of a donor or patient.  But with the monoclonal antibodies, they can be so potent that they appear to be nonspecific or they're picking up extremely small amounts of the opposite antigen.

            And anyone who wishes to request any of these standards including the new ones, I included the address to send the request, and I wanted to mention also that this address is stated in the CFR.  That's it.

            CHAIRMAN SIEGAL:  Any questions from the audience?

            (No response.)

            CHAIRMAN SIEGAL:  Okay.  At this point, we will take a break.  Let's take only a ten minute break so we can try to get back on track.  Thank you all. 

            (Whereupon, at 10:10 a.m., the above-entitled matter recessed and reconvened at 10:26 a.m. the same day.)

            CHAIRMAN SIEGAL:  Could we please reassemble, ladies and gentlemen?  Okay, our first topic for the later morning session is the response of the Office of Blood Research and Review Office Level Site Visit for Research, July 22, 2005.  Kathy Carbone will introduce this.  Dr. Carbone.

            DR. CARBONE:  Thank you.  Today I would like to start with sort of an overview of CBER research, CBER's research mission, and some of the research management initiatives that have been initiated in the past few years as an overview and then I'll turn it over to the Office to respond directly to the site visit comments.

            But let me start by thanking everyone for their efforts in doing the first, at least, in my history at CBER, the first office level research site visit.  The site visit was valuable, provided wonderful information in the report and gave us a lot of good things to respond to.

            Basically, I'll start with a little introduction about CBER in managing the research to program goals.  The important part about the research, it has to cover like many of the regulatory bases we have to cover, it has to cover the gamut.  We have to provide and maintain a long-term programmatic, scientific expertise base to be able to respond to the variety of challenges that reach us.  But similarly, we have to be prepared to respond to crisis and I should say actually try to be prepared to respond in advance and prepare for the crisis because as you all know, research is the Titanic.  You can't turn on a dime.  So you have to be very forward thinking and get out of the old crystal ball.

            Clearly, in our job, the FDA has a clear job to do and, therefore, we are driving research management to continue to be outcomes driven.  In other words, there are specific high priority challenges that are holding up product evaluation that are making product prediction of risk and benefit difficult and these are the scientific challenges that have to rise to the top to be resolved.

            We focus on the critical gaps and scientific tools and knowledge for product evaluation.  There's been a tremendous investment in product discovery, biomedical discovery, and unfortunately, the same investment in the ability to develop the evaluation tools and knowledge to regulate those discoveries has not been forthcoming.  That's changing with the Critical Path Initiative through the Office of the Commissioner, but we really need to recognize that evaluation science is a special needs science and has been under supported and not given enough attention along with the biomedical discovery boom.

            So basically, our goal is to support product development for critical unmet public health needs.  CBER's products in general, the vaccines, the bloods, the cell tissue gene therapy, all have major public health impacts.

            CBER research solutions.  We've approached this and I think in many ways I'm very proud of the staff at the Center because we've achieved something which given our disease orientation and public health orientation is critical and that is multidisciplinary type research.  We use coordinated teams for regulatory challenges.  Everybody has a piece of the elephant to grab onto but we all are talking about our piece and keep in communication and must support that and facilitate that in the Center.  In addition, the external communication piece is very important and part of this discussion is -- and this discussion is part of that initiative.

            CBER research quality initiative is important because obviously, the work that's done in the Center needs to be communicated to the outside, evaluated by the outside scientific community, confirmed or refuted in the scientific process because the science that we use to do product evaluation must be the soundest science possible.  And, therefore, peer review journals, external arbitrary site visits and this kind of input is critical and we appreciate your time.

            It's also important to increase CBER research impact by providing more visibility because what we do to help promote and facilitate product evaluation should benefit all products and all classes of products and that's one of the benefits of being a nonconflicted government group but doing research is that what we do can provide benefit for every product and every sponsor.

            Funding these efforts is always a challenge.  It's a challenge for everybody and working with the Office of the Commissioner for Intramural Funding as well as partnerships for leverage funding is a critical part of our goal.  And providing core research support, it's not always possible to give a complete and thorough introduction of every scientific issue at CBER, but I do want you to know that, having been an extramural scientist for many years, we do internally at CBER have a very good support system for the staff including animal facilities, core facilities.  We have a flow cytometry core.  We have proteomics core.  So all these and sort of cooperatively across the offices facilitate the research at CBER.

            The research management initiative, this is one slide in a nutshell and I'm going to walk you through it in a little more detail and that is the first thing to do when you're trying to figure out what to do is you have to figure out what the job is.  And so we initiated a regulatory and public health portfolio analysis which is done on a yearly basis and updated and the bottom line is by taking a quantitative look at the applications, for example, that come into the Center as well as the pre IND meetings, we actually get a quantitative view of the scientific base of the issues that are coming to the Center.

            One can track documents, of course, and they must be tracked through PDUFA, etc. in terms of where they go, which office, whose doing the review, is the review done in a timely fashion.  This is a different kind of tracking.  This is tracking based on the scientific challenges within those particular applications.  In addition as the public health center, if you will, we also must scan the horizon, look outside, deal with the Department and other organizations, CDC and NIH, to get a good feel for the public health issues that are coming down the pike as well as the ones that are here.  And that analysis basically gives us the universe of needs which is tremendous obviously.

            From that universe of needs, we set the specific CBER research priorities.  This is a cross-office effort including the Office of Compliance and Biologics Quality which has been very, although they do not actively do research at CBER, they've been very contributory to this process and this research priority setting includes the regulatory scientists, the regulatory scientists leaders, the research regulator scientist and the research regulatory scientist leaders.  This is a common effort across CBER.

            And what this does and I'll show you in a little more detail how we set this, this basically tells us what specifically we're going to be working on because clearly we can't work on the universe.  From that, each office then derives its specific plans for the year.  They propose that over the year they will be working on these issues and they will be listing their deliverables as well as in this office research plan reporting on their achievements. But the main purpose of the office research plan is to talk about in the coming year what is the research plan for that office.  Those are all, again, shared across the Center.  It's a combined sort of CBER research plan and then off we go.

            At the end of the fiscal year after the research has been done, there's a careful scientific program review, both of the individual scientists as well as the offices, and a report is prepared.  In fact, we've just completed the individual research program reporting on our web-based system this week.

            Then this become the effort we are doing right now that at least one year we commit to coming to the advisory committee, talking about the research priorities, talking about some of the achievements, talking about the research plans coming up for the future, and getting the advisory committee and the public input in these plans.  We, of course, seek input throughout the year and, in fact, as one of our deliverables we're encouraging staff to provide with every research program or research proposal the communication deliverable that goes along with that.  How are they going to communicate the results and get feedback as well as communicate the design and get feedback.

            So in terms of the portfolio analysis, as I was saying, we talked to the policy leadership about key policy activities.  There are prioritization lists of guidances that need to be put out and the scientific dilemmas and challenges that come with those guidances that we can sometimes help resolve through our intramural and collaborative research program, the regulatory workload analysis as I mentioned, what kinds of scientific challenges are coming in and what's coming in in the future with the early as well as current issues and, of course, the public health.

            The research priorities are a complicated activity done jointly across the Center.  But basically, we take into account the regulatory workload which may or may not come with scientific challenges.  Sometimes there's an area of large regulatory activity but it's fairly standard, fairly historically accurate, a comfortable level of workload.  Then there might be even a small area, relatively speaking, where the challenges are enormous and the science is simply not there to do the regulation which we would like to do it science-lead.

            We look at product quality issues that are either anticipated to come down the pike or are there.  Safety and efficacy issues, the public impact of what needs to be done, the unique expertise we have available to do it.  Obviously, we want to be able to set priorities that are achievable with our given resources and given staff and also in seeking out the right collaborators to have and then the impact on product success.  Sometimes the high priority research items are not what you would call major impact, new discovery type.  They're often sometimes very standard, assays as you've heard, the standards.  These are sometimes critical elements that get the products through.  So we obviously look for things that will be high impact and things that aren't being done in the outside world.

            This is just a massive list of the `07 research priorities, and keep in mind these are sort of the areas that we think are important to work on.  Each office will then take these priorities and then  work down and say "And this specifically is what we're going to do within these priorities."  And now since this is a blood review, I won't take up a lot of time.  You have this in your book.  But the Office of Blood will be talking specifically about their priorities in detail in the next talk.

            So the research plan as I mentioned is misspelled.  I apologize.  My spell checker missed that.  But the research plan is actually a combined plan for all the offices, and as you notice, the leverage research projects which we have several working with NIH and Cell Substrates, etc., are incorporated within this research program plan.  It's not done separately.  In addition, it's incorporated as a separate element in the research program reporting.  So we track that as well.

            Not to get into too much detail, but we have an administrative process, for example, that before a grant or a partnership is made in the outside world, it has to be circulated and approved for issues of relevance, etc., within the office leadership before the application is even permitted to go outside the Center.

            Communication piece.  Since in the last four years, five years, since I've been the Associate for Research, we've managed to get up on the website, the research program summaries for all our research programs.  They include a, if you will, sort of public, plain language summary of the research efforts within that program, the issue of relevance, the public health issue, the outcomes and how research is solving these problems followed by a list of publications for the more scientifically inclined, and through this mechanism we're able when we go out to talk to other agencies and partners and stakeholders and people want to know who to talk to about what issue, we direct them at the website and similarly with collaborations.  We direct them at the website.

            But in addition to the office by office because our researchers are also direct regulators, they have product expertise, they are sorted by administrative lines within the product, we also recognize though that there's scientific expertise across the Center.  The greatest example I like to use is retrovirology in blood.  It's retroviral contamination of blood.  In vaccines, it's HIV vaccines and in cell tissue and gene therapy, it's retroviral vectors.   So we have product experts in each of those areas who all happen to be retrovirologists, and to facilitate communication within the Center and in speaking with the regulatory scientists leaders who all were delighted to hear about this to be able to have a resource to go within the Center to find out who your compatriots are, these individual teams are -- currently we call them the Virtual Teams because they're outside the administrative lines.  But, in fact, the plan is to bring these people together as teams for communication efforts and appoint team leaders who won't be responsible necessarily for the administration of budget issues, but for bringing the scientists together in critical mass and keeping everybody communicating.

            So research program evaluation, it's critical when you make changes.  When you're doing these sort of management, do a follow-up to see how well you're doing.  And we try and do that on several levels.  One level is as I mentioned, we have a web-based extensive research program reporting which includes research achievements from the past year.  Research achievements include publications, guidances, policies, etc., workshops held.  They also list future plans.  So they're rated on an individual basis, what somebody achieved and how, what their future plans are for that coming year.  We also use this web base to do sort of laboratory management, freezer database, staffing models, etc.  So it's quite a utilitarian web-based reporting.

            But, in addition, at the next level up from the view, maybe the 15,000 foot view, every four years, each laboratory program consisting of several PIs undergoes an external site visit, and this is through the advisory committee and chaired by a member of the advisory committee, actually two members, along with bringing in the expert scientists based on each of the individual lab's expertise, and that report is generated.  It's sort of, if you will, a small version of the office site visit, and every staff member gets reviewed every four years.

            This also feeds into our Promotions, Conversions and Evaluations Committee, internally the peer review which is composed of research regulators/scientists and regulatory scientists who will be doing cyclical reviews.  FDA has just established these cyclical reviews every four years of all staff members, so even if a promotion or a conversion issue is not at hand.  These are very helpful and, in fact, just like this site visit where we're responding back to the site visit -- the advisory committee, the four year research program laboratory site visits will also be generating a written response back to the advisory committee based on the suggestions given, and from this, every year we formulate as part of the annual program report the successes and future plans for research.

            The web based reporting is reviewed internally by leadership and by achievements.  Let me give you a little more detail, with achievements, a return on research resources expanded, the direct impact of the research on the regulatory challenges, the quality of the research which is critical obviously, the contribution to guidances, policies and workshops.  So we're not talking simply counting papers here.  We're talking about the whole ball of wax for the regulatory impact.

            Future research plans.  We do short-term, yearly basis.  The long-term are proposed in every four year research assessment research site visit, and it's similar sort of criteria.

            This slide is in your book, and I won't go into this in great detail.  But the bottom line is this describes how we do the site visits for each of the laboratories.

            And then the four year cycle internal review and I was talking about the cyclical assessments.  We have formal operating procedures for all of these because when staff come in on day one we want them to know what's expected of them as they come in.  So all of this is formalized and done with as much communication.  We have a website internally to communicate to the staff.

            So stakeholder input, that's what we're doing today.  This is part of our external input.  We ask for input into all levels, all, the entire circle of research management at CBER, and today Blood will be responding to the office site visit that was kindly provided by many of these Committee members.

            So I just want to quickly review some of the things that were said in site visits which these are a compilation of all the office site visits that we had, all the three major laboratory research offices and the Office of Biostatistics and Epidemiology were planning their first office site visit soon.

            Basically, we had actually an individual on one of the office site visits who also sat on the 1998 CBER Scientific Review, and this was a quote from that individual who felt "there's been a striking improvement since that time and focus in relevance and quality."  That was very kind to hear.  The site visits as a rule, the Site Visit Committee, strongly supported the FDA's research on -- the emphasis on the importance of research and also gave suggestions for the importance of maintaining support.

            The strengths and summary from the multiple site visits, productivity, scientific merit, mission relevance.  They well recognized the staff for the outreach efforts that they do, the complimentary cross office expertise, success of recruitment and retention, core facilities, and then leveraging and collaboration.

            However, the concerns were numerous.  Some of the concerns were increasing regulatory workload and decreasing support.  This may not be in toto.  It may mean sometimes in specific areas where the resources decrease and yet the workload is increasing.

            Best mechanism, trying to understand how to manage research to make sure that we get the end result without it being a process of micro-management.  To allowing sort of the creative juices to flow, if you will, but just trying to direct those juices in the right direction.

            Covering research bases versus focus on quality in fewer areas.  As you know, our portfolio is tremendous and yet we can't cover every base.  So how to approach that successfully.

            And then developing an explicit and strategic plan for research with regulatory and stakeholder input and as you can see that we're on the road to doing.

            The issue of mentoring came up in some of the site visits.  One of the research regulatory staff actually initiated through one of our internal research committees, coordinating committees, mentoring efforts that they sort of started.  They got a manual together and started to promote this and thanks to our Office of Communications and Training they have picked this up and there's now a formal mentoring program at CBER that's been piloted this last year and next year, there's a plan for expansion.

            Recruitment and retention.  Sometimes we do well and sometimes we haven't done so well and we need to continue to attend to that.  They suggested we needed increased research program visibility, continuing education support, making sure the scientists are given the opportunity to stay up-to-date, increased collaboration within and outside the FDA, increased FDA base funding, continuing leveraging support, public relations campaign, and a system for reward for successful research.

            And I want to thank you very much for your attention and overview and rush through it at the 50,000 foot level, and I would be happy to take any questions if there are any.

            DR. FINNEGAN:  You talked about your website.  Do you know how many hits you have, and how many of those are unique visitors, and how many of those are people outside of the government?

            DR. CARBONE:  You know, that's an excellent question, and I haven't tracked that.  I will ask.

            DR. FINNEGAN:  Because you can very definitely -- there's auditing.  So you can very definitely --

            DR. CARBONE:  Yes.

            DR. FINNEGAN:  My reason for asking this is because my bigger question and I don't know how to help you answer it is do you know where you fall into Google.  In other words, if I were to Google Chagas disease in transfusion medicine, would you show up in the first 50 or 75 because I'm pretty such most people don't go much past those numbers, and I do know that there's an art to how you put your titles in order to come up first in Google.

            DR. CARBONE:  That's an excellent suggestion.  We have a staff member in my office, Tom Madrew, who has done a marvelous job with the web with the support of the Communications group and we will look into that.  Jesse would like to say something.

            DR. GOODMAN:  Just to recognize the importance of what you're saying in how we communicate, the FDA as a whole is taking a very -- is devoting some resources now to taking a systematic look at how we make our web-based communications have the maximum impact and we're very -- the Center is very gauged in those efforts.

            But I think you highlight that we tend to focus in those efforts on our direct public health and product related communication and there's also a lot of other layers including the scientific communication, and we need to be attentive to that.  It's one of these areas that when you're resource constrained you tend to have less time and expertise to devote.  But it's very, very important, and we're also trying to bring into the center an expert on strategic scientific communication and again, that's mostly focused around our complex risk messages and our interactions with the public sector and the media sector.  But I think the point you raise is an opportunity there also.  Thank you.

            DR. FINNEGAN:  The two groups I'm sort of interested in are college and senior high school level and also public health people because I think that this is information that would be useful for them, and they actually can be your allies if they can figure out how to get to you.

            DR. CARBONE:  Thank you very much.  In fact, I was very appreciative of the Office of Communication that moved the scientific research expertise information from a little nine point sentence in the middle of a paragraph and we moved it to the side in a big bar of the same size there.  But I think it's important to see how we're doing and thank you for that suggestion.  We will look into that.

            DR. ELGIN:  I had a question regarding the four year cycle for individual, I think, this is individual reviews.  I'm just a little old city doc with internal medicine in a small nonprofit organization where we do our reviews biyearly or twice a year and I just want to understand better if you're saying that you only review individuals every four years for promotion.

            DR. CARBONE:  This is external scientific experts.  Internal reviews are yearly.  So you'll see --

            DR. ELGIN:  Okay.

            DR. CARBONE:  -- under this, the annual internal review occurs yearly by supervisors and by my office.  That's the -- the four year cycle is with external scientists.  For example, it would be really tough to review Dr. Nakhasi's Chagas program because we don't have any other Chagas Disease experts or Leishmania experts.  So we actually go out every four years and bring people in, and a research program as you know may take three or four years to become productive when new directions are taken.  So that -- In fact, the rest of the Agency went to five years, and I got on my knees and begged and said "I don't want -- any more than four years because our staff trainees, the staff fellows, senior staff fellows, they are on a seven year cycle and this four years gives us right around the middle of their tenure.  They get an assessment from the outside world and that gives them time to fix it.

            So, yes, we do internal evaluations every single year and four years --

            DR. ELGIN:  The next slide I think says four years.

            DR. CARBONE:  This is the promotions and conversion.  That's a third level review.  So there's the internal yearly, the external every four years and then once the external is done, that goes back to a separate committee which is across the Center.  So every year the internal supervisory chain reviews it as well as my office, and then every four years a committee that's composed of regulatory and research scientists from across the Center does a formal assessment.  This, if you will, is sort of a counterbalance as the internal supervisory with an external/internal review.  So that's really three levels of review.

            CHAIRMAN SIEGAL:  All right.  Next we're going to hear from Dr. CD Atreya from FDA.

            DR. ATREYA:  Good morning, everybody.  I have a little cough.  So bear with me if I have coughing in between.

            I will briefly comment on the OBRR which is Office of Blood Research and Review response to the BPAC and the recommendations that the Office has received for the research program and the Office site visit actually happened on July 22, 2005 and then the BPAC recommendations came back to us on February 10, 2006, and now we are reporting back to you as of a response as August 16th.

            The OBRR response, what we would like to say is that the CBER and OBRR office management actually thank the Blood Products Advisory Committee for its in-depth review and general support for the OBRR research programs, and the recommendations of the committee have received very closely attention at the FDA resulting in some programmatic changes to establish a structured and a transplant management system for OBRR research and also to improve research focus and prioritization as Kathy was mentioning before.

            So I'll come to the actual issues raised by the committee right away, and there are like four items, issues.  One is the sufficient time and qualified personnel available to perform mission related research with respect to enrollment and the retention aspects of it and then to the support for mission critical research.

            The concerns are that since the funding is really low are you able to find any alternate funding paths and how are you doing the outside funding and leveraging the resources.  Those items came up in that review and also the adequate laboratory space which is a problem for everybody on NIH campus and research prioritization process.  What it is is that there seems to be a need for a transplant process because there was a process but it was not transmitted to the public.  So I think that was a concern.  So we are going to address that.  And then there is a need for broad expertise or to have a tightly controlled focused research programs so that the funding will be sufficient for those programs and then, at the end, also as Kathy mentioned, the visibility of the OBRR research programs.

            Let me take up the first one which is the sufficient time and qualified personnel to perform mission-related research.  I assure you that the OBRR is committed to resolving regulatory scientific challenges by providing adequate time for its research and review staff to engage in relevant laboratory work and also to ensure that research and review staff are up to date with current scientific and technological advances by encouraging attendance at scientific meetings and supporting other training opportunities, also conducting periodic workload assessment within the Office to address any imbalances in a timely fashion.

            And then comes the support for mission critical research, how we are addressing this issue.  Within CBER, OBRR provides actually seed moneys wherever possible.  There is no guarantees, but always we try hard to get these funds as seed moneys and also the non-FTE that is the -- not -- the soft money post-doctoral positions to support research for the young investigators embarking on new priority research projects.

            We also try to participate in cross office partnerships for co-research support specialties as Kathy was mentioning like for major equipment purchases, service contracts for flow cytometry, TaqMan or sequencing facilities, etc. and we also evaluate laboratory space needs as a part of an interoffice effort rather than just an office effort.  This is a new improvement over the years and also CBER expected to relocate to a White Oak facility somewhere around 2012, and we expect that this move will probably facilitate and provide additional laboratory space for not only just to the OBRR research staff but in general to the CBER research staff.  That's one expectation we have.

            And then how we are doing the support for the mission critical research in the other part is that the Office, OBRR, actively seeks external support like many other offices within the CBER.  It's not unique to OBRR, but we have our own set list of how we do that.  When appropriate, OBRR leverages out set collaborations and partnerships.  The Office participates in developing CBER SOPs and memorandum of understandings, the templates to facilitate management of the application process for external grants, and we took recently a leadership role in bringing George Washington University under Center Scientific Training Program to allow student participation in CBER labs, and this is very successful and so far we have like around six or seven students came up from their MPH programs to do their practicum in CBER labs especially right now in OBRR labs, and that's a trend that actually has some implications.  In the future, probably these students can engage in having jobs in FDA because they may be interested.  They know that CBER does research, that helps as a PR, and also the successful OBRR collaborations have been established with many other government agencies like NIAID, NHLBI, NCI, DOD and others.  So these are the efforts we are doing.

            And also at the office level, a senior leadership team has been established in OBRR, and this SLT team what it does is it identifies and monitors progress in critical areas of regulation and Critical Path research within the Office.  And the SLT also collects input from both research reviewers and full-time regulatory scientists on regulatory science needs and then develops a comprehensive prioritized office's portfolio consistent with CBER's overall plan as Kathy was mentioning about, and then we also do review the applications for external grants both at the division and office levels to ensure that they are within the context of mission relevance.

            So how are we doing about the visibility of OBRR research programs?  We use research to address scientific issues that are critical to regulation.  So that means the visibility of OBRR research is important to us to ensure that all the information is publicly available, the science that we do, and external measures of quality and significance are there and to promote these objects what we do is, of course, we do publish in scientific work and peer review journals, present these, our data, at local and national and international meetings, organize scientific workshops as appropriate of regulatory interest, present scientific information to advisory committees as we do now and provide information at major scientific conferences and regulatory meetings and also provide opportunities for our scientific staff to interact with external scientists at seminars within CBER and FDA.

            Now I'll come to the point of how OBRR is managing the research.  What is its research plan?  How we identify key scientific needs?  The way we do that is that we anticipate actually the regulatory scientific needs that are identified by analyzing recent, like one to two year product application submissions and public health needs and policy portfolio.

            What we do is that we regularly review workload by product class.  We analyze that.  We look into all the guidance documents, recent ones that we  develop and then we analyze the product failures and safety reports.  We also do observations at the inspections.  We get information from the inspectors, field inspectors, and then input from scientific workshops and interactions with the regulatory industry, other HHS agencies and international partners like WHO.  And then what we do also is that research is targeted to identify the scientific needs where the output could lower regulatory barriers, product development or improve product safety, efficacy and consistency as well as availability.

            So with that, we have some scientific needs identified over the years, in the last year or so.  Those are the list of things here, practical and effective control of an expanding number of known and emerging transfusion/transmission of infectious diseases that request new technology for donor testing and product processing.  That means actually these technologies include adaptable platforms for rapid response to EID and bioterrorism agents; novel methods to detect malaria and other parasites as well as TSEs; nanotechnology based donor screens; new pathogen reduction methods for blood components and derivatives.

            Then we come to the point of efficacy and safety of immune globulin products enhanced by improved characterization for effectiveness that is useful for the treatment of primary immune deficiency disorders as well as for passive immunization against pandemic influenza, anthrax, etc.

            The second tier of scientific needs that we identified are all improvements in the storage enhancing blood component safety, quality and availability; tests for sterility to improve safety and permit extended shelf life; biomarkers of quality and efficacy to reduce needs for clinical trials; advancements in the development of better predictive  preclinical tests of safety and efficacy for blood substitutes such as hemoglobulin-based oxygen carriers; and biochemical characterization of HBOCs linking its structure to the clinical risk outcome as well as better preclinical models to predict HBOC safety and efficacy.

            And the third slide that shows these, the pharmacogenomic and proteomic studies to improve safe use of blood products.  Under that, genetic determinants to predict risk for development of clotting factor inhibitors comes under that category and genomic based blood grouping and typing to improve blood compatibility determinations.  And then lastly, the radio-frequency ID technology for blood product labeling and tracking which is a promising approach to reduce errors in blood transfusion management.  So these are the key issues we found out.

            So out of that, how do we deal with that and as a plan we cannot do everything on that as Kathy was mentioning.  So what we do is based on the identified scientific needs and available resources and expertise within the office and the feasibility of success and public health significance of the expected outcomes as well as the expertise of the Office that we have.

            What we have done so far is we've identified using all these criteria around six high priority areas for the current research program.  They are -- number one, a priority.  They are not prioritized as they are listed, but all the six programs are all important. 

            Number one is the novel methods of pathogen reduction and inactivation in blood and blood products.  What we expect out of this research is that as a development impact probably more rapid assessment of candidate commercial methods can be happening with this knowledge and then open new avenues to achieve safe and effective pathogen reduction for cellular blood components and we also probably expect that this research area will provide insight into the mechanism of cellular damage by pathogen reduction methods.

            The second one is multiplex platforms and high sensitivity methods for pathogen detection including genetic variant and imaging infectious diseases and bioterrorism agents.  What we expect out of this is that as usual the more rapid assessment of the candidate commercial methods, but also it could probably provide insight into the practical limitations associated with the new technologies.

            Then the third priority area is to develop infectious agent panels for assay standardization and standards and reagents for product lot release testing which you already heard a couple of talks on that before and what we expect out of that is that probably strategy preparations through development of lot release panels for new infectious agents will be available and replenishment or replacement of existing control panels is a possibility and also international standards for hematological products to ensure product potency.

            And the fourth one is the development and evaluation of proteomics and genomics based biomarkers for efficacy, quality, toxicity and consistency of blood components, blood-derived products and their analogs including blood substitutes.  Out of this what we expect as a regulatory impact is provide probably surrogate biomarkers for product efficacy and safety for more efficient clinical trials.

            Priority area five, development of predictive models for preclinical evaluation of blood components, blood derivatives and their analogs including blood substitutes and to study pathogenesis of blood-borne EID agents.  The regulatory impact that is expected out of this is an appropriate animal model to improve HBOC safety and the in vitro infectivity studies of blood components that could support changes to current policies on donor deferral and reentry.

            So the area, the last one, is development of methods to evaluate efficacy of immune globulins of pandemic and BT importance.  The expected outcomes for the regulatory impact are to provide a scientific basis for dose labeling of immune globulin products to prevent known and emerging infectious diseases and establish protective levels of specific antibodies in immune globulins to treat immune deficient patients.

            So in conclusion, what I can say is that  OBRR and CBER have carefully considered all of the recommendations of the BPAC review of OBRR research.  In particular, program changes have been made in response to the major recommendation of the BPAC for more structured and transparent management of research.  OBRR and CBER have developed and are implementing a managed research program as you heard from Kathy based on prospective evaluation of regulatory science needs, our available resources and the expected impact of the research.

            So therefore, we look forward to ongoing and frequent discussions with the managed research program to assist OBRR and prioritize, focus and streamline our research to best address the scientific needs of the day.  Thank you.

            CHAIRMAN SIEGAL:  Thank you very much.  Are there any questions?

            DR. DI BISCEGLIE:  I had a couple questions at this time.  The one was I was pleased to hear about the commitment of the Office to provide protected time for research for staff.  I wanted to ask a little bit about how that is done.  How much research, how much time is protected for a particular person?  How is that measured?  How is that assessed?  How is that enforced?  In other words, how real is it?

            DR. ATREYA:  I mean, there is some reality to it, but do you want to comment on that or you don't want to comment on that?

            DR. NAKHASI:  That's a very excellent question because I think what we do is at least in the divisions we look at the portfolio of a particular researcher, PI, and based on the workload of regulatory workload.  Because in the past, if it was not looked at, one person would be overwhelmed with so many regulatory applications and time goes down for research.  So now we have definite parameters where we protect, at least let's say, if it is a first time, an initial person.  When the new investigator comes into the division, we protect at least 70 percent of his time or her time to research.  As the time goes on, as the experience goes on, it can increase to 50 or 60 percent of the regulatory work and 40 to 50 percent research work.  It again depends.  It varies.

            Sometimes in the month, in a year, a person is busy with -- for example, last year there was a Chagas application for -- we approved the Chagas test.  A person who was involved in it had a 70 percent of time in the regulatory.  But the demand of the application, now his time has been brought into the research area where he can focus on the research.  So it has to be an adjustment but made by the managers, but at the same time, looking that you have a protected time.

            And Jay reminded me that we have an RRS system that is the time reporting system, how much we spend on the regulatory as well as on the research and so that gives an idea.

            DR. DI BISCEGLIE:  But is this coordinated across the laboratory level, the division level or the office level?  At what levels is this sort of scrutinized and coordinated?

            DR. NAKHASI:  The RRS is at the Center level and so it looked at the Center level because every three months it is done.

            DR. GOODMAN:  You know, I just want to add one comment.  We do have -- we do think, and this is from the commissioner to me and everybody, we want to have a strong scientific infrastructure.  We feel that in our area of products that's particularly important.  We think our decisions should be both science based and science led.

            That said though, we're an agency that has a pretty vast portfolio work under constrained resources and I just want to say that whenever a public health problem or a review issue that pertains to a product's quality or safety or availability comes along we all, whether we're the Center director or a junior researcher, we have to have the right people flexible enough to move to be able to do that.  So an important long-term challenge for the FDA is to attract scientists who can work in that kind of way and many of us who are in academic medicine are -- I know there are people who can work in that kind of way, but that's exceptional.  And also people who are interested in these unique opportunities who look on the importance of developing a new assay, let's say, to replace antiquated assays for influenza vaccines as a major public health contribution but sort of can approach these things flexibly and move to new problems.

            But I did want to emphasize that often every day we make tough calls about what we're going to devote our time and energy to and it's very important I think as we recruit and develop people, both laboratory people and other people, that they understand the environment that they're working in and that to the extent we can though we pay attention to their personal development as well.  So it's a tricky balance and it's made especially challenging in a resource constrained environment.

            The other way we try to build and develop people is through these collaborations with colleagues at NIH, academia, etc., and one of the things we've done, for example, in starting to evaluate research projects and I think I heard Kathy say this is to explicitly say do we have the right collaborators, do we have the right communication plan and that's not just communicating results but getting input about what we do and that's part of being here.  So I think for an extraordinary small amount of resources and for people who are often busy with a number of other things we can be proud of some of the impacts that people have had on public health and I think when you hear, you know, just hearing the list of active standards development and these are things that somebody else just, they're not going to get done if we don't participate and they improve patient safety and they improve industry's ability to get these products which often don't have huge financial incentives out there.  Thanks.

            DR. CARBONE:  There's one more level I'd like to mention and that is proactive rather than reactive, you know, having a staff member and trying to protect their time and that is that the analysis of the regulatory workload actually gives us a prediction of where the workload is going and using that mechanism you can then balance staffing models.

            For example, in another office, they identified a hugely increased workload in two areas that they don't have anybody working in.  So to avoid having to sort of task everybody or overtask, they then look at those areas and say, "Well, when resources become available, those are the areas we're going to staff up."  So this sort of proactive way of the analysis of the workload gives us the opportunity on a big picture to staff areas that need more, the time for research or staff areas that are bigger regulatory demands so that the staff members aren't so overwhelmed individually.  So there is also that planning level too.

            DR. SCHREIBER:  We did the site visit a little over two years ago now and I was just wondering if there's been any change in the ability to recruit and the retention of staff because that was a major consideration or discussion and even Dr. Goodman mentioned it again in his point.  So I just wondered if in the two years you've had any differences or seen any changes.

            DR. EPSTEIN:  Well, there are always changes because we live in a dynamic environment.  We're always in the process of recruiting and hiring people and also we always lose people to attrition.  I would have to tell you that the last year was a difficult year because we had a difficult situation with funding and we did have a temporary freeze on hiring and we did continue to attrit staff during that period and that for the last several months we've been rebuilding.

            So I think the honest answer is that we have some critical unfilled positions and that we're working very aggressively to fill them.  I think that the positive side of the equation is that we do get applicants and our programs are seen as a good place to come work.  So I would say right now the situation is that we're in transition.  Some of the groups did suffer significant losses of persons who had been at the FDA a long time, were holding major responsibilities, were very active at the bench and so forth and we have had to do a little bit of restructuring and some aggressive recruitment.

            DR. GOODMAN:  I could just comment again a little from the Center and the Agency point of view.  I think I agree with what Jay said.  The Federal budget process is complex, but I think the good news is I think some of the potential opportunities to strengthen the Agency, etc., are being recognized and we're hopefully entering into a period of more budget stability.

            I would say that there have been some very fine recruitments within CBER of scientists, of new people.  So I think it can be done and I think making the process for how we will manage the research transparent to people who come in can help in that and also showing as we have what are some of the unique opportunities.

            But it's a continuing challenge.  I mean it's very -- as everybody who has worked closely with us knows it's a very challenging situation.  I was in academia for a long time and I can say that the five or six major issues I deal with every day at FDA are more complex and more challenging and that's another reason why we really want the best people and to make it a good place for those people to be.

            So one thing I would mention, for example, we're about to be doing very high level recruitment and this is relevant to your question for a new office director for the Office of Biostatistics and Epidemiology and we see that as a very important scientific not just service that does our safety activities and our statistical activities, but a research and scientific area of incredible importance to the Center.  I'm saying that publicly and to you because we welcome and we really try to go outside, both develop our people inside, but also bring outside people in and we welcome the committee supporting us to do that.  Thank you.

            DR. EPSTEIN:  I just want to add another dimension to this discussion from your question and Dr. Di Bisceglie's question.  We have had a change which was noted both by Drs. Carbone and Atreya which is the ability to seek outside funding support through grants.  We can't compete for R01s.  It was noted that there's been an assessment that we're at the same standard of people compete for R01s.  We can collaborate with holders of R01s.  We can compete for interagency grants and we can apply for foundation grants.  We can also collaborate under cooperative research and development agreements with industry, although the persons who are in those collaborations cannot also be the reviewers of products from that industry.  Obviously, we have to be careful of that issue.

            But the fact that we're able to bring in outside grants does mean that we have another mechanism to support the laboratory program and I can tell you that where we're most short even though we're constrained in terms of number of people, full-time equivalents, that we can support with tax dollars, we have a worst situation with operating dollars because the operating dollars per capita for a principal investigator are nowhere near the standards that major research institutions whether they be government, NIH or academic.  But the ability to bring in ability to bring in grant funding we have somewhat improved the situation and that does have an effect both in terms of protecting the research because you can fund support persons.  In other words, you can fund contract hires and of course, you can leverage effort through collaborations and at the same time it has an effect in improving retention because our scientists are able to remain more productive.  So they're happier staying within the organization rather than feeling, "I can't do the work I'm interested in unless I move on."  So I think that that becomes a very important matter.

            There's a flip side to it, of course, which is when people apply for and obtain grants.  They are also making commitments to the work under the grant.  So within this program of management of research, we have to pay a lot of attention to what people are allowed to apply for because we have to ensure that looking over a multi-year time horizon which is, of course, typical for grant funding that the work is highly mission relevant and it does meet our sense of on-going priorities, future-looking for product development.  So I think that again grant funding is another mechanism by which we are both protecting the program and also keeping people in the organization.

            DR. KATZ:  I'm going to change focus a little bit with this question, but certainly in our community, in the voluntary blood community, biovigilance is the latest jargon and while FDA may find it difficult to actually do research in biovigilance, there's going to be a body of data developed over the next three to five or eight years that's going to have regulatory implications and I don't see in the research program anything that explicitly begins to prepare the Agency for dealing with the kind of data that we're going to see.

            DR. EPSTEIN:  Okay.  Well, let me just give a brief answer and then if Dr. Goodman wants to comment.  But we're actually very heavily invested in the whole issue of safety.  We're very mindful of the  Institute of Medicine report on safety in medicine.  We're very mindful of Congressional initiatives and in fact, there is legislation pending which will put a great emphasis on safety reporting.

            Within CBER, the lead entity is Office of Biostatistics and Epidemiology which is very involved with the whole issue of databases, use of data mining tools and strategies for monitoring safety.  We also have increased the focus on Phase IV monitoring of products post approval.  We have safety teams that Dr. Goodman has requested be created across CBER and we do have a safety team for blood.  We do have a safety team for tissues and we do participate very principally in the interagency activities.  The PHS has established a task force on biovigilance.  I know you're aware of that and FDA and in particular, the staff in my office are leading participants in that cross-agency initiative and within the blood safety team, the leads are cooperatively with Biostatistics and Epidemiology and with my Office of Blood Research and Review.

            So there's a lot of activity in that domain and I would say in terms of the research focus at our level it's principally about the databases.  It's about how to orchestrate data so that we can extract useful information, report it back out publicly.  We've built bridges, for example, with CMS where there's a tremendous amount of hospital data which was not historically available to the FDA and we're also, of course, interested in building bridges with the initiative of AABB and other components of the private sector.

            So we are very active in that area, but within the research program, I would say the lead is in the Office of Biostatistics and Epidemiology.  But we're certainly big time players.  Did you want to add?  Do you think I covered the base?  Yes.  Okay.

            CHAIRMAN SIEGAL:  Okay.  Any other comments?  Mark, I'm sorry.

            DR. BALLOW:  I was on a site visit not too long ago.  Maybe it was in the spring if I remember right and one of the issues came up about the White Oak site or location and whether that's going to have all the core laboratory facilities, particularly animal.

            Whether the White Oak facility is going to have all the core facilities including animal facilities and of course, it takes them away from the NIH campus where a lot of collaborations take place and the travel distance between the new facility and NIH is a potential barrier particularly with the traffic in Washington.  Of course, that may translate into recruitment because one of the nice things about your location now is such a huge research campus.  I mean it's like it's the most desirable thing that I could think of anyone engaged in basic research would like to see is to be surrounded by other top notch researchers and be able to interact and collaborate with them.

            So I don't know.  How are you going to address some of the barriers or some of the concerns of moving your facility outside the NIH campus?

            DR. CARBONE:  I'll take that on because I'm part of the, well, lead for the White Oak Subcommittee for Laboratories within CBER and also part of the OC's effort.  Just sort of as background, White Oak is located sort of northeast of the D.C. area just outside the Beltway and currently CDRH and much of CDER is located there and the plans are to move everybody but Foods to that campus and there are a couple of issues.

            I mean the one issue about leaving the NIH community is what it is.  But the bottom line is we actually will be joining up for the first time with our FDA colleagues which is a wonderful scientific base that we have not had previously.  For example, the CDRH group developed a wonderful new engineering building that's just state-of-the-art and has facilities there that don't exist elsewhere.  We are given the opportunity for building our research buildings and the animal facilities will be ditto.  We currently do not have primate facilities.  Right now, for example, we don't have BSL-3 small animal facilities.  We've had to work them into our BSL-3 laboratories which is less than ideal conditions.  So the new animal facilities actually have been designed with CBER input, with CBER numbers and we'll be addressing things like putting in BSL-3 small animal facilities which we currently don't have.

            The campus is actually quite nice and the opportunities to design buildings, the Building 29 currently is an ancient building and is actually very difficult to do research in.  We had a pipe burst and it flooded our 200 freezers and put them all at risk in 29A and in 29B we had to decommission a BSL-3 laboratory because the ventilation was not up to the new standards.  We had to build new laboratories on the top floor because of ventilation issues.  So the opportunity to actually construct novel facilities is really tremendous, the ones we can design for ourselves.

            The issues such as adjoining with NIH have been discussed.  We've been talking with the Agency, for example, on our access to NIH library system and they are currently in discussions with NIH to try and see to actually maintain that.

            The other options we've discussed are shuttle buses to the NIH campus to give staff an opportunity to come down for seminars, etc., and for example, I for most of my academic career collaborated extensively at Hopkins with staff at the University of Maryland that we weren't physically co-localized with.

            So we will do everything we can.  In fact, we've already surveyed the staff to say tell us exactly what you will be losing when you leave the NIH campus and about two-thirds of their concerns are actually covered, things like who will take care of radiation, who will do safety and other things that we can address directly with White Oak.

            And the remainder, such as travel.  We're looking at innovative ways to address it.  We actually established tours with the help of the Office of Management to get our CBER staff over to tour the facilities because a lot of people were expressing concerns without ever having visited the site and about an 80 percent response rate of people who visited was actually tremendously positive when they saw the opportunities at that site.

            The rest in terms of distancing from our NIH colleagues, we will be doing our best to address and resolve those.  But the opportunities for joining at White Oak are actually many.

            DR. GOODMAN:  We actually just had a meeting of our leadership within the Center yesterday to discuss this and learn from some of the experience of some of the people who are already there.  These are real concerns that you've identified, I think.

            One thing I would say is I think that what we're trying to do since this is a planning decision that's been made is say what is our vision of how we want our science to be and how do we maximally enable that.  For example, we have the opportunity to think about how does the architecture of our offices and laboratories, how can that instead of be an impediment to how we work, fit with how we work and fit with the mission.  So there are various models we're going to consider internally and with the architect of bringing laboratory, sort of like many people have gone through in academia with translational research.  You know, how do you bring the Ph.D. scientists together with the M.D. scientists and in our case, how do you bring the people who are full-time reviewers together with the scientists.  So actually, there are a lot of opportunities.

            I think a critical, critical thing is going to be we do have many life science relationships and projects that are leveraged with NIH and many personal relationships and also as you said that is an attractive thing in recruiting, etc.  And I think we want to look at those and try to be sure we can continue to support those or build other opportunities.  I think it's going to make on-going, explicit support for science at FDA very, very important and we're starting to see recognition by the outside and Congress and industry that there should be support for science at FDA because of its value and I think there's going to be this need for our scientists and again, I don't view this as just the laboratory science.  I think this is everyone to feel that there is support for building knowledge, improving knowledge, etc.  What we're trying to do overall with the research program should strengthen that.

            I'm not sure exactly how it will play out, but in legislation that Congress is considering, for example, there's a provision for some kind of potential foundation that can support certain scientific activities and things like that again may enhance our abilities.  But I know many, many people are concerned about this.

            The other thing I wanted to mention, I think you guys may have heard this before, but there's a review of science at FDA in toto, the whole Agency, that's being done by a group called The Science Board.  It's -- I can't remember the whole board, but it has been chaired this visit at least, the board I think is chaired by Ken Shine who is the former president of the Institute of Medicine and many of us know Ken and then this Review of Research which is on-going is being chaired by, I think, him and Gail Cassell who is the Vice President of Eli Lilly and a former president of the American Society for Microbiology.  So they're looking at for FDA to be a 21st century effective science-led organization, what is needed, and I think that report hopefully will help articulate the future going forward.  So we've been an active participant in that.

            And as much as this is a challenge for CBER, there's much of the scientific tradition at CBER and the interactions with NIH that has really helped support us and keep us going and some of the other centers have had even more challenges than we've had.  Thanks a lot.

            MR. ALLEN:  Mr. Chairman, I beg your indulgence.  We seem to have sort of gotten in the open committee discussion here.  So let me just make a couple of comments as the chair of the Review Committee.

            Dr. Goodman, Dr. Carbone, Dr. Epstein, Dr. Nakshi and Dr. Golding, I would very much like to thank you and your staff for your response to the report.  I think it goes far beyond what I had hoped might come out of this and I feel very gratified that we've been able to be part of a process.  I'm extremely impressed that this has been responded to not only by OBRR but by the entire CBER structure.

            I like the Research Management Initiative concept that has been put forward.  I like the Research Leadership Council, the Senior Leadership Team and the development of priority research areas as well as the rest of the responses.  I think this clearly -- the report that the Committee put forward was looked at very, very carefully and appropriate responses have been developed.  They are in the process of being implemented.  I don't at all get the sense that this was a one time, it's done, we don't have to respond to it anymore.  This is an on-going process and I'm very encouraged between the 1998 CBER report and our 2005-2006 OBRR report clearly there was an improvement in the quality and the focus of the research.  I'm encouraged that this is going to continue despite one of our major concerns which was the paucity of resources and I hope that this issue will continue to be addressed.  I think it is from what Dr. Goodman has said, because clearly it's important to have the appropriate resources, both financial, personnel and the facilities and the equipment issues are being addressed also.

            So I want to thank the Office for their response and to the entire CBER staff for the way in which they've responded to this report instead of just putting it up on a shelf somewhere to gather dust.  I think it's been useful.

            CHAIRMAN SIEGAL:  Thank you for your comments, Dr. Allen.  We now ostensibly have an open public hearing, but I understand that no one has signed up to speak.  Is there anyone from the audience or anyone who wishes to contribute at this time?

            (No response.)

            CHAIRMAN SIEGAL:  And that point we can dispense with the conflict of interest statements.  Then we might as well open our committee discussion at this point unless people want to take a break.  Let's proceed.  Is there any further open committee discussion?

            DR. FINNEGAN:  Mr. Chairman, you're allowing me one rude question per topic.  Right?


            DR. FINNEGAN:  My question has to do with considering managing your regulatory loads the same way you are managing your research protocols.  As we were sitting here this morning and I will tell you in advance I have no expertise in potency and standards and after this morning's presentation, that's just fine.

            But it struck me that a whole bunch of things came due at the same time and perhaps if this was managed and there was a rolling sunset or a rolling review of these things that perhaps this would help with getting more resources to your research.

            DR. EPSTEIN:  Well, I can perhaps shed a little bit of light on that which is that there's an annual review that goes on with standards.  In other words, CBER is a WHO collaborating center for biologics and one of the standing components of the WHO is an expert panel on biological standardization and annually there is a meeting convened, generally in October, of what's called an expert committee for biological standardization.

            And so what goes on is that at that meeting proposals for these reagent standards are reviewed, work plans are established, collaborating centers volunteer their agreement to help develop the standard and then over the course of the year the work goes on generally with additional collaboration from multiple expert laboratories.

            So when you say that there seems to be convergence of deadlines, what it reflects is the fact that there is an annual cycle for establishing the work.  Every year, there's a deadline of one sort or another.  Either the deadline is for submitting the proposal or the deadline is for review of the data or the deadline is for determination of the potency of the standard, etc., etc.  It's an ongoing effort.

            With respect to renewal of the reagents themselves, there's a certain level of happenstance here because for example, as you saw with the blood grouping reagents, many of them were established in the 1970s.  They're only now running out.  But it's not that that hasn't been recognized.  In other words, there's been a planning process for several years how one would go about renewing those particular reagents.

            The bottom line here is that the same could be said every year.  Every year something needs renewal.  Every year there's some deadline for a new initiative.  It's an annual process.

            DR. FINNEGAN:  What struck me this morning is that blood transfusions from 1950 to 2000 has gone from being a rapidly changing learning to sort of a maturing process and it would seem to me that a standard that was set in 1958 or a standard that was set in 1970 probably -- I mean, I would assume that every group has the same resource problem and the same we would rather be doing other things type of process and so it's inertia of the entire group that's letting it go this long rather than someone saying "Look.  This is now 15 years old.  Maybe as a group we need to say for this particular problem it needs to be moved up the scale."  Does that make sense to you?

            DR. EPSTEIN:  Well, I'm not sure I follow the argument fully.  What goes on is a constant reexamination whether the available reagent still works.  So for example, we participate with a collaborative study that's organized by the Council of Europe.  Every year, there is a review of serological reagents for blood grouping and typing.

            The question is whether the current international reference material or international standard is still operating the way we want it to and as long as it is, it's fine.  And it's only as new needs get recognized do we generate new types of reagent and I think what you heard today is that right now there's quite a lot of activity in new types of reagents.

            For example, we have moved from an era solely of serological reagents to an era of antigenic reagents and now to an era of genomic reagents and now we're looking at genomic subtypes and of course, we also have to keep up with the evolving evolution of agents, for example, HIV and all of the substrate of subtypes, yes, HCV, etc. and you heard it also for Papovirus B19.

            But when you say if you have the same reagents in place for, say, Anti-A or Anti-B, why aren't we modernizing?  The answer is we are.  The answer is that standards for monoclonal reagents are being developed.  But it hasn't made the polyclonal reagents obsolete and as long as they're not obsolete, they're doing what they say they're supposed to do and they haven't lost their potency and they're still available.  Well, you don't need to do anything about it except ask every year if they're still good.

            I just think that the situation is dynamic even though some reagents stay on the scene for a long time, especially polyclonal reagents.  I mean they do tend to be valuable for a very long time precisely because of that nature and for many things, you know, the changing in biology isn't so quick anyway.  Look at human blood groups.  They're not evolving the way the viruses are evolving but we do have new reagents to deal with new technologies to be sure.

            Is that helpful because again I'm not sure I precisely understood your question?

            DR. FINNEGAN:  I think my question was less about the blood typing.  I agree with you completely on that.  I think I was more perplexed as to why there was depletion of so many standards at the same time and some of those standards have been around for a long time.

            DR. EPSTEIN:  Again, some of it has to do with when they were made and some of it also has to do with the fact that as more manufacturers may enter a field there is an acceleration in just the utilization of reagents.  But I'm not sure that I have any greater insight than that.  You know, we tend to target something like a seven to ten year life span for one of these international standards and so there's a certain amount of guesstimate that goes on about the rate of use and sometimes the guess was right and sometimes the guess was wrong.

            But to the extent that when a field kind of emerges -- let's look at it this way.  Right now, we're generating a whole class of RNA and DNA reagents and it's happening over a relatively short span of years.  You know, over a two to three year span of years you're going to have HIV, HCV, HBV, B19 genomic reagents.  Well, one could say that won't they all get exhausted, for argument sake, five years from now and it will be because there is a cohort effect.  In other words, the science has matured to the point where we recognize the need for the reagents and we're making them, but that's all kind of happening in a cluster.

            Now I can't tell you that a B19 reagent will be exhausted more quickly or more slowly than an HIV reagent.  But to the extent that they all mature at the same time, that the fields do, we may see another cohort effect a few years hence.

            DR. FINNEGAN:  Why could you not monitor the use of the reagents and figure out what's going to be depleted?

            DR. EPSTEIN:  We do.  Again, that's  part of the annual review at the WHO is how quickly are they being exhausted, how much is left, are they still stable, are they still the reagent that you want, are they fit for purpose.  So we do that.

            DR. GOODMAN:  One -- I was at the committee meeting last year at WHO about this and there was a similar portfolio of things that each year people are taking on or identifying.  But what I would say is this is another area.  It's not sexy.  It's not finding the gene for disease X and it's not necessarily -- there's not necessarily funding dedicated to it.  So at the WHO level, at our level, there are only a few places in the world that do this stuff.  The Paul-Ehrlich-Institut is another one which is a counterpart of ours in Germany, the National Institute of Biologic Standards in Great Britain.  But among that group, that said, there is not the possibility of taking on every standard preparation or assay improvement effort that could be done.  So by necessity, people are looking at what are the priorities, what are the most critical needs.

            One of the things we've tried to do with this research management and with the whole FDA critical path initiative is identify that this is an area of science that needs attention and everybody benefits from that.  Patients benefit on the quality and safety end.  Industry benefits on the quality and availability end.

            So I think in a way it's good we're having this discussion.  It's good that we do this work.  But it's not something the world has paid the same attention to as, let's say, standards for semiconductors or something where there's a huge economic drive for it.

            DR. EPSTEIN:  I just wanted to --

            DR. DI BISCEGLIE:  Can I ask a related question?  Sorry.

            DR. EPSTEIN:  That's fine.

            DR. DI BISCEGLIE:  For either of you.  Just the idea of the distinction between mission-related research and mission-related laboratory work.  This development of standards I would think of more as very important, very necessary laboratory work but not necessarily innovative, and therefore, not necessarily research.  Or maybe I'm wrong and I'm just thinking about how you measure in terms of time and effort and so on, those two types of laboratory work.

            DR. CARBONE:  Actually, in some ways I'll reiterate what Dr. Goodman just said which is the lack of recognition of the development of standards and assays as a science is one of the things we hope to change.

            Developing a standard requires that you have an adequate way of measuring it.  It requires that you have an adequate way of measuring the disease.  It requires that you have an adequate model sometimes of starting out.  So there are quite a few scientific creative elements and the end product is "just a standard."

            So we define our research not -- we don't use other people's definitions of what is quality research.  We define our research as what we need to do the job well and in many cases, there's a great deal of science and if you will, the lack of knowledge or the science makes it difficult sometimes to generate these standards.  So the element -- the end product I agree with you.  It's a standard.  It's fairly -- by definition, it's standard.  But the act of getting there in the right manner often requires some innovative science.  So from our perspective, it is counted as a laboratory research endeavor and it gets the scientist credit.

            We do obviously the peer review publications which is kind of the standard academic extramural NIH type measurement because we feel it's important to have our science peer reviewed, have our science out there in public.  But in fact, we measure that as important and it's important science for CBER as well.

            DR. EPSTEIN:  I would say that there tends to be an underestimation of the scientific element of this endeavor because the end product looks simple and everybody understands that certain aspects of it are rote.  After all, if you want it lyophilized, how much science does it take?  That's straightforward.

            On the other hand, what goes into it as Dr. Carbone was explaining is really multi-factorial.  I mean it starts with epidemiology.  What's out there?  What are we trying to measure?  Why are we trying to measure it?  What are the characteristics of the assays?  For what assays and what types of assays are we trying to make a standard?  So that requires a certain kind of exploration.

            Then you can get into many, many subtleties about the assays.  For example, we didn't go into the details, but let's say you want a standard for von Willebrand disease.  Well, what are you looking for?  So there's a lot of effort that goes into figuring out the standard assay as well as the standard reagent and it's full of betwixt and betweens.

            And then you come to the reagent itself and should it be liquid?  Should it be lyophilized?  Should it be purified?  Should it have a single specificity?  Should it be multiple specificities?  Should it be naturally derived?  Should it be recombinant?  Should it be the natural sequence?  Should it be a consensus sequence?  So there's a lot of judgment that goes into relating its characteristics to its utility and of course, that requires a scientific dialogue and often some experimental work.

            Then you come into the whole issue of now your goal is to have a physical material that has a meaningful unitage.  But when you then characterize it with an array of assays through a scientific collaboration what you end up with is a range of answers and then you're trying to figure out what's meaningful in that range of answers and that gets you into a whole set of questions about the methodology.  It raises statistical questions.  If you have an assay and it gives you an outlier result or you have an assay and it has high variance, just exactly how do you deal with that result when you assign unitage and what's going to be the significance of giving a unitage that may not work in that assay and is the problem with the standard or is the problem with the assay?  And we mustn't forget that that has a lot of implication for product potency.  I mean, if that's a standard for Factor 8 and you want to reliably dose the patient with Factor 8 or Factor 9, you want to be very, very sure that you've measured the right thing.  So you have that whole aspect to it.

            So what I'm trying to explain is that although some aspects of it may be mundane science because it's well established.  I mean, we know we should refrigerate liquids.  Right?  But on the other hand, you get into all these subtle questions.  Should it be inactivated or not inactivated?  If we inactivate it, does it change its character in an adverse way because it's no longer a natural material and we don't know what assay is going to come next.

            So all I can say is that a seemingly simple activity is actually laden with myriad scientific questions that require extensive collaboration and for which the answers are not straightforward.  Just to give you one more example, there's this whole debate about what's called metrological traceability.  If you give an unitage which is always an arbitrary unit, should you be able always to relate it to some actual physical measure?  For example, is an antigenic potency unit sufficient or must it be referable to physical mass or if it's only referable to antigenic mass, is that with a standard antibody and how do you know that the standards stayed the same?

            And a lot of the effort goes in -- Dr. Finnegan was talking about refreshing these reagents.  The immediate question is how do you determine sameness and sameness is very difficult to assess.   You're going to have a new reagent.  It's going to come from a different human donor or a different human pool and you want to figure out whether the unit is actually traceable to the prior unit because if the unitage turns out not to be equivalent, when for example, Mei-Ying was explaining the unitage for the Factor 8 standard, you don't want to have a shift in product potency because you misidentify the equivalent unitage of the new reagent compared to the old reagent.  But then the question is how is it traceable to the original potency and does it require merely a functional determination or does it actually require a biochemical determination and how exactly can that consistency be demonstrated?

            So all of these issues converge into a scientific effort and I think what you heard Dr. Carbone say and what I've tried to illuminate is that it's actually a science onto itself and I think that that's the point that's been underappreciated that you do need people who understand all of the details of that at the very, very simplest level.  You know, should it be delipidated and lyophilized to the most sophisticated level which is is it or isn't it representative of the genomic variation of the thing you're targeting and that's just the science.  That's the science piece.  Does that help?


            CHAIRMAN SIEGAL:  That was very good.  Thank you.  Okay.  Are there any more comments?

            DR. KATZ:  That was neat, Jay.  Good job.  That was not mine.  This may be for Jim because lo these many years ago I was doing site visits as well and writing reports and actually the evolution of management of the research program is pretty spectacular over the last ten years.  So that's one side of the field of endeavor.

            But we keep talking about the resources and I'm just wondering what the Committee says about what anybody who's interested can do about the resource issue and I didn't know then and I don't think I know now.

            DR. ALLEN:  It's hard to say.  Certainly, those of us who are not now in any way connected except through this committee with the Federal Government, we are certainly free to contact Congress and to advocate on behalf of the Agency and the need for those resources.  I think that's an extremely important function that we all should be doing.  We should be talking with our own Representatives and Senators about the importance of this and trying to get our colleagues at academic environments to do likewise.

            There isn't a good lobbying group out there for the FDA.  The NIH certainly has a very broad-based research community that is out there and has organized to assure that their message is heard by Congress and by others.  The CDC was slow to do so, but has subsequently developed a reasonably active public health support group.

            The FDA has a lot of industries that it regulates or is regulated by the FDA and these groups have their own special interests.  They aren't out there in the same way as a strong support group for the Agency and resources for the Agency.  But I think it's really incumbent on all of us to do what we can to try to get that message out.

            I'm delighted to hear that there is an FDA review group that's out there and certainly I assume that they have been given copies of the report.  Dr. Goodman certainly indicated that he's been talking with them.

            This whole issue of perhaps a foundation  to support research efforts hasn't come to fruition yet, but at least it's being discussed and I think that's helpful.  Again, support from those of us who believe that that might be useful certainly might be helpful.  And I think we just need to look at ways that we can do that to always in everything that we do be supportive of the Agency and in particular, of the programs that are important to us.

            DR. CARBONE:  I just briefly want to mention that as part of the total FDA review we supplied the office site visit reports for all the offices to the Office of Commissioner.  So that message certainly has been delivered.

            CHAIRMAN SIEGAL:  Okay.  Anybody else prepared to lobby?


            CHAIRMAN SIEGAL:  Dr. Szymanski.

            DR. SZYMANSKI:  I was quite impressed about the response I think in all areas as Dr. Allen said.  But I was wishing that there would be one other area included, but I guess it doesn't belong to FDA and that is the standards of transfusion of various products.  I think this is such a very important area clinically and it would be lovely if some overall agency would look at this because now it seems to remain in each hospital their own affair and I would love to see an overall scientific review of the standards of transfusion.

            DR. KATZ:  Clinical Transfusion Medicine Committee at AABB is embarking as we speak over the next several months on a very formal guidelines development process.  It doesn't carry force of law or regulation, but I think most physicians would prefer that clinical guidelines come from clinical organizations as opposed to regulators.

            CHAIRMAN SIEGAL:  If there are no other comments, then perhaps we should adjourn for lunch.  But it's actually about 15 minutes early.  So that means we should come back 15 minutes early.  So let's reconvene at 1:00 p.m.  You're allowed to check out in your lunch hour. 

            (Whereupon, at 12:01 p.m., the above-entitled matter recessed to reconvene at 1:03 p.m. the same day.)















          A-F-T-E-R-N-O-O-N S-E-S-S-I-O-N

                                         1:03 p.m.

            CHAIRMAN SIEGAL:  Let's resume please.  We're going to have to revise the schedule slightly.  But the topic this afternoon is Measles Antibody Levels in U.S. Immune Globulin Products which we already began to discuss a little bit earlier.  We're going to have an introduction by Dr. Basil Golding from FDA.  Dr. Golding.

            DR. GOLDING:  Thank you and good afternoon.  Before I start, I would just like to give credit to people who provided very important input.  Some of the presentation is going to involve information that was generated at the FDA, worked on across offices, between people in the Office of Vaccines and the Office of Blood.  Judy Beeler is the virologist that does the measles titer assays together with Susan Audet who is the first author of the paper that was generated and a lot of that information relates to the position that we're in where we're able to deal with this project.

            And keeping in mind what was discussed during this morning's topics, I think it's very apt to remind people that the research that was done here was very mission related and was very proactive because we realized that the titers were dropping and people in the research group, in our group, Dot Scott and Mei-Ying Yu, collaborated with the Office of Virology and started looking at the lots and trying to figure out what was going on and that led to an information base which we can use to formulate some kind of approach which we're going to discuss this morning.

            I also want to thank the other speakers who are coming and some of them haven't yet arrived but who are going to present certain aspects which will help inform us and hopefully inform the Committee to make a decision regarding the questions.

            I'm going to be talking about measles antibody levels in the United States related to immune globulin products and the main issue that we've come to address is FDA seeks the advice of the Committee on a proposal to lower the minimum recommended lot release titer for measles antibodies in immune globulin intravenous IGIV and immune globulin subcutaneous IGSC.

            The background for this is that measles antibody titers serve as a potency test for lot release of all immune globulins licensed in the United States.  Measles antibody levels in products have been declining in recent years and a failure in potency testing which is a release test would result in rejection of lots with a negative impact on product availability for primary humoral immune deficiency diseases.  CBER proposes to lower the minimum measles antibody titer of IGIV and IGSC to levels expected to be effective in pre-exposure protection in patients with PIDD.  Immune globulin intramuscular or IGIM is indicated for post exposure protection mainly in normal individuals and will not be considered at this juncture, but we will have to deal with this separately.

            In general, a lot release test, what are the regulatory requirements?  Well, this comes from the CFR.  "Laboratory controls shall include the establishment of scientifically sound and appropriate specification standards, sampling plans and test procedures designed to assure that drug products conform to appropriate standards of identity, strength, quality and purity."

            Potency testing for immune globulins, the rationale is based on the assurance of strength and quality and what do the specifications really provide?  They allow for a measure of lot-to-lot consistency for assurance of product integrity, especially tests that measure a function of antibody rather than just binding and they measure activity that is relevant to the indication, in this case, for patients with primary immune deficiency disorders.

            So in general, what are the current U.S. immune globulin product potency tests?  The current requirements are that you measure antibodies to measles, diphtheria, polytype 1203 and hepatitis B surface antigen and it came up in a question before by Dr. Siegal, you know, what about testing for more appropriate antigens.  Well, we are working on that and this was discussed at the workshop and we will be developing hopefully in the near future a testing that will be more relevant to the antigen such as haemophiles and influenza and strep pneumococcus.  So all the above tests except the antibody to Hepatitis B surface antigen are neutralization assays, functional assays.  But the anti Hepatitis B surface antigen titer does provide additional assurance of viral safety both for manufacturing and for pre-exposure prophylaxis in the patient group.

            IGIV and IGSC in measles antibodies, the measles antibody levels are a standard measure of potency for these immune globulins.  Historically, when measles was a much more serious problem as a public health issue, having this protection was important.  Potency tests are available and correlate with protection in normal subjects.  They are measured by bioassay and the two types of functional assay are the hemagglutination inhibition assay and a neutralization assay which is really a plaque reduction assay.

            The important issue that we have to face now is that declining antibody levels have been observed in these products over the past several years.  The first question is why are these antibodies declining in donors.  Well, natural infection does result in higher antibody levels and the proportion of vaccinated as opposed to naturally infected donors is likely to be increasing.  The vaccine was licensed in 1963 and implemented over ensuing years and naturally infected populations of donors are aging and these people are more likely to be deferred and there are pure donors now available who were naturally infected.

            This is from a paper by Markovitz which just compares the titers from natural measles infection with those from the vaccine.  On the X axis, you can see time after natural infection or immunization.  On the Y axis you see the actual titers and the upper graph shows the titers with natural measles infection remaining higher for a longer period of time compared to the titers from attenuated measles vaccine immunization.

            So the measles potency test for immune globulins has a history.  In 1944, a paper by Stokes demonstrated that measles prophylaxis by IGM is effective.  Around about 1953, the NIH came out with a statement that there should be a minimum requirement for immune serum globulin.  This is the intramuscular.  Several lots should be effective in prophylaxis of measles.  And as measles potency tests became available, CBER developed standards to facilitate the potency testing of these products.

            This is the history of the actual antibody potency standard.  In 1961, the Lot 1 was the first standard.  It was serum from immunized nonhuman primates and ISG or intramuscular the standard was required that it should be at least 0.25 times the standard Lot 1.  The cutoff was established based on a study of 60 IM preparations, IM lots, considered potent for measles prophylaxis and the cutoff permitted future lots to pass specification with a probability of 95 percent.

            Many years later, 1971, Lot 1 was replaced with Lot 175.  Then again in 1992, Lot 175 was replaced by 176 which is the current standard.  The current lot release criteria lot should have at least 0.6 times the potency compared to Lot 176 when compared at the same IGG concentration and we now have a plan that was mentioned, alluded to, by Dr. Yu earlier today to replace Lot 176 with Lot 177.

            Incidentally, we're not going to have time to do it, but each replacement lot was carefully titered against the previous lot to make sure that there was a continuity and that we weren't changing the standard and that the standards are all connected one to the other based on actual functional assays.

            So the clinical issues.  Measles prophylaxis in PIDD patients.  Measles incidence is now rare in the United States, only 66 confirmed cases in 2005 according to the CDC.  Reports of measles infection in PIDD patients are rare.  A lack of exposure to measles could be due to lack of exposure to measles or due to protection with immune globulin.  So these patients are on treatment.

            The last major outbreak in the United States was `89 to `90 and it was one with more than 55,000 cases reported and this was prior to widespread use of two dose vaccination.  Since 2001, measles outbreaks in the United States are rare and usually attributable to exposure outside of the United States.

            Nevertheless, measles remains an important pathogen worldwide.  Twenty-one percent of disease related deaths in children less than five years of age worldwide are due to measles.  Antibodies are needed to prevent infection while measles virus clearance is dependent on CD8 positive T cells.  So this is important because antibodies are not the entire story.  Primary immune deficiency disorder patients especially those with combined humoral and T cell deficiencies are susceptible in severe measles disease.

            Protective titer against measles infection and this obviously comes from vaccine studies.  This is based on a study by Chen, but we actually, the people in the Office of Vaccines, Susan Audet and Judy Beeler, took the titers from the paper and using our standard were able to make calculations to refer back to our own standard.  So we can use this in looking at this problem.  A serum titer of 120 mIU per mL was found to be protective against clinical disease in healthy vaccinated individuals.  But you need a higher titer, greater than 1,052 mIU per mL to protect against infection, in other words, to achieve sterilizing immunity.

            There's a lack of published pharmacokinetic data analyzing measles titer in IGIV products administered and the consequent trough level measles neutralizing antibody in PIDD patients, but you will hear from subsequent speakers from industry that they are going to present some data today which is relatively new data and which we should take into consideration. The protected level in PIDD is unknown.  More than 100 distinct PIDD syndromes exist.  Therefore protective measles antibody levels may vary as well because these people may have varying degrees of T cell deficiency.

            The rationale for new measles antibody specification.  The package inserts, if you look at package inserts for all the immune globulins, the IGIV and IGSC preparations, you will find that they range between 200 to 800 mg of IGG per kg given every three to four weeks.  Now even though that is correct for the package insert, from a practical point of view, most if not all physicians that are treating these patients will use 400 mg/kg or even higher doses.

            So in considering trough measles antibody titers for patients receiving 400 mg/kg every four weeks, the estimated range of the measles titer would be 250 to 718 mIU/mL based on CBER testing of lots and calculated trough levels.  In the paper that I alluded to earlier, they looked at 166 lots from seven manufacturers, calculated, not calculated, assayed them and then based on their value, calculated what the trough levels would be if you gave a dose of 400 mg/kg to PIDD patients and that's the range they calculated which is more than twice what is needed for a protective level.

            On the other hand, if you look at the last bullet which would be a worst case scenario, if a physician decided to use the lowest dose on the label and used 200 mg/kg, that would achieve a trough level of 120 mIU/mL which would be 1,200 IU/mL or 0.48 times the CBER standard Lot 176.

            Just to remind you, the current lot release standard in order for the lot to pass it has to be 0.6 times the CBER standard.  So what we're saying is even the worst case scenario if you gave a lower dose, you would achieve a protective level at the time of trough level prior to the next dose of product.

            What could be the possible strategies to address declining measles antibody titers in immune globulin products?  What we're going to propose is to lower the recommended measles lot release specification titer for IGIV and IGSC if there is assurance that the minimally protective titers are present.  Another approach could be to revaccinate plasma donors in an attempt to increase antibody levels, but unfortunately the likelihood of achieving substantially higher and durable levels is estimated to be low in adults and you may see in a subsequent presentation actual data to show you that the second immunization is not associated with a very big increase in titer.

            What are the questions to the Committee?  First, we're not going to ask you obviously to answer but to frame the questions so that you'll have these in mind during the coming presentations.  Do committee members concur with the FDA proposal to lower the minimum measles antibody specification for IGIV and IGSC from 0.6 times the CBER standard to 0.48 times the CBER standard?

            CBER is considering requesting additional studies to confirm that PIDD patients will achieve trough levels of measles antibodies above the protective level, in other words, 120 mIU/mL, if treated with IGIV and IGSC products that meet the proposed revised potency standard of 0.48 times the CBER standard.  Do the committee members agree that this information is needed?

            Thirdly, please comment on the need for feasibility of any alternative strategies that CBER should consider to reduce the likelihood of failed lots of IGIV and IGSC based on potency testing for measles antibody in order to ensure availability of product for PIDD patients.

            Thank you.  That is my talk.

            CHAIRMAN SIEGAL:  Okay.  Thank you very much, Dr. Golding.  Are there any questions for Dr. Golding at this point?

            DR. FINNEGAN:  Do you have any idea about the CDC patients?  Were they never vaccinated?  Were they older and far out from their vaccination?  Were they wild type that had never been vaccinated?

            DR. GOLDING:  I'm not sure which cases you're referring to, but most of the cases that have occurred in recent years they've been imported, so, in other words, somebody traveling to an area where measles is endemic coming back to the country.  Now you're asking were those people who got the infection locally, were they vaccinated or not.  I don't have that information.  My guess is that -- I know the vaccination is effective.  So my guess is either they weren't vaccinated or they were long time off the vaccination.  Because what happened is that it was shown an epidemic of `89 -`91 with 55,000 or more cases who were infected was at a stage where people were not getting two doses.  So it could be that people between the first and second dose had their titers dropped sufficiently that they are now getting infected.  But I'm not sure.  But Jane Seward is going to be here from the CDC hopefully in about an hour.  So she can answer that more correctly.

            CHAIRMAN SIEGAL:  Mark.

            DR. BALLOW:  I was just curious.  Going over the historical data about the IM gamma globulin, the first slide was 0.25 or something like that and then all of a sudden it jumped to 0.6.  What's that all about?

            DR. GOLDING:  Yes.  For the first lot was more -- Let me think.  Was it more potent or less potent?  It was more potent.  So you could have a -- Now why did it drop over 20 years?  Again, I think it's related to there were many more natural infections at that time and the titers in the donors -- This lot didn't just drop out of the air.  It was an regular industrial manufactured lot that we were able to acquire to use as a standard or part of it was acquired to use as a standard.  So what you're pointing out is that it's not that it's just dropped over the last few years.  Since 1961, the titers have dropped considerably.

            CHAIRMAN SIEGAL:  One more from Mark.

            DR. BALLOW:  Nell and I were just talking and we were asking what's happening with the Hepatitis B titers.  In other words, you have all these -- You use polio, measles, Hep B titers and I can't remember the fourth one.

            DR. GOLDING:  Diphtheria.

            DR. BALLOW:  Diphtheria.  I mean obviously with diphtheria and polio it may not be an issue, but what's happening with the Hepatitis B surface antibody titer?

            DR. GOLDING:  As far as I know the Hep B titers have not been a problem, but Dr. Yu looks at this more carefully than I do.

            DR. YU:  Well, there is a minimum requirement by CBER for the Anti-HBs present in immune globulin product and that 1 IU/g of IGG, per gram of IGG.  So you have a five percent albumin.  No, five percent of immune globulin.  Then you need to divide it, 1 IU divided 20 mL because that is 50 mg/mL.  So that's a minimum requirement for us.  It's very low.  But in actual reality, the titer is much higher, but it's the minimum requirement is 1 IU/g of IGG.  That's what we set.

            DR. BALLOW:  But has it changed?  Has it changed over the last --

            DR. YU:  -- Usually --

            DR. BERGER:  I think the question about Hepatitis B titers in IGIV products is whether the titers are moving in the opposite direction of the measles titers because now the population is getting immunized.  So perhaps the titers are actually going up.

            DR. YU:  I think the titer certainly is not decreasing.  It's not.  That's what we understand.  It's anti-measles is decreasing, but not anti-HBs or other markers that I know of.  But many manufacturers are here and they may be able to provide the answers.

            DR. GLYNN:  Yes.  I had a question on the level of 120 that you've been using for your calculations.  After looking at the paper, I'm not really -- Can you go over why you chose 120 because from what I see there was a patient who got full-blown measles at that level.  So I'm not sure why you're saying that that level is protective.

            DR. GOLDING:  That level is from the vaccine studies where they showed that that level was a protective level for pre-exposure prophylaxis.  Now it's 120 was the lowest level that was protective.  So I don't think that it's surprising that now and again you'll get a breakthrough infection.  But on aggregate, the 120 was a protective level in the vaccine trials.

            Now I'm not saying that we should aim -- What we're proposing is to aim for achieving a titer that's at least double that even if we reduce the titer.  So if the intent of your question is say are you happy with the 120, I would say no.  We need to have a margin of safety and what we're proposing is at least having immune globulin products out there that are delivering a dose which would give you at least twice that level, somewhere in the range of 240 or 250 which would occur if you're using 400 mg/kg.

            DR. KATZ:  Are you actually failing lots at this point?

            DR. GOLDING:  That's a very good question.  So I can't give you details of that because it's proprietary information.  But there have been and even in the paper that was appended to your package, there was one set of lots that were failing based on our testing.  So there are lots that are failing.  It's a small number at this point.  But if you're looking at declining titers, I think we can't wait for more lots to fail because this is a very important product for a life threatening disease.

            At the moment, I would say that there are failing lots or lots that are very close to the cutoff and that if we waited much longer or even longer, we would start to see more lots failing and there would be a problem of availability of this product.

            DR. DI BISCEGLIE:  Basil, you sort of used IGSC and IGIV sort of interchangeably.  Are there any differences with regard to levels of antibody and is this something the Committee needs to consider?

            DR. GOLDING:  Okay.  Well, what happens is this is really that the answer is based on pharmacokinetics and what happens when you're giving IGIV every three to four weeks is you get a sawtooth patent.  When you're giving it every week as a sub cut, you're getting a much flatter curve which means that your peak levels are lower and also means your trough levels are higher with the IGSC.  So if anything, the IGSC trough levels are higher.  I think it's less worrisome to some extent with the IGSC concerning the actual trough.

            But on the other hand, you still want to have sufficient titers in those products that are also going to have a high assurance that through the period they're going to be above, considerably above, the 120 mIU/mL.

            DR. SCHREIBER:  Do you have any information on whether there have been any patients with immune deficiency disease that have experienced measles while on IGG?

            DR. GOLDING:  That's also a very good question.  At the workshop, we discussed this and they're putting a registry in place.  I don't think, if somebody who was at the workshop recalls, but I don't think anybody, we've seen cases to my knowledge in this country of PIDD patients developing measles while they were on treatments.  An assumption from that is that the current treatment is very effective in pre-exposure, but the truth is that it hasn't been tested very well in the last few years because as you see there have been very few cases for the last 20 years.

            DR. GLYNN:  And so do you have an estimation of the current levels right now with the current IGG?

            DR. GOLDING:  Yes.  We can calculate it based on pharmacokinetic principles.  But better than that, you're going to get these two presentations today where the manufacturers are going to talk about the actual measured trough levels.  We don't have, as I mentioned in my slide, a lot of data especially published data on that.  So the speakers will provide us with some information about actual levels.  What we have is mainly based on what the titer is, either product, and then based on PK principles what we expect the trough levels to be.

            DR. SZYMANSKI:  Can you tell me what percentage of IGIV products are given to immunodeficiency patients and which ones to other patients for other diseases?

            DR. GOLDING:  I'm not sure I have an accurate answer.  I think there may be somebody in the audience who can help.  But we know when we looked, when there were problems with the availability of the product and we started asking treaters and major centers what is going on in terms of IGIV usage, we found out that 60 or 70 percentage of the usage was off-label and there are some other indications besides PIDD like ITP, Kawasaki and a few others.  So I'm guessing, but I would think that only about 20 percent, 20 to 30 percent, is used for PIDD and the rest is used off-label or for other indications.

            CHAIRMAN SIEGAL:  Do we know what proportion of IG product is used subcutaneously these days as compared to IV?  Do we have any idea about that?

            DR. GOLDING:  We have one newly licensed product for IGIV sub cut and we have six or seven -- other manufacturers.  I don't know what the market share is.  I don't have that with me.

            CHAIRMAN SIEGAL:  But we don't know in practice how it's being used?

            DR. GOLDING:  But do you mean to what extent compared to the IV?

            CHAIRMAN SIEGAL:  Yes.  I mean you can use the same product sub cut.

            DR. GOLDING:  Right.

            CHAIRMAN SIEGAL:  And so the question is how much is actually being used sub cut as compared to IV?

            DR. GOLDING:  Well, I don't know offhand.

            CHAIRMAN SIEGAL:  Anybody have any sense of that?  Okay.  All right.  Basil, thank you very much.  I think we should go on.

            DR. KATZ:  I don't see anywhere on the agenda where I think this could be answered but I'm kind of interested in the implications of FDA changing its criteria and maybe the manufacturers can address this if I bring it up ahead of time.  If they are manufacturing in some way with an eye on what gets approved in the U.S., would lowering the threshold make a difference in the rest of the world where measles might be more common and I think probably you can give an FDA perspective and they can talk about what they think.

            DR. GOLDING:  I think that on balance we have to make a decision which I think we can make and have the best of both worlds in the sense that we can lower the titer and still be reasonably assured that the product is going to be safe and effective in preventing measles.  But we may reach a point sometime in the future where the titer had declined to an extent where that won't be the case.  As far as public health in the United States, it seems that this is such a rare disease that it may be a much more compelling reason to have that titer outside the United States and we may not need it.  So I think the manufacturers surely have to deal with that.

            CHAIRMAN SIEGAL:  Mark.

            DR. BALLOW:  Just a comment.  You know, even though the package insert says 200 mg/kg, I and my colleagues are actually tending to use higher doses because of the recognition that even at 400 mg/kg some of these patients are still developing chronic lung disease and bronchiectasis.  So, for example, in patients with Bruton's disease or X-lined agammaglobinemia the suggestion is to use 600 to 800  mg/kg.  So that means that they would be getting more measles antibody.

            CHAIRMAN SIEGAL:  All right.  I understand that Dr. Seward has in fact arrived.  So I would like to introduce Dr. Jane Seward from CDC who is going to talk about the epidemiology of measles in the United States.

            DR. SEWARD:  Good afternoon and sorry I was late.  It wasn't the weather.  It was a GameBoy that got dropped down the toilet in the plane I was on.


            DR. SEWARD:  So that two hours delay for that reason.

            CHAIRMAN SIEGAL:  Terrorist attack.

            DR. SEWARD:  And then we had to get off the plane.  They cancelled the plane altogether.

            So I'm here to talk about measles epidemiology in the United States and I think that will give you a good understanding of what the risks are for exposure to measles now and where we are with measles control and elimination.

            As everybody knows, I'm sure, measles is a highly contagious viral disease.  In the pre-vaccine era, there was nearly universal infection during childhood because of its contagiousness.  Morbidity and mortality in the United States by the 1950s was described as 450 deaths annually, 48,000 hospitalizations and 4,000 cases of encephalitis among other complications.  The morbidity and mortality was much higher than this earlier in the century.  So this was after a lot of improvements in health care and in hygiene, etc.

            Measles vaccine was licensed in 1963.  Almost all the vaccine now is administered as the combination MMR vaccine and when it's available I guess the MMRV vaccine which is not currently available, although it's licensed.  Measles vaccine is highly effective.  It's one of the most effective vaccines that we have.  One dose administered at 12 months or older is 95 percent effective.  Two doses at least four weeks apart administered at the same age on or after the first birthday is 99 percent effective. These effectiveness estimates are lower if measles vaccine is given at a younger age, but this is the age of recommendation for the United States.

            In the U.S. we give two doses of measles vaccine to children, the first at 12 to 15 months, the second dose at four to six years and two doses is recommended for all school students, for college students or other students in post high school educational facilities, health care workers and because of their risk of exposure overseas for international travelers.

            The strategies to control and eliminate measles in the United States are to maximize the population immunity to measles by delivering the first dose on time as close as possible to the 12 months, to increase the second dose coverage in school children, although that is already extraordinarily high as you'll see in a minute and to vaccinate high risk adults, to assure adequate surveillance so that we understand the risks of measles and what's happening in the country with measles disease, to respond rapidly to outbreaks and to work to improve global control because that will reduce the risk of importations into the United States.

            This shows reported measles cases.  Is there a pointer?  Reported measles cases in the United States from 1950 through 2006 and it's on log scale as you can see there.  I can't get this to work, but it doesn't matter.  You'll see the vaccine was licensed in 1963 and measles disease in terms of reported cases declined rapidly after that.  There was a big push for school immunization laws in the 1970s and 1980s in response to measles still occurring in schools.

            There was an increase in measles in the late 1980s, around 1989 and 1990 there was a resurgence of measles in this country and you'll see why in a few slides and then in 1989, there was a second dose measles recommendation made and improved first dose coverage in preschool children.  Since 1998, we've had measles incidence in the United States has been less than one case per million population and measles elimination was declared in 2000.

            I'm sorry for that red color for total.  I have two slides here, one showing the total number of cases and then some breakdown by age.  You can see that in the late 1970s there were still 50,000 to 60,000 cases reported a year.  However, that dropped rapidly as there was better implementation of school requirements.  The resurgence that you see in 1990, up to 30,000 cases reported in one year, was mainly due to low vaccine coverage in urban communities in preschool children and that led to an influx of money into vaccine programs and the Vaccine for Children Program being established and then monitoring of vaccine coverage in children 19 to 35 months.  That is the current ongoing coverage that is monitored and there's been a dramatic improvement in vaccine coverage among preschool children since that time.

            This shows the breakdown by age without the totals showing that in the late 1970s the highest number of cases were in the school age children.  But the resurgence in 1990 occurred mainly in children under five.

            If you look at age specific measles incidence by less than 15 and greater than 15, again we're at extraordinarily low levels.  So this doesn't mean a whole lot.  Most people 50 and above aren't susceptible to measles.  So you can see there that incidences are very low in both.  For less than 15, it's a little bit higher.

            These are the largest outbreaks that we've had in the United States from 1999 to 2006.  As you can see, they're pretty small.  The largest was in Indiana just two years ago.  All the outbreaks have originated from imported cases as you can see there except for one unknown source case that were likely to be, two unknown outbreak sources that were likely to be imported.  Almost all of these outbreaks have occurred in unvaccinated populations and as an example, the top two, the Indiana one was an import from Romania and a remaining U.S. resident who had been working with a church group in Romania.  She came back, went to church, her church.  This was a day after she returned which was her day of rash onset and this was a church group that didn't believe in, a lot of the people that attended this church didn't believe in vaccination and so there was an outbreak of about 34 cases, of exactly 34 cases.  Measles can still be serious.  One of these cases in an adult health care worker was hospitalized with severe complications for a week with AIDS.

            The Boston outbreak that occurred last year was an import from India into inner city Boston in a computer group.  The person, the import, was from India.  He was a computer contractor who then went to work and 17 other people mainly at the worksite, mainly adults, got infected.

            The Indiana outbreak was published last year in New England Journal and one of the things that we really highlighted in that article was there was absolutely no spread into the community and that's the case for most of these outbreaks.  We had extraordinarily successfully high population immunity because of our high coverage of measles vaccine in the United States and these outbreaks just do not penetrate into the communities.

            This shows the age distribution of measles cases showing by age just the number of cases and this shows the vaccination status, again, to show you that most of the outbreaks have been because of introductions into small vaccine objector groups or into groups that are not as highly vaccinated such as the adults in Boston.  Adults sort of 30s to 40s were little children when the vaccine program started in the `60s and that's the age group that most susceptible that may have missed out on exposure to disease and vaccination and that's why they were affected in the Boston outbreak.  Nevertheless, it was a pretty small outbreak.

            This slide is to show that as our surveillance has improved the number of cases has gone down.  We've been able to do virologic confirmation and molecular epidemiology on all these cases and we can show that almost 100 percent of cases now are definitely imported.  We can look at the genotype and then look globally where that genotype is circulating, know where that person came from and say it's an importation or an import associated case if it leads to a small outbreak in the United States.  In 2007, 100 percent of our cases are import associated.

            This shows one of the evidences that was used to document elimination of measles.  By elimination of measles, I mean absence of endemic transmission of measles.  You know as I've highlighted I think we stay at risk for importations in this country until those global measles are eradicated or eliminated.

            And there will always be some spread.  I mean, you can vaccinate children under one.  One of the small outbreaks that I didn't point out a few slides ago was in a daycare center where a little child came back after visiting with his family in the Philippines and nine out of ten children in his baby room in the childcare center got infected.  That's how infectious measles is.  But it didn't spread it to the older children who were vaccinated.  So there's no way to have no cases at all, but we have very few cases in the United States.

            During the resurgence in `89 to `92, all the viral isolates were D3 genotype.  There weren't many specimens taken for genotyping before that time.  Since that time, since 1993 onwards, there have been probably now more than 150 isolates and they're all just different genotypes from different parts of the world.

            Just to show you the countries that these importations come from which reflects measles in that country and also the probability of travel from those countries.  There are a lot more measles in some other countries like in Africa, but not so much travel from there.  Japan does not have a good vaccination program and they have a lot of measles.  In fact, they had a huge outbreak this year and we've had six importations just this year from Japan.

            In the United States last year and these are provisional data, but the final data, we had 55 cases reported from 16 states.  Eighteen of those were the outbreak in Boston, Massachusetts, 10 in New York, California, Florida.  Ninety-five percent of the cases were import associated which either means they were direct importations or epi-linked to imported cases such in the Boston outbreak or they were a virus genotype that we don't think circulates here.

            We can't always find the original source. We've had instances in the past where we've had a call from a European country that some person from their country developed measles rash and they flew through Utah the day before and then there's a case in Utah two weeks later which we pick up.  I mean that's sort of low probability of finding the original source if there's an exposure in an airport.  But we sometimes do find those.

            This just shows last year's source countries:  India at the top; Ukraine because there was a large outbreak there; China, we have a number of children come in from China as adoptees and China doesn't have a great program for their children and orphanages anyway and quite regularly we do see measles coming in among their adoptees with some spread.

            The largest outbreak last year, I mentioned the Boston one and the others are just very, very small.  You know, three cases in Florida among cruise ship employees.  Three cases in Yemen, one who came back from Yemen and then two spread cases in the Yemen community and then three mothers exposed in China during their adoption.  So a little cluster of cases related to adoptions in China.

            And this shows you the cases in 2006 with the genotypes and we can just say where every one of them comes from.  We've even been able to document exposure at Disney World and mixing there with a case from another country and just to highlight that it's exactly the same pattern in the year before, in 2005, and in years before that.  This was the year that we had that fairly large outbreak from Romania.

            So the evidence for elimination of endemic measles or elimination of endemic measles transmission in the United States, the following, we have extraordinarily low incidence.  The majority, essentially 100 percent of cases, are internationally imported or import associated.  Our surveillance system is adequate and that was scrutinized very closely during an external review meeting we had to examine evidence as to whether measles had been eliminated in the United States.

            Population immunity is very high.  There is no endemic strain of measles virus circulating.

            The evidence for adequate surveillance to detect endemic measles are these.  We have consistent detection of imported measles cases.  We have detection of isolated cases and small outbreaks.  High level of investigative effort for measles to which we thank the state and local health departments who work incredibly hard.  In that Boston outbreak, the City of Boston administered 10,000 to 15,000 doses of MMR vaccine in response to that small outbreak.

            Molecular typing is consistent with elimination of indigenous genotype of measles virus.  We have very high population immunity with high first dose coverage of greater than 90 percent since 1996 for preschool age children.  First dose coverage being greater than 97 percent of school age children.  Second dose required for 82 percent of school children as of 2001 and that's higher now, but we haven't calculated it again recently.  And then the most recent seroprevalence data from 1999 to 2004 shows 96 percent immunity, well I should say, antibody measured by Eliza in ages six to 49 that may or may not indicate immunity but it's the best measure that we have.

            These are slightly older data from Ann Haines from the National Health and Nutrition Examination Survey that were published that were presented of evidence of immunity for the measles elimination meeting to show the dip in seroprevalence in the age group of people born between 1967 and 1976.  That was the age group most affected during the Boston outbreak.  So we do have populations at risk in the United States, but their risk of exposure now is incredibly small.

            Now we worry a little bit about duration of vaccine-induced immunity.  It's not because we see any evidence waning to susceptibility from our epidemiological data, but just because we're now 40 years into a program.  The younger cohort are not being exposed at all to wild measles virus, so aren't having any external boosting and we think it's very important to monitor population immunity including whether immunity remains above the so-called protective level.

            This paper was published earlier this year by Charlie LeBaron and Judith Beeler who is probably here today showing measles antibody response measured by neutralizing, plaque reduction neutralization testing, I think, in children vaccinated, I'm sorry about the quality here, but hopefully it's better in your slides, children vaccinated in the left-hand graph at kindergarten, getting the second dose at four to six years versus getting it at 10 to 12 years, showing that there's quite a boost in immunity with the second dose at whatever age you get, but then immunity declines again and you tend to stay in the quartile that you were before you got your second dose.  Most of these levels are above the protective level still though.

            Dr. LeBaron then tried to model these data to project out 30 years in the future what might happen.  He acknowledges in the paper that this is just a model and that you may not get decline at the slope as shown there on the left, but if you did, we will have a more susceptible population in the future and so we need to monitor this very closely.

            Another small study that's been done following up people from a vaccine trial in 1971 and they were about 30 years after their last measles dose with no known exposures to measles, nine percent of that small group had PRN titers of less than 120, not considered protective but, of course, they may have good cellular immune memory still and may be able to mount that in response to exposure to measles.

            In conclusion, measles is no longer endemically transmitted in the United States.  Almost 100 percent of cases, I mean, 100 percent are import associated.  We just can't show that all the time. This time 100 percent of our cases are import associated.  Importations continue to challenge our population immunity, but we see extremely limited spread from importations due to high population immunity.  There's no indication of immunity waning to susceptibility from our epidemiological data.  With these small outbreaks, there is no spread into schools, in daycare centers age groups, etc., but we should continue long-term monitoring of vaccine induced immunity.  Thank you very much.

            CHAIRMAN SIEGAL:  Thank you very much, Dr. Seward.  Are there any questions?

            DR. SEWARD:  I would like to thank a lot of people at CDC that provided the data for the slide.  I didn't make an acknowledgment slide but Charlie LeBaron, Susan Redd, Susan Reef and a number of people in the MMR team.

            DR. DI BISCEGLIE:  You pointed out that measles can still be a very severe disease.  What's the evidence?  Is there evidence of its increasing severity in patients with immune compromised situations of one kind or another?

            DR. SEWARD:  Well, we don't see it in those people anymore.  But, yes, my understanding is it is more severe.

            DR. DI BISCEGLIE:  People on corticosteroids or post transplant.  Is it just because we don't know because they don't get it anymore?

            DR. SEWARD:  They don't get it anymore.  My understanding from the literature is that it is more severe in those people.

            CHAIRMAN SIEGAL:  Is there any boosting effect to bystanders from MMR?

            DR. SEWARD:  To bystanders --

            CHAIRMAN SIEGAL:  In other words, do parents of children just immunized have a vaccine effect?

            DR. SEWARD:  Yes, that's a good question.  Not that we know of.  We did a study looking at wild virus to see if there was any evidence of subclinical transmission and boosting and there was not with wild virus.  So it would be much less likely with vaccine virus.  I don't know that that's been looked at specifically though.  It has been for wild virus.

            DR. BALLOW:  And a related question.  Transmission of two siblings from other siblings that have been immunized, I mean, that hasn't been reported, has it?

            DR. SEWARD:  No.

            DR. BALLOW:  No.  Okay.

            DR. SEWARD:  I don't know the detailed literature on that as well as I do Varicella for example.  That's sort of my specific area of expertise.  But if there is, you could count them on one hand and there have been hundred of millions of doses administered.  So it's not considered a problem at all.

            DR. QUIROLO:  Can you say something about the PRN value of 120 and where that came from?  In the paper that we were given, the people in this outbreak that didn't get measles all had much, much higher PRNs than 120.

            DR. SEWARD:  Right.  That value comes mainly from a study by Bob Chen at CDC who was fortunate enough to find blood from a blood drive that had been done before an outbreak, I think, in a college and examined the data and noted that the attack rate was much higher in people below that level.  That was clinical disease as I remember.  I haven't read the paper for awhile and between eight and 120 seemed to be the range for protection from infection.

            I mean, it's a small study.  There hasn't been -- I think there's another study from Europe that indicates approximately the same level.  It's a small study with limitations that go along with that, but it's the best that we have and we don't have that for almost any other of that same for preventable diseases.

            I think the immunity that we're seeing, measuring, in the community using similar testing and the absence of measles and spread, I think, in vaccinated people 10, 15, 20 years out from vaccination would lead me to believe that's probably it's a reasonable level.

            DR. QUIROLO:  That does sound right except that only thing that I'm just thinking about is that that may be the case in college students who have a normal healthy immune system.  But in people who are getting IVIG who have PIDD or something, they may not have T cell response after it.  So I wonder if these college students were getting infected but not getting clinical disease and I don't know that paper.  So it's hard to know the answer to that.

            DR. SEWARD:  I think some got infected but they had levels between eight and 120 is my --

            DR. QUIROLO:  Right.  But would you not recognize people who maybe had a level of 200 who got infected but never progressed to clinical disease.  You would never pick up those people in this study.  Right?

            DR. SEWARD:  Yes, they had bloods before and after -- Oh.  I think they did.  I'm sorry.  I haven't read the paper for awhile.

            DR. QUIROLO:  They didn't take everybody's blood after the fact to see who got infected.  Every single person.

            DR. SEWARD:  I think they took some who developed measles and some who didn't to try to answer that question.

            DR. QUIROLO:  Okay.

            DR. COLVIN:  Yes, in that paper actually I think they have evidence of viral replication with boosting reaction between levels of 120 and 1052 if you have a copy of that paper.  So it looked actually only levels above 1052 were protective.  That's how I read the paper.  So that I had asked also my question before where the 120 came from.

            DR. SEWARD:  So it protected from infection not disease.

            DR. COLVIN:  That's right.

            DR. SEWARD:  Right.

            DR. COLVIN:  But these were healthy vaccinated college students.  We're not talking about immunocompromised patients.

            DR. SEWARD:  Right.  Maybe some clinicians would like to comment.  Many of you are.  I mean measles, my understanding is that it's more severe, but not dramatically so compared to something like Varicella.  That is just extraordinarily more severe in immunocompromised people.

            DR. BERGER:  We can only imagine.  We don't have data as several people have pointed out.  But certainly we must imagine there there are one year olds in homes, immune deficient one year olds, in homes where the four year old is being immunized when they go to kindergarten.

            DR. SEWARD:  I think there are children with Skid who are immunized at 12 months who were late with their diagnosis.

            DR. BERGER:  Right.  But I mean but with Bruton's and antibody deficiency and a lot of the other immunodeficiencies there must be kids in homes where an -- You pointed out --

            DR. SEWARD:  I think some children who are severely immune deficient are being immunized.

            DR. BERGER:  Right.  This is also unquestionably true.

            DR. SEWARD:  Yes.

            DR. BERGER:  And we don't hear cases of -- I don't know -- Again, we don't have any sort of accumulated data, but I certainly have never a case of severe measles in an undiagnosed Skid patient.

            DR. SEWARD:  Right.

            DR. BERGER:  Whereas, for example, we hear about Varicella in undiagnosed Skid patients.

            DR. SEWARD:  Right.

            DR. BERGER:  But there must be -- but you pointed out this outbreak in a daycare in the baby room.  So your implication is that there might be one year olds whose protection by maternal antibody has waned and they have not yet reached the age of immunization.

            DR. SEWARD:  Yes.  A lot of these children are --

            DR. BERGER:  So there must be a lot of babies like that in homes where a four year old is getting immunized for the second time when they go to school and you don't hear a lot of cases like that, although there is no systematic data of which I'm aware of.

            DR. SEWARD:  About transmission?

            DR. BERGER:  Yes.

            DR. SEWARD:  It's not a problem.  It is not a problem.  We've stopped looking for it it's so rare.

            CHAIRMAN SIEGAL:  Any other questions?

            DR. FINNEGAN:  This may be a really simple way to look at things, but we're here today because the protective level in the donor blood is dropping from people who have been vaccinated.  Do you not see this as a potential public health problem down the road?

            DR. SEWARD:  I was at the previous meeting where some of these issues were discussed and my own feeling is that, right now, the population is very adequately protected and to the levels in IVIG from vaccinated individuals will be adequate.  I know there's another issue with the testing and pass/fail on the EIA test that's used for the lots which is a separate issue.  But right now, I wouldn't be worried about the levels in IVIG.

            Now 10 or 15 or 20 years from now, it might be a different story depending on what happens with that graph in Dr. LeBaron's paper.  But right now, vaccinated people are absolutely adequately protected.  There's no spread in this country.  So I'm not worried from a public health perspective for today.  Twenty years from now, perhaps, but we can continue to monitor immunity levels in vaccinated people.

            Measles vaccine is just a phenomenal vaccine.  It was very, very effective and immunogenic.  We had a large mumps outbreak in this country last year with 6,000 cases and I won't say the same for mumps vaccine.  But measles and rubella are just very, very good vaccines.

            But it doesn't mean, as I said.  I concluded by saying we need to continue to monitor.  But we see absolutely no evidence, epidemiologically, that there is waning to susceptibility in any of the vaccinated populations.

            DR. SZYMANSKI:  Would you in any phase consider a third vaccination at some age, later age, when levels are very low?

            DR. SEWARD:  Not unless we see waning to susceptibility.  I mean, we'll continue to watch very closely.  I think that's the big challenge with the U.S. vaccination program now is the duration of vaccine-induced immunity.  We have the most mature vaccine program in the world and absence of disease doesn't mean absence of risk.  We know the 30-year olds out there, 10 to 15 percent of them, or 40-year olds are susceptible.  So we'll monitor very closely vaccine-induced immunity and it would only be if it wanes and we see the epidemiology changing with outbreaks in vaccinated people like we saw with mumps last year.  Then we would consider changing vaccine policy.  There is no indication right now that we need to.

            CHAIRMAN SIEGAL:  All right.  If there are no more questions, thank you very much and let's proceed to Dr. William Moss who is going to talk about measles infections and estimated protective titers in primary immune deficiency diseases and potential reemergence of epidemic measles in vaccinated individuals, from Hopkins.

            DR. MOSS:  Thank you very much.  I'm here in part representing Dr. Dianne Griffin, who gave a talk at the immunoglobulin workshop in April of this year and will be giving a similar presentation.  The title on the agenda was not my title.  So I hadn't seen that title, to be honest, before.

            But the questions regarding measles in the immunocompromised hosts are a nice segue into what I'll be talking about and because most of what we know about measles in immunocompromised hosts is not in children with primary immunodeficiency disorders, as a number of people have already mentioned.  I'm going to use some other examples, particularly malnourished children, HIV-infected children and studies in immunosuppressed monkeys to provide some insight into measles and immunocompromised hosts.

            I'll also come back to some of the issues that have been already touched upon, particularly this magic number of 120, that we talked about a number of times.  I also want to just reiterate the point that was made, but there have been no documented cases of transmission of measles vaccine virus.

            So let me just briefly run through measles in the immunocompetent host and talk a little bit about the normal immune responses and that will set us up for talking about measles and the immunosuppressed host.  Measles has very characteristic clinical features.  It starts off with what I'll refer to as the three Cs, cough, Coryza and conjunctivitis, then early papoules that occur on the buckle mucosa called Koplik spots.  During this time, there is fever and then the characteristic morbilliform rash that typically starts on the head and neck and extends over the entire body and that's typically when clinicians will diagnose measles, though a very astute clinician can diagnose it based on the presence of Koplik spots and these are just some photographs, a little difficult to see, but the characteristic morbilliform rash on the left and this will be important because we'll talk about different rashes that can occur in the immunosuppressed host and then the child on the right a little bit of conjunctivitis and crusty nasal discharge.

            And then on this picture again, it projects a little.  It doesn't project very well, but there are small white papoules that are seen on the buckle mucosa.  Those are the Koplik spots that proceed the rash.  But what I want to point out on the right side is that on that middle panel just summarizes briefly the clinical manifestations we talked about.  But I wanted to just mention that the virus is very active during the asymptomatic incubation period before the onset of fever with replicating, initially, in the upper respiratory tract and spreading to the lymph nodes.  Then there's a generalized viremia and replication of measles virus in many organs, including the skin.

            In addition, there's also an intense immune response and I'll come back to this, but initial CD-4, primarily TH-1 type response, with production of interferon gamma and a cytotoxic T cell response that starts about the time of the rash and you can also see that when the rash is beginning, the level of virus replication decreases.  So really the rash is a manifestation of the host cellular immune response and I'll come back to this.  But there have been a number of cases of confirmed measles particularly in persons with AIDS without a rash, and that makes sense understanding that the rash is a manifestation of the immune response.

            There's initial IGM antibody response that's transient that lasts several weeks and then an IGG response follows.  It's initially an IGG Type 1 and then switches to an IGG Type 3 predominantly and that's the titer, the protective antibody class that we've been talking about.

            The immune response of measles virus is more complex than that.  I just want to touch on it briefly.  There's as with all infections an early innate immune response with Type 1 interferon.  It appears that wild type measles virus has evolved mechanisms to inhibit the host interferon response that are not seen in the attenuated vaccine response and I should mention, although you all probably know this, that the vaccine is a live attenuated vaccine that requires replication in the host in order to induce protective immune response.

            Then there are the antibody responses we talked about, the IGM and various subclasses of IGG that are protective.  There are also IGA responses and it's not clear what role they play in protection from disease at the mucosal surfaces.  The cellular immune responses are very complex.  I talked about CD-4 responses, early Type 1 response and then that's followed by a Type 2 response with characteristic production of IL-4 and IL-5 and IL-13.  There is also prolonged increase in IL-10 production that may be related to the immune suppression that follows measles.

            Measles is a strong inducer of immunologic memory, particularly wild type measles.  Some of the classic epidemiologic studies of measles were done by a Danish physician named Peter Panum in the mid 19th century on the Faroe Islands where he observed where there was an outbreak of measles that he was called on to investigate.  The prior outbreak was 65 years earlier and no one who was live during that prior outbreak got measles again, suggesting really life-long immunity following wild type measles virus infection.  Dr. Seward talked a little about whether that occurs after vaccine-induced immunity.

            Measles is an immunosuppressive virus and much of the mortality and morbidity from measles results from secondary infection. So it's actually a immunosuppressive virus in itself and these are just some, I won't go through this in detail, potential mechanisms by which measles virus has been suspected or studies have suggested how measles virus may suppress the immune system.  It's unclear whether or how much measles vaccine virus suppresses the immune system.  Some of these differences have been documented following measles vaccination.

            So measles and the immunocompromised host, Bob Good several decades ago with others published a paper that suggested that children with deficient antibody production, with B cell deficiencies, would have normal recovery from measles and would clear measles virus, but would have limited protection from reinfection because of the absence of antibody.  But it was really children with T cell deficiencies, with deficient cellular immunity, who had delayed viral clearance and progressive disease.

            So one way, a common way of thinking about immunity to measles, is what immune responses are required to actually clear the virus once infection has taken place and in children with impaired clearance, there are kind of two broad clinical pictures.  One is a desquamating rash and I'll show you a picture of that.  That's been best characterized in severely malnourished children who have deficits in cellular immune function and then in people and children and adults who are most severely immune suppressed as a progression disease that can often occur without a rash as I mentioned and with measles virus replication particularly in the brain and in the lungs.

            And then in terms of protection, and I'll come back and talk about the difference between protection from clinical disease and we've already touched on this and protection from actual infection, the best correlative protection is the neutralizing antibody titers that we've talked about.

            I'm going to be presenting a little bit of data using a rhesus macaque model.  Obviously, monkeys are the best animal model for studying measles and there have been several studies I'll show you in which the monkeys were immunosuppressed and then challenged with wild type measles virus.  But this is just to show that rhesus macaques developed a characteristic measles rash, a type of viremia that's very consistent with what humans develop and measles also induced a peripheral lymphopenia that develops that's shown here that was also observed in macaques.

            Sallie Permar, who was at Hopkins, but then went onto Harvard and worked Norm Lepton's lab did some studies where, first, they depleted monkey of CD8  T cells and then challenged them with bilthoven which is a wild type measles virus strain.  On the left side, you see log infected cells per 106 peripheral blood mononuclear cells in control animals and then in CD8 depleted animals and I just want to make a few points.  So these animals were depleted CD8 T cells with monoclonal antibodies.  They had higher levels of measles virus and for a prolonged period of time, but they all eventually cleared measles virus and none of them developed a progressive fatal measles virus infection.

            They followed that up with an analogous type of study, but instead of solely depleting CD8 T cells, they depleted B cells as well using a monoclonal antibody to CD-20 and let's just focus on the right-hand side.  This is using a real time PCR assay.  So you have a log scale quantitating measles virus on the right side.  The top is a control group.  The middle panel is our monkeys depleted of B cells.  So they won't have an antibody response and then the bottom panel are monkeys depleted of both CD8 and B cells and, consistent with the early observations in humans, monkeys depleted of B cells had a normal clinical course of measles.  They didn't have prolonged viremia or higher levels of viremia and they had the disease progression similar to that of the control group, whereas again the CD8-depleted monkeys had a more prolonged viremia.  So there was a delay in clearance of measles virus.

            Interestingly, some of the monkeys that were CD8-depleted also developed a desquamating rash and that's another type of rash that can develop in immunosuppressed hosts, as I already mentioned and, I won't go through this in detail, but on the right side is a picture of the rash and you can see in that small insert on C the desquamating characteristic of the rash in the monkeys and then the histopathology in F of that rash with inclusion bodies of measles virus shown in the insert.

            So in humans, what we know about in children and adults who have immunodeficiencies and fail to clear measles virus, there are two broad category of disease that are frequently described, a giant cell pneumonitis, measles caused syncytia formation and a measles inclusion body encephalitis and I'll come back to that.  Often, as I've already mentioned, there is no rash at the time of measles virus infection and again, this has been best described in HIV-infected children and adults.  But there is this progressive pulmonary or CNS disease and in the absence of rash, this is a very difficult diagnosis to make and really has to be suspected and looked for.

            The desquamating rash was first described by David Morley who was working in Nigeria in the 1960s, and this is a little cartoon showing the complications of measles particularly in severely malnourished children and most children with measles in sub-Saharan Africa die of secondary bacterial pneumonia and diarrheal disease and then on the bottom, he describes this characteristic desquamating rash that occurred in severely malnourished children.  I primarily work in Zambia with measles, studying measles in HIV-infected children and this is an HIV-infected child with that desquamating rash that you can see is peeling off this child's face.

            There have been, and we've already alluded to this, case reports, but no real extensive case series of progressive measles virus infection associated with various immune deficiencies both in primary immune deficiencies, usually combined deficiencies of T and B cells.  There have been a few small case reports, particularly one of a measles inclusion body encephalitis, of a child in whom the underlying immunodeficiency was not well characterized.  And then in addition, there have been case reports, but again not a lot of experience in part because the exposure has been low in the United States of children with secondary immune deficiencies related to malignancies or immunosuppressive therapy in transplants of progressive measles disease.  So we don't have a lot of information on these groups of children.

            We have a little bit more in HIV-infected children and I'll talk a little bit about that.  Measles in HIV-infected children was first, best described by a report from the Centers for Disease Control back in 1988, during that last big measles outbreak that we've already talked about, where severe and unusual measles was described in five HIV-infected children.  There were a number of case reports out of that outbreak and about half of the children, half of 19 co-infected children in the United States, had either an absent or some unusual type of rash with measles.  About three-fourths had pneumonitis and about one-third of these children died of progressive measles virus infection which is much higher case fatality ratio than is otherwise seen.

            There have been a few small reports of HIV amongst children in Africa.  This is just showing what the measles giant cell pneumonitis looks like.  It forms some syncitia and you can see the staining for measles virus nuclear protein in these cells.

            We've conducted studies of measles in HIV-infected children in Zambia and I just want to say that during hospitalization, so this would be a country with high prevalence of HIV and endemic measles virus transmission, there was increased mortality during hospitalization among HIV-infected children.  There was also increased mortality in children who had a desquamating rash, suggesting again that this is a marker of severe disease and perhaps underlying immune defects.

            We've also looked at the ability of HIV-infected children to clear measles virus and this is using an RT-PCR assay approximately one to two months after rash onset and a higher proportion of HIV-infected children failed to clear measles virus RNA during this time period after measles.  It's not clear whether these children are still contagious, but this indicates that they have failure to clear measles virus.

            I did want to mention that there's been one report of fatal infection with measles vaccine virus in a person with AIDS.  This was a young man who received a second dose of MMR.  As part of the regulations for a second dose that Dr. Seward talked about, this young man had no rash after MMR vaccination, presented 11 months later.  Really at the time of immunization, he had no clinical evidence of severe immunosuppression although his CD-4 count was very low.  He had been previously vaccinated against measles and he had a number of invasive procedures that eventually identified measles vaccine virus in his lung tissue and he died 15 months after MMR vaccination and this one case actually helped shift measles vaccination policy by excluding people with severe immune suppression.

            I mentioned briefly the neurologic disease that can be due to measles virus in immunosuppressed hosts.  There are a number of different neurologic diseases associated with measles.  There is an autoimmune demylinating condition that can occur several weeks after.  That's not an immunocompromised host.  But then there's this measles inclusion body encephalitis where the actual measles virus replication within the brain that occurs in immunocompromised hosts and that has been described in children with primary immune deficiencies as well as persons with HIV/AIDS.  And just briefly again, one sees within brain tissue inclusion bodies and staining for viral antigen.

            As I've mentioned the best evidence is that cellular immune responses are critical for clearance of measles virus.  There is some evidence, though it's not strong evidence, that antibodies may play, at least, assist the cellular immune arm in clearing measles virus.  There are some studies by Don Forthal suggesting that antibody-dependent cellular cytotoxicity is associated or correlates with clearance of viremia.  There is certainly evidence, older evidence, that low antibody responses predict poor outcome and some in vitro studies suggesting that antibodies can down regulate intercellular virus replication.  So some evidence that antibodies play a role in clearance.

            But where antibodies are really critical is in protection from disease and I think probably one of the most important questions facing the committee, for which I, unfortunately, don't have evidence for is, what role the cellular immune arm is playing in protection that might assist in a way the antibody responses and either require higher or lower titers of antibodies for protection.

            The evidence that antibodies alone are protective against measles come from numerous studies showing that young infants with passively acquired maternal antibodies are protected against disease.  Obviously, the passive administration of immune globulin which this committee is considering and really as we've talked about the best correlate is this neutralizing antibody titer and I'll come back to the 120.

            Just to remind you, neutralizing antibodies are primarily to the two surface glycoprotein of measles virus and particularly hemagglutinin which is the larger structure shown there which is what binds to measles virus receptors on host cells, human cells.  There is also a fusion protein on the surface and there's probably some contribution of neutralizing antibodies to these.

            So when one is measuring neutralizing antibody titers using a plaque reduction neutralization assay, one is primarily measuring antibodies to the H protein.  Just to show that, show how those antibodies to different proteins vary in relative amount, we'll just focus on the right-hand.  You can see antibodies to H there in the middle.  Most of the antibodies to measles virus are made to internal protein, the nucleocapsid protein.  So one uses an ELISA assay to measure antibody titers, one is primarily measuring antibodies to N rather than the functional neutralizing antibody to H.

            This is just evidence in a graphic form from Neal Halsey showing declining levels of maternal antibodies and an increasing incidence of measles and showing just to reiterate the fact that passively acquired antibodies from the mother can protect the young infant and this might be one of the best ways to try to get a handle on what are protective titers in children who lack cellular immune responses to measles, though these would be in otherwise normal infants.

            It's known too that these levels of maternal antibody can inhibit response to vaccine and this is one study from, again, Laurie Markowitz, showing that seroconversion rates to the vaccine were much higher in infants who had very low or no neutralizing antibodies to measles virus and as I mentioned before, in order to get a protective response to the vaccine, the vaccine has to replicate within the host and basically cause mild measles and these maternal antibodies will neutralize that vaccine virus and prevent the immune response.

            So this is the data that each of the prior speakers has alluded to, that magical 120 number, and it was really a serendipitous discovery and I think that explains partly why we have so few data about what the protective titers are.  There was a blood donation program at Boston University and concurrently a measles outbreak.  So at the time of exposure to measles virus there were blood products, serum, available to test for neutralizing antibodies at the time of exposure.  So it was really kind of a unique epidemiologic situation and the investigators were clever enough to take advantage of it.

            But as I think as a number of people have suggested, this is not written in stone and it's the best data we have on levels that protect and this is protection from disease, protection from clinical disease, this 120.  But you can see the numbers of individuals were small in the group with levels less than 120.  It was really the highest titer in the college-aged students who developed measles was exactly 120.

            They did look at, as was already mentioned, boosting antibody responses.  So young adults who boosted their antibody response, but didn't have clinical disease presumably had a subclinical infection but were protected against disease and this is where that 152 comes from and again the number are very small.  But this is what we have, because that kind of epidemiological circumstance has not been repeated.

            In Dianne Griffin's lab, they've done studies with a number of -- these are DNA vaccines, so very different vaccine construct that what's used in people, but I just want to bring up again this issue of protection from disease compared to protection from infection and these are monkeys that got different kind of constructs of DNA vaccines.  But you can see the neutralizing titers there and some monkeys, particularly those with a titer of 135 or greater, had evidence of viremia without rash.  So they didn't have sterilizing immunity and then those between three and 105 had a rash as well as viremia.

            But I want to mention that titers below 120 although they may not protect against clinical disease, they probably protect almost certainly against severe disease.  So there's an entity vaccine-modified measles where children will get a milder form of measles if they have some level of immune protection but not enough to protect clinical disease.

            And the vaccine itself, particularly the first vaccine used in the United States, the Edmondson B vaccine, actually induced fever and rash in 15 percent or so of children and immune globulin was given concurrently with that often to modify that.  So this 120 may in the normal host certainly would prevent severe disease.

            But I think the critical question is what the impact is of cellular immunity on these protective titers and part of the problem is the inability to really quantitate cellular immune responses in a good way or at least in a way analogous to antibody titers in children and certainly there are assays to measure cellular immune responses, but there is not the same threshold that's been identified.

            In summary, clearance of measles virus is dependent primarily on cellular immunity.  Defects in clearance are associated with unusual manifestations of measles and those with the most severe immunosuppression, they can have a progressive disease without rash. Those with moderate immune suppression may have a desquamating or unusual type of rash and we've talked about this neutralizing antibody titer being the best protection but the data is rather limited on what those thresholds are.

            And I'll just thank my colleagues, but particularly Dianne Griffin for her help.

            DR. BALLOW:  If I may, I have several questions for you.  Thank you for that presentation.  It was really an excellent overview.

            DR. MOSS:  Thank you.

            DR. BALLOW:  You mentioned that in order for the measles vaccine to be productive there has to be replication of the virus.

            DR. MOSS:  Right.

            DR. BALLOW:  So we give a booster immunization at preschool age.  Correct?

            DR. MOSS:  Right.  Well --

            DR. BALLOW:  And presumably they have antibodies.  So is the virus still able to replicate and what's happening?  Is it boosting up the cellular immunity as well as the ambient response of the IGG?

            DR. MOSS:  The -- I may let Dr. Seward respond.  But I'll just say that the real reason for the second dose is not a booster dose.  It's not to booster antibody titers.  The reason for the second dose is twofold and it's part of a measles -- the second dose is critical to measles elimination, to really interrupt measles virus transmission, so to obtain a very high level of population immunity.

            So the second dose is really to do two things and I think more globally it's often referred to as a second opportunity by WHO and it's to immunize those children who never received the first dose to provide an opportunity for those children and to immunize those who don't respond to the first dose.  So at 12 months of age, it's 95 percent is kind of the dogma, the percentage of children that respond.  But that leaves five percent of children aren't responding to the first dose.  So that second dose is to immunize those five percent.

            I don't think of the second dose as -- the purpose behind it as boosting the antibody response.

            DR. BALLOW:  But there must be data though.

            DR. MOSS:  There is some.  So there is some boosting and the amount of boosting will depend  upon, is a function of the pre-existing antibody titer.  So those who have had some waning of immunity, you'll observe more boosting of the antibody response.  Those who have very high titers, you may not see an increase in the antibody response with the second dose.

            DR. BALLOW:  That makes sense.  The second question; with HIV children, do they take away the recommendation to give MMR vaccine?

            DR. MOSS:  For HIV-infected children, it's an interesting history because prior to the 1989 -- I'll talk about for the United States, because the WHO recommendations have not always been consistent with the or not consistent with the U.S. recommendations. But prior to the 1989 outbreak of measles, people were very concerned about giving a live, attenuated virus to HIV-infected children.  So a lot of those children didn't get the vaccine.

            Then when these severe cases were described during late `80s and early `90s, there was kind of this shift toward providing MMR.  It was recognized that it was very important to protect HIV-infected children against measles.  That case report that I showed you actually changed the policy back.  So the current recommendations are not to give the MMR vaccine to persons and particularly children with HIV who are severely immunosuppressed, defined as a CD-4 percentage less than 15.

            DR. BALLOW:  Less than 15?

            DR. MOSS:  Less than 15.

            DR. BALLOW:  Wow.  Okay and then the last question to get back to patients with primary immune deficiency, as we enjoy the day and engender some conversation about now and what's going to happen over the next 10 or 15 years, one wonders whether it would be beneficial to give patients with antibody deficiency, not T cell deficiency, but antibody deficiency, even recognizing that some of those patients like CVID may have some subtle T cell abnormalities but nevertheless to give them MMR vaccine to try to elicit or enhance their T cell responses so that if there is an outbreak at least they'll be able to clear the virus more readily.

            DR. MOSS:  Right.

            DR. BALLOW:  But at the same time, since all these patients are IVIG, one wonders whether they will be able to actually develop a T cell immune response, given the fact that they have measles antibody.

            DR. MOSS:  Right.

            DR. BALLOW:  I guess we don't know unless we try it.

            DR. MOSS:  Right.  That's a very interesting question and the tools for measuring measles virus specific T cell responses have just really been developed and perfected over the past couple years.  Before people would do lympho-proliferation-type assays but you can really do very precise assays now.  So I think we now have the tools to begin to measure some of those responses.

            There are a number of groups and Dianne Griffin's group is one that are working on new measles vaccines that are nonreplicating vaccines and not all people in the measles world agree that that's a -- certainly as has been mentioned, the current measles vaccine is highly effective and it's a great vaccine, a very safe vaccine.  And some people question the need for a new measles vaccine, but that might be a population where, if you could immunize with a non-replicating vaccine, a DNA-based vaccine or there are alpha virus-based vaccines, there is a whole array of different types of vaccines that are development, that might be a select population where that might be useful for inducing T cell responses.  Yes.

            DR. DI BISCEGLIE:  I have a question if I may.  Are there any antiviral agents effective against measles virus that might be given to immune-deficient -- I'm thinking of Ribavirin in particular.

            DR. MOSS:  Yes.  Obviously, there have been no large trials or studies, but there are case reports of using a number of agents particularly ribavirin is the most experience with and people feel that -- or certainly that has been used in that situation and some people have used it in combination with alpha interferon.

            CHAIRMAN SIEGAL:  Thank you very much.  That was a nice talk.  Next we'll hear from Toby Simon from CSL Behring on measles antibody titers in plasma donors.

            DR. SIMON:  Thank you.  I'm very grateful for the opportunity to be here on behalf of my colleagues at CSL Behring and also speaking for our industry group, PPTA.  It was also a pleasure to work with Dr. Scott and the group from FDA on the workshop and to work on developing this issue for presentation today.

            I'll just set up the stage quickly.  With the information that you've already seen, in the pre-vaccine era, there were approximately 500,000 cases per year in the United States.  In 2005, there were 66 confirmed cases, 34 from a single outbreak associated with a traveler and that's the largest outbreak in the U.S. since 1966.  The current incidence is less than one in a million.

            The measles vaccine was introduced in 1963.  By the 1970s, most states started requiring it for school entry and that was pretty complete by the 1980s.  And in 1989, the two-dose vaccine requirement was phased in.  In 2001, 96 percent of states required two doses for school entry and the median coverage was 97 percent.

            Our problem, as you have heard, is that the antibody titers as quoted here from a text on vaccines "elicited by vaccination do decline over time as do those induced by natural infection and may become undetectable."  Vaccine-induced antibody titers are typically lower than those induced by natural infection.  So as younger donors enter our donor programs, they come in with lower titers than what we had seen in our older donors.

            And we have been measuring these titers in our donors using the ELISA method for measles IGG.  The particular methodology that we'll be using in the report today is from the Eddie Mac system, manufactured by Diasorin with an internal calibrator that we have developed using the WHO 66/202 standard.  The reporting range is 0.5 to 10 IU/mL and the coefficient of variation goes from 2.7 to 14.7 percent and that, unfortunately, is higher at lower concentrations which means we lose sensitivity in those donors who have very low values.  We have correlated this with in-process testing by our manufacturer's assay aboard using the  Dade-Behring ELISA and it's a very high correlation of 0.95.

            And this is the data that we showed at the workshop, which shows that the donors depending on the birth year as you see on the left side of the slide, the donors who are older and then with the introduction of the vaccine in 1963, which is that inflection point before it goes down, we get to very low levels with universal employment of the vaccine below 0.5.  Many of the donors will actually have a 0.0 level on this test and so we assign them a low value of 0.1 to get the mean.

            This is based on a random sample of 4,356 source plasma donors conducted in three snapshots, March of 2006, December of 2006 and then March of 2007.  So the aggregate picture here is of falling levels of titers in the donor population and then as young donors replace the older donors we see a falling or decline in those titers in the product made from their donations.  Based on the current age profile of our donors, the group that has greater than 1.5 as the titer shown on the left of the slide constitutes about 20 percent of our source plasma donors at the present time.  By 2010, if the age profile remains the same, they will constitute less than 15 percent of our donors.  So we're rapidly moving to plasma that will reflect our current younger vaccinated donors with the lower titer.

            And that gives us the problem that we face in terms of making product with a higher titer that's currently required.  Now about 20 percent of the plasma product in the United States comes from normal recovered plasma obtained from whole blood donations at community blood centers and that does have a higher level because of more older donors.  However, that percentage is declining as more and more blood centers go to collecting red cells by apheresis.  That is they'll collect two units of red cells and no plasma.  So the amount of recovered plasma available is declining.

            Now you might ask why aren't we recruiting more older donors and we would like to do that.  However, source plasma donation is relatively physically demanding.  It's about an hour and a half process and our donors can donate twice a week. The typical donor donates four or five times a month in contrast to the normal whole blood donor who donates once or twice a year or up to about six times a year.  So it's a more physically demanding process and what we find is as people age they tend to leave the donor pool and then younger donors come in and, of course, one of our most successful recruiting areas is among students.  I think it will be with great difficulty that we will make very significant change in that age profile over time.

            When we presented this data in the workshop, Dr. Scott and Dr. Epstein asked that we go back and measure titers using the neutralization assay and the reason for this is twofold.  First, that is the assay that we use for the product release.  So we do have a disconnect here, this assay that we're using to screen donors versus the viral neutralization or functional assay that we use for product release.  In addition, we do have the problem of the very low levels in donors and the doctors pointed out at the workshop that they do get measurable levels in individuals who have been vaccinated of about 1 IU/mL using the neutralization assay.

            So for this reason, we conducted an additional fourth snapshot of our donors on June 20, 2007 in order to compare the enzyme immune assay with the viral neutralization assay and we set this up using our statistician's advice on how to conduct mini-pools.  The neutralization assay is much more technically demanding than is the EIA which is the reason we don't use it to screen donors.  It's more difficult to perform.  It's performed on tissue culture systems.  It's more expensive to perform and therefore, in order to practically do this, we needed to create mini-pools.

            So this is a snapshot actually of 520 donors based on the statistician's advice of how many donors to have in each age group, based on the data that we had previously obtained.  And then on each group, we sampled a certain amount for the mini-pool.  So in the older age groups we were sampling one in three or one in five for the mini-pool and the younger age groups one in ten to one in eleven.  We constituted a mini-pool for each of the age groups and then we took five aliquots from each of the minipools and sent them to the laboratory in Bern, Switzerland that did the viral neutralization functional assay.  That assay is calibrated against the third WHO standard 21 IU/mL of anti-measles activity.  So it gives a different measurement than the EIA.

            I'll proceed now to show you that data and this graph shows the five datapoints, one from each of the aliquots for each of the age groups based on birth year and for those individuals born before 1962, the first two groups on the left, you can see a relatively high level of approximately 4 IU/mL.  Then the next group, during the years when the vaccine was first introduced, individuals born in 1963 to `67, a reduced level, but still higher than the younger individuals  born after the vaccine had been completely introduced in the United States from 1968 on.  Pretty tight `68 to `72 and then the aliquots tend to vary a little bit more, but still fairly consistent levels of between 1 and 2 IU/mL for the younger donors compared to 2.5 in the individuals from that period when the vaccine was introduced and then the higher levels of around 4 IU/mL in the older donors.

            And then this slide we've put the data from that one snapshot in June of 2007 for both the EIA assay and the viral neutralization.  The viral neutralization are the higher numbers shown in red and with the one standard deviation above and below the mean shown on the graph they are consistently higher and the statisticians tell us that that is consistent and that the difference is, of course, greater in measurable units at the higher levels than it is at the lower levels.  So this data does give us more confidence in the younger individuals who have the lower levels of antibody.

            And for the ELISA test, we have shown both the minipools that we measured by ELISA, comparable to the minipools that were measured by viral neutralization, plus all the individual units, individual samples, that were measured on the ELISA assay as well, and those values are quite close, and a very consistent picture emerges.  So individuals born before 1963, before the introduction of the vaccine on the ELISA still have a measurement of around two IU, on the functional assay about four IU.  That falls on individuals born between 1963 and 1967 to about two to three IU on the viral neutralization assay, about one on the ELISA, and then below one on the ELISA for the younger individuals, and slightly above one, about one and a half, for the younger individuals on the functional assay.  So what you see on the right will be the donor pool that will emerge as time goes on.

            And to show you the impact on this, we've created this histogram from the May 2006 measles snapshot using the EIA.  If you look to the right, that would be the percentage of individuals that are below 10 IU/mL.  And then as you move to the left, we go to lower levels.  So if you focus at about two, two and a half IU/mL, you can see among what we call the senior donors, the individuals born before the introduction of the vaccine, that about 60 percent of them, or about half, will be below this level, and about half will be above the level.

            If you look at our junior or younger donors, you can see that 90 percent of them will be below that level, so would not be able to constitute a pool of around two to two and a half IU/mL, which is what we calculate we would need to reach the current CBER standard.  And as you can see, the total donors are beginning to approximate the curve that we have shown for the younger donors.

            So the message that we're trying to give you is that the donor pool is moving over time to represent the vaccinated population with the lower level of antibodies that will, in turn, be reflected in the product, making it more and more difficult for us to produce product to meet the current CBER requirement for release.

            Now the next obvious question is, why don't we go ahead and immunize donors, because many of you may know that plasma centers are capable of doing this, and we do this for several products.  This was analyzed by one of my medical colleagues, who was with the organization before I was, who looked at 2005 as the problem started to become acute, whether an immunization program was practical, and concluded that it was not.

            First, I think we have what I have termed here the "ethical issue."  If there's no clear patient benefit to offset the donor risks, then we have a problem putting donors through the discomfort and risks of the immunization. And I contrast this to our rabies program.  In other words, what we heard at the workshop from the clinicians who treat patients who are immunodeficient is that measles is not a significant clinical problem, and that we could not tell donors that participating in one of these immunization programs was making a difference in either quality or quantity of life for the patients.

            By contrast, if one of you were to be bitten by rapid animal, the injection of a rabies immunoglobulin would likely be lifesaving for you.  So we can certainly tell our donors to whom we give the rabies vaccine that we are producing a product that is likely to save human lives.  So I think that is one thing to keep in mind.

            Another very practical point is that the measles vaccine is constituted with live attenuated virus, and we do not conduct, at the present time, vaccination programs in our centers with live attenuated vaccine, and have some issues doing so.  The virus replicates in the body for six weeks, so there would be issues in drawing those donors while they have a replicating virus, particularly for an immunoglobulin product for that virus.

            The side effects are slightly higher with the measles vaccine than with some of the other vaccines that we use, and the handling and management of the vaccine is more complex than is the case with our other programs.  The vaccine has to be protected  from light, it has to be shipped and maintained at refrigerated temperatures, and while these may seem minimal for clinics and hospitals, for a busy donor center, it creates more complexity from the program than our other vaccination programs do.

            And importantly, in our discussions at that time with the experts from Merck who manufacture the vaccine, there was significant uncertainty about the levels that we would achieve in order to make a product that would have adequate antibody.  Their estimate was that 25 to 50 percent of the individuals would boost to the high levels that we were looking at, and there was a question about how long that would be maintained, and as has already come up in the discussion, there was question about the effectiveness of the second dose in helping with that.  So we have concluded that an immunization program is not the way to go here in order to create a more effective product.

            It was brought up in the workshop of, why don't we seek out individuals who are vaccinated, and the couple of instances were brought up, for example, military recruits who are frequently vaccinated, and further discussions with the military, and I realize we have an expert that can amplify on it here today, indicates that they generally get the vaccinations at the end of their basic training, shortly before they're shipped out, and as you know, many of them now are being deployed to foreign locations, and it's questionable whether individuals preparing for combat would want to enter a plasma apheresis program at that time.

            Health care workers were also suggested.  One of the speakers from Johns Hopkins said that hospital immunizes health care workers if they have low immunization levels, but that is not the common practice in the United States.  In general, individuals who go to work for hospitals and say that they have been vaccinated are not further tested.  Individuals planning international travel would obviously be going off overseas in the near future.  So we don't believe that there are, on a practical level, populations available who are being vaccinated whom we could bring into our plasma apheresis programs.

            Therefore in summary, falling measles titers are anticipated over time in normal donors. It's about a nine percent drop per year in recovered plasma, perhaps a little bit higher in source plasma.  It's increased when we have times of significant growth, when we're bringing in more younger donors, and we have verified that by snapshot data, particularly in our source plasma donors on four different occasions in the last year and a half.

            Reductions in the plasma titers currently being seen will make it very difficult for us to achieve product specifications in the future, and it's already creating some difficulty currently.  Immunization programs pose significant issues, and are not seen by us as a solution to the problem.

            And therefore, we believe that measles antibody specifications for the immunoglobulin products need to be reconsidered, as has been done by the Agency, and we certainly would support movement to the lower standard that's been recommended, and I think based on the data from the donors, and I think some of the data that you're going to hear from my colleague who has data on the patient side, it might be possible to even move to a slightly lower level for the specifications, as well.

            This presentation does represent the efforts of a global group at CSL Behring.  The serology work was done in our lab in Knoxville, Tennessee.  I thank Robin Jenness, Connie Farrar for that work.  Nancy Danvers organized that, and the June snapshot, the viral neutralization assays were done in our laboratory in Bern, Switzerland.  Peter Bailloid and Marian Kuehne were responsible for those measurements.  The statistical analysis was referred to our chief economist at our headquarters in Melbourne, Australia, Sam Lovick, who brought in a statistician, John Small, who helped us, who works in New Zealand.  I also thank Jonathan Knowles and Gordon Naylor from our executive group for helping with the presentation.

            CHAIRMAN SIEGAL:  Thank you, Dr. Simon.  Are there any questions for Dr. Simon?

            DR. SZYMANSKI:  I just wonder what effect the multiple donations have at the titer level.  Do they go down in the young donors, and what about the older donors who are naturally immunized by natural virus?  Do they go down, or is there any difference?  Do you understand?

            DR. SIMON:  Yes.  Of course, with the snapshots we have newer and older donors all included  at a given point in time.  All the protein levels are subject to decline over time, and donors, depending on their frequency of donation, we do monitor this every four months.  I don't actually monitor the total protein at each donation using a refractometer.  We  use the serum protein electrophoresis every four months, and individuals are rested when their protein levels fall below a certain level.  But there is an element of decline involved in frequent serial donations.

            DR. SZYMANSKI:  But also the measles titers.  Right?

            DR. SIMON:   Well, all proteins.

            DR. SZYMANSKI:  Yes.  All proteins.

            DR. SIMON:  All the immunoglobulins are subjected.

            DR. SZYMANSKI:  Do you think they go the same way?

            DR. SIMON:  Yes.  I think they -- our data indicates they all decline pretty much the same.

            DR. SZYMANSKI:  Thank you.

            DR. GLYNN:  Could you please quantify a little bit more?  You're saying, if we do not do anything, if nothing is changed, what is going to be the impact on the amount, the supply, of the IGG products, I guess?  I have a hard time understanding.  It's going to be difficult, but is it going to be possible, or is it going to be impossible, and it's going to be going down by 10 percent, 20 percent?  I mean, can you quantify?

            DR. SIMON:  I think maybe one of the industry speakers on the product side after me, perhaps, could do a better job of quantifying that.  Perhaps Don Baker could do that.  But what will happen over time is that more and more lots will fail the specification, and if they can't be released, then they will be unavailable for product for patients who need the product.  So the exact quantification is difficult.  Obviously, our product people do everything they possibly can to mix the product to meet the specifications, but we've been seeing increasing difficulties in the last couple of years, which was what caused this whole subject to come up for discussion, why the FDA organized and included it in the workshop, and have brought the question today.  So more and more lots will fail over time, and that will be progressive problem.

            DR. GLYNN:  And I guess you asked the same question before, but how many right now are -- what's the failure rate right now, I guess?

            DR. SIMON:  I think the product side would have to answer that.  I don't have a specific number on that right now.

            DR. KATZ:  Toby, it looks to me like you're kind of approaching the asymptote now that I'm actually surprised that 20 percent of the donors were from that higher titer age cohort.  I couldn't tolerate plasma apheresis, and I'm just a kid.  So it looks like most of the impacts been seen in the titers, if I'm looking at the histogram that you showed correctly.

            DR. SIMON:  Yes.  We try to do what we can to make up the product and to enrich it with the older donors to the extent possible.  But it's simply a progressive problem.  They constitute, as I said, about 20 percent right now.  In 2010, approximately 15 percent, by 2025, zero percent.  We have a 65 age limit.  So you can see it simply becoming progressive, and I think it became a big problem as this group entered their 40s in the last few years, and that's when we began to see it.

            CHAIRMAN SIEGAL:  Thank you very much.  The next speaker will be Don Baker from Baxter Healthcare, measles antibody levels over time in licensed product, and patients with primary immunodeficiency diseases.

            DR. BAKER:  Okay.  We've had a lot of discussion so far today, and I bet if I turn this -- is this mike on?  I can't tell.

            We've had a lot of discussion today about the potential for decreasing measles antibody titer in final products, and now I'm actually going to show you some data on decrease over time.  Longitudinal studies are conceptionally one of the most simply studies you can do.  You just study a variable over time.  However, everyone knows that, despite their simplicity in concept, they are tremendously difficult in actually carrying out.

            And what this study today is going to do is, we're going to examine the change in the measles antibody titer and Gammagard S/D IGIV for the period January 1997 through June 2007.  This is a product that has been in continuous production at Baxter since 1994.  The reason I didn't go back to 1994 is because I didn't have the data in electronic format that allowed me to easily recover it for the time since 1994.

            Now, Gammagard is produced from two plasma flavors, our source plasma donors, these are apheresis donors, and this is the demographics of our source plasma donors. And as you can see, the cohort that are currently naturally immunized to measles is somewhere probably south of 20 percent of our total donors.

            I didn't have the same demographic data for our recovered plasma donors.  These are the donors where the plasma is collected and recovered from a whole plasma donation.  This data I got from the Red Cross.  However, you can see obviously the same general decline in the older donors with time.  I would estimate that the recovered plasma donors, there's probably about -- the prevalence of this, as Toby put it, the senior donors, is probably about twice what it is in our source plasma donors.  So if we have somewhat less than 20 percent in our source plasma donors, who are naturally infected with measles, there's something little less than 40 percent in the recovered plasma donors.  But again, time will gradually result in a total reduction of these naturally infected individuals.

            Okay.  What do we assume in a longitudinal study?  We are assuming that the only thing that is changing is the percentage of donors that were naturally infected with measles.  In terms of the other potentially confounding variables, the assay, we have used the hemagglutinin inhibition assay continuously to test the measles antibody titer in our final product.  There has been no change in the assay.  In the assay site, all of these were performed at our plant in LeSiens, Belgium, and I would dare say, given the stability of the European work force, probably no change in the people actually conducting the assay.

            The standard has been the same, the CBER reference, there's no change there.  The process, we have obviously tweaked the process over the last ten years.  However, I did go back and take a look at the significant process changes.  Obviously, all of these were evaluated at the time to not impact the product, and in going back over them, I would conclude with that original evaluation.  I don't see that there's any reasonable likelihood that any of the process changes would have impacted the measles antibody titer.

            And the donors.  There has been no change there.  The majority of donors over time on the source side were from our Baxter Source Centers, and we used ARC recovered plasma.  So by in large, the donor screening questions, the donor testing, the donor selection criteria, there have been minor changes over this ten year period, but again, nothing that I think would impact the demographics or the measles titer.

            This is just some selected characteristics of Gammagard S/D, just for those of you that may not be familiar with the product.

            Okay.  So what do we see?  This is the source plasma product.  As you can see, the specification is 0.2 relative to the NIH 176 reference standard, and for those of you that are baffled by numbers, why do you see 0.2 as opposed to 0.6?  The 0.2 is the adjustment for protein concentration.  This is a five percent protein concentration, IGIV concentration.  The reference standard is 16.5 percent, I think.  So the 0.2 is an adjustment for the protein concentration.

            As you can see visually, there appears to be a decline in titer.  If you look at the trend, you do see a more or less consistent trend, or the rolling average, again, a consistent trend downward over time.

            The situation with recovered plasma, again, is somewhat similar, and exactly what you would expect given that the percentage of donors is older.  The older donors are more represented in the recovered plasma.  So there the titers are somewhat higher.  But again, the same trend decline over time, and the same trend in decline in the rolling average.

            So, the data from the longitudinal study does support the hypothesis.  The decline of donors with a history of natural measles infection is leading to a decrease in the titer of antibody measles virus, and absent a change in specification for measles antibody or any mitigating step, we will have IGIV lots that will begin to fail the measles titer requirement.

            Now there was a question from one of the committee members about how many lots are we losing.  The fact is that right now we don't lose any lots, because the measles antibody titer is not required in Europe.  So lots that don't meet the measles antibody titer we redirect to European or other distributions.  So right now, we're not losing any.

            However, the issue is, for our company, for example, the vast majority of this product is distributed in the United States.  So were we to continue to divert product to Europe, obviously the American consumer would, a patient would lose product. Given the, I would say, fine balance between IGIV supply and IGIV demand in this country, then we would begin to lose product for distribution in the United States.

            Okay.  That was it.

            CHAIRMAN SIEGAL:  Thank you.  So we have time for a couple of questions.

            DR. COLVIN:  I'm curious as to what is the measles incidence in Europe?

            DR. BAKER:  I don't know.

            DR. COLVIN:  Because I'm assuming, based on what we've heard before, it's a bit higher than it is in the U.S.

            DR. BAKER:  It is higher than in the U.S.

            DR. COLVIN:  So in other words, I'm just throwing something ethical out at you for a second.  So you're saying that when the measles titer is lower, perhaps not reaching the level that people who have an immunodeficiency might need to, in fact, prevent infection with the virus, you're sending now this product to try to protect people from infections in a place where the incidence of this infection is actually higher than it is here.

            DR. BAKER:  You know, there's two responses to that.  Number one, the European community and the regulators in the European community have taken a different perspective on measles antibody titer.  They feel that the titer that we have in the product is adequately protected.  So that's a difference in regulatory view, and I'm certainly not going to get into that right now.

            Secondarily again, we have not seen, in the primary immunodeficient patient population in Europe, any cases of measles infection, either.  So that would suggest that the titer in the product distributed in Europe is adequate for protection.

            DR. COLVIN:  Or it could be that most of the time they're getting European source plasma that actually has a much higher titer because it has more naturally infected patients donating.

            DR. BAKER:  Fair enough.

            CHAIRMAN SIEGAL:  Anybody else?  Okay. Very good.  Thank you very much.  Now Othmar Zenker, M.D., from Behring.

            DR. ZENKER:  Good afternoon.  I am representing CSL Behring.  I'm head clinical research in Bern Switzerland.  So I'm coming from Europe.  The measles incidence in Europe is definitely higher, I think, mainly due to less vaccinations.  So the vaccination program is not as good as here in the United States.  But I would like to talk about measle antibody titers in primary immunodeficiency patients.

            A short introduction.  I think this is all repetition.  We have heard this this afternoon.  Falling measles titers are anticipated over time in normal donors.  The measles antibody titers serve as a potency test for immunoglobulin lot release, with a cutoff level of 0.6 times the CBER standard.  We've heard a lot about the history of this cutoff level in the previous talks.  This should usually not lead to any issues.  But here, one has to think about, is the lower measles titer that will come into the product into the future.  Can patients be protected against measles?

            If there are more and more lots that will not fulfill the current cutoff level, there is an increase of immunoglobulin shortage.

            Now back to the patients. The titers for immunocompetent persons that are protective are known.  This is 0.12 IU/mL.  This has been associated with a protection against the clinical measles disease in several outbreak studies.  We mentioned a study by Dr. Chen published in 1990.

            Currently, there seems to be no concern for primary immunodeficiency patients with respect of measles.  Even in Europe, where there is currently an outbreak in Switzerland, and also a smaller outbreak in Germany, we have not heard from any case that our patients are affected on that, and this was also, I think, discussed intensively in the workshop in April.  Nevertheless, the accepted protective titer for primary immunodeficiency patients is not known.

            What we did is we used retention samples from two of our clinical studies and tested these samples at the trough levels in functional assay and with ELISA.  This obtained us results on anti measles trough levels after subcutaneous and intravenous immunoglobulin treatment in PIDD patients.

            These are the methods we have used for the ELISA.  We used a commercial kit, and calibrated it with in-house plasma standards against the 3rd WHO standard.  The neutralization assay is the assay we use normally for a lot release, and we measure the measles antibody in relation to the reference immunoglobulin in Lot 176, and we converted these into units per mL by using a factor of 2.54 for a one percent immunoglobulin, as published by Dr. O'Day last year.

            So now to the clinical studies.  The first one is a subcutaneous study.  We have chosen 20 subjects with available retention samples, analyzed them by the neutralization assay, and in addition, 60 samples by ELISA.  The demographic data of these patients are typical for primary immunodeficiency patients, as shown here with respect to IGG trough level, and also the weekly subcutaneous dose.  The treatment was given every week, and for this analysis, we have calculated the anti-measles specific dose in units per kilogram per week by using the lot release test.

            As a lot could have been changed during this study, so a patient could have been treated with several lots. Even just prior to the drawing of the samples, we took the four last infusions into consideration, the four infusions that were given prior to the trough level sampling, and used the mean of these values.  This takes into consideration the half-life of three to four weeks of the immunoglobulin, so that we have no carryover, or less carryover effect from different lots.

            Here you see the results of the dose response in the neutralization assay.  On the X axis, we have drawn the anti-measles specific dose, and on the Y axis, the anti-measles titer.  At 0.12, we have drawn a line which represents the minimum protective level in healthy patients, not to develop measles disease.  It's obvious that, here in this study, all patients are well protected.  There was no single patient that had an anti-measles titer below one IU/mL.  The mean titer in this patient population is 3.17 IU/mL.  So I would say at least two to three times higher than the usual donors, as shown previously by my colleague.  Just for your information, this is a graph that shows the IGG trough levels, and the anti-measles titer.  As expected, there is also a correlation between the dose and the trough levels.

            Now to our second study, the results after the intravenous infusion.  Again, we have chosen retention samples here, 53 subjects, 58 of the samples were analyzed by neutralization assay, and 140 samples by ELISA.  As you can see from the numbers, we have some repeated measurements in some of the patients.  Again, the demographic data are typical for primary immunodeficiency patients.  Here the treatment was given every three to four weeks.  In this case, the dose was the dose of the three weekly treated patients were intercollated to monthly dose so that we can compare the three and the four weekly dosing groups.

            Again, to avoid any carryover effect of different lots, we have chosen here for this study samples only if the same lot was given on three consecutive infusions prior to the sampling.  Here you can see the result of the neutralization test assay.  Again, all patients are protected.  They were well above the 0.12 cutoff level.

            The mean titer here is 2.98 units per mL. When you compare these results between the intravenous and the subcutaneous administration route, there seems to be a higher anti-measles titer during subcutaneous treatment.  This is not unexpected.  I think we have just discussed previously that the difference between the intravenous and the subcutaneous administration route is that, by the intravenous route, we have a high trough level and a somewhat lower -- a high peak level, sorry -- and a somewhat lower trough level than compared to subcutaneous administration.

            In the following, I will present to you a simulation, a trough level simulation.  We have the important question "how do the previous shown results translate into trough levels when we are using a lot with a lower anti-measles titer than given in this study?"  For that, we had to do some assumptions.

            The first assumption is that we use a hypothetical lot with a potency of 0.3 times the CBER Standard Lot 176.  We calculated the dose of anti-measles antibody given to the patient according to this hypothetical lot under the assumption of a linear dose titer correlation.  We did not take into consideration that some of the patients would probably have some endogenous anti-measles antibody titer.  So in our view, this is a very conservative approach.

            We did a simple mathematical model, and I will show you now the results.  Or I will show you graphically how we did it.  You see the red line.  For one of these patients, this is the patient 1010.  He had an anti measles titer of a little bit less than one in the retention sample.  We drew the line through the zero calculated, the hypothetical dose.  With a lot of 0.3 times the CBER standard, here this is approximately 30 units per kg per month, and so now that, with this interpolation, the patient would have at least an anti-measles titer of 0.15.

            So we did this with all the patients, with all the dots you see here in this graph, except of one.  We had to exclude one patient where we saw no dose trough level correlation in the ELISA test.  Here you can see that, even with a higher dose, the patient showed no increase in the trough level.  Therefore we have excluded this patient from the following chart.

            So this is the result of this simulation.  Again, all the patients would be protected.  They would have shown a trough level that is above the 0.12.  The difference between the cutoff line and the calculated numbers is not so high as in the real samples that should be considered.  But once again, we have to mention that this is a conservative approach as the endogenous production of anti-measles immunoglobulin was not taken into consideration.

            So let's summarize.  All the tested samples were well above the protective level of 0.12 unit per mL.  Treatment with subcutaneous immunoglobulin results in a higher trough level than intravenous immunoglobulin.  Three or four weekly IGIV treatments with product under the current specification of trough levels is far above the protective titer of 0.12.  Even a hypothetical lot with a potency of 0.3 times the CBER Lot 176 would be sufficient to protect patients in the study, as shown by the linear interpolation.

            The FDA has proposed to lower the cutoff level to 0.48 times the CBER lot standard.  With this data, this cutoff level -- or it could be taken into consideration to lower this level of 0.48 even more.  So the data show that patients are protected with a lot of 0.3.

            These are my acknowledgments.  Thank you.

            CHAIRMAN SIEGAL:  Okay.  Thank you very much, Dr. Zenker.  Are there questions for Dr. Zenker?

            DR. EPSTEIN:  First, thank you very much.  These are the first data that we've seen on trough levels in primary immunodeficient patient, so it's very much appreciated.

            My question is about the methods for estimating administered dose.  Did you base the calculation of administered dose in a patient on the actual known content of the product lots administered, or did you simply assume that they were at 0.6 times CBER standard? Because in reality, many of those lots might have been much higher than 0.6 times CBER standard, and then you would have had an incorrect extrapolation for a lower potency.

            DR. ZENKER:  No, we have used the actual dose --

            DR. EPSTEIN:  The actual dose.

            DR. ZENKER:  -- that were given in the analysis.

            DR. EPSTEIN:  Okay.

            DR. BALLOW:  On the patients that were receiving immunoglobulin by the intravenous route, I noticed your trough levels -- I think that was a trough level.  It was like 971 mg/deciliter.  Was that what I saw?

            DR. ZENKER:  The average trough level, the immunoglobulin trough level?

            DR. BALLOW:  Yes.

            DR. ZENKER:  The average trough level was 970, yes.

            DR. BALLOW:  Yes.  I mean, that's extraordinary.  That's much higher than many of our patients achieve unless we infuse above 700 millirems per kilo.  So in the real world, I know that was part of a study, but in the real world, I mean those are trough levels much higher.  So I'm a little bit worried about using some of the data, given that high of a trough level, because we just don't see that in our patients.

            DR. ZENKER:  So these were the data from a clinical study which was performed mainly in the United States.  So these are --

            DR. BALLOW: No, I understand that.

            DR. ZENKER:  -- these are reflecting the treatment in this clinical study in the United States.

            CHAIRMAN SIEGAL:  Anybody else?  Dr. Szymanski.

            DR. SZYMANSKI:  I have a question for you.  Now, when measles is so rare, and so what do you think?  Is it necessary to protect these immunocompetent individuals all the time, so that they will all the time have good titers, anti-measles titers, or would you let them go down, and when there is a problem, increase, give them more immunoglobulin?

            DR. ZENKER:  Maybe this is more a question to the clinicians here.  From the data we have seen, it should be possible to reduce the measles titer in the product, and when we all assume that the 120 is a sufficient cutoff level, then we can reduce the lot specification.  As I stated before, in Europe, there is no lot release specification at all for immunoglobulins.

            CHAIRMAN SIEGAL:  Anyone else?  I would certainly agree with Mark that most of our patients don't achieve a trough level of 900 mg. It's more like the lower limit of normal, if we're lucky.  So that might make a difference in terms of the titers that are actually achieved.

            Anyone else?  Okay.  Well, thank you very much.  Now we're already about 20 minute behind.  I don't know how the committee feels about it, but I know that some of us have to make planes and trains, and that perhaps we ought to forego the break and move onto the rest of the program.  Is there a sense that people need to take a break for a moment?

            (Off the record comments.)

            CHAIRMAN SIEGAL:  Do you want to do five minutes?  But really a five minute break.  Okay.  Not 25.  Off the record.

            (Whereupon, at 3:36 p.m., the above-entitled matter recessed and reconvened at 3:41 p.m. the same day.)

            CHAIRMAN SIEGAL:  On the record.  Let's get started.  Because we are having an open public hearing, I'm obligated to read an announcement for such meetings concerning conflict of interest.

            Both the Food and Drug Administration (FDA) and the public believe in a transparent process for information gathering and decision making.  To ensure such transparency at the open public hearing session of the advisory committee meeting, FDA believes that it is important to understand the context of an individual's presentation.

            For this reason, FDA encourages you, the open public hearing speaker, at the beginning of your written or oral statement to advise the committee of any financial relationship that you may have with any company or any group that is likely to be impacted by the topic of this meeting.  For example, the financial information may include the company's or 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 chose not to address this issue of financial relationships at the beginning of your statement, it will not preclude you from speaking.  With that in mind, I understand we have two representatives.  The first will be Mary Gustafson from the PPTA, the Plasma Protein Therapeutics Association.  Dr. Gustafson.

            DR. GUSTAFSON:  Thank you very much.  And in terms of conflict of interest, I am a salaried employee of PPTA.  PPTA is the international trade association and standard setting organization for the world's major producers of plasma derived and recombinant analog therapies.  Our members provide 60 percent of the world's needs for source plasma and protein therapies.  These include clotting therapies for individuals with bleeding disorders, immunoglobulins to treat a complex of diseases and persons with immune deficiencies, therapies for individuals who have Alpha 1 antitrypsin deficiency which typically manifests as  adult onset emphysema and substantially limits life expectancy and albumin which is used in emergency room setting which is used to treat individuals with shock trauma, burns and other conditions.  PPTA members are committed to assuring the safety and availability of these medically needed life-sustaining therapies.

            PPTA agrees with FDA's proposal to lower the minimum titer for measles antibodies and immune globulin intravenous (human) and immune globulin subcutaneous (human) recommended for lot release.  The original measles antibody release requirement was related to a standard obtained from a donor population with different immunologic profile.

            In the 1960s, the immune globulins were licensed by FDA.  Today's immune globulin products are used by people with immune deficiencies to protect them on a day-to-day basis from pathogens in their environment.  Routes of administration are intravenous or subcutaneous.  As in the 1960s, the antibody composition of the immune globulin products reflect the herd immunity of the population from which the source material is collected.  Today's donor is more likely to have been immunized against childhood infections including measles rather than having had the illnesses.

            Both demand for and production of immune globulins are rising.  In 2006, the distribution of intravenous immune globulins in the United States was a record high of approximately 32.4 million grams.  Manufacturers increased the distribution of intravenous immune globulins over 60 percent between the years 2000 and 2006.  This increase has resulted from proactive steps such as incorporating yield improving technologies to obtain more globulin from each leader of plasma, increasing plaque capacity and implementing new product formulations.  The increased distribution is dependent on the antibody composition of the final product reflecting the herd immunity of the donor population.

            Manufacture of immune globulins is complex.  It is important to recognize that it can take up to 12 months to manufacture a single batch.  Failure of a batch to pass lot release specifications has serious ramifications.  It is important that each lot release specification is relevant and realistic.

            The proposal by FDA to lower the minimum titer for measles antibody is based on both clinical relevance and the realities of manufacturing immune globulins from today's donor populations.  And if I could add, based on data in Drs. Simon's and Zenker's presentations, we ask that the committee and FDA consider if an even lower titer is clinically appropriate to help ensure the continued sustainability of the product.  Thank you.

            CHAIRMAN SIEGAL:  Thank you, Dr. Gustafson.  The next speaker will be Marsha Boyle from the Immunodeficiency Foundation.

            MS. BOYLE:  Thank you, Dr. Siegal and the committee for allowing me to present.

            The Immunodeficiency Foundation is the national patient organization for the primary immunodeficiency diseases.   Many of our patients depend on regular infusions of life saving preparations of IVIG in order to replace the immunoglobulins and antibodies that they themselves are unable to produce because of a genetic defect involving their immune system.  The primary rationale for using this treatment is that these products contain sufficient titers of antibodies to be effective in preventing and treating a broad range of infectious diseases to which our patients are likely to become exposed.

            When the original potency standards for immune serum globulin, IGIM, were established, they were based on the titers of antibodies to measles, diphtheria and polio.  These potency standards have subsequently been applied to the preparation of IGIV and IG subcutaneous.

            IDF has been aware for some time of the concern by the FDA and the industry about the gradually falling titers of anti measles antibody in the general donor population that has been reflected in similar reduced titers and preparations of IGIV.

            Along with the FDA, we were pleased to cosponsor a workshop held at the NIH campus on April 25 and 26 of this year.  The workshop brought together experts from the FDA, CBER, industry, academia and the CDC to explore in the detail this problem and potential solutions.  BPAC's consideration of this issue today is very timely.  From what we understand, it appears that we're nearing a time when newly manufactured lots of IGIV may need to be rejected solely because they did not meet the standard for titer of anti measles antibody.

            The supply of IGIV has been tight for several years.  In addition, the amount used by other disorders has been increasingly substantially, further adding pressure on the supply of this lifesaving treatment for patients with primary immune deficiency.  Measles is a serious disease and the protection of our patients from measles via immunoglobulin replacement is highly desirable but it is only one of a myriad of infectious diseases against which our patients need the protection afforded by this treatment.

            If new loss of IGIV or IGSC products are rejected because this single specificity is below the potency standard originally established for IM that was given in much lower doses than currently possible with IGIV, we fear shortages of these products would inevitably occur.  This could then result in infections with many other organisms with predictable consequences for patients with antibody deficiency.

            In addition to these supply issues, we're encouraged that the levels of measles immunization in the general population has been sufficient to keep herd immunity high enough to prevent epidemic outbreaks of measles during recent years in this country.  Certainly the risk that a primary immunodeficient patient would encounter, wild type measles is much lower than their risk from other agents that are not part of the potency standard.  And we also encourage CBER to continue efforts to define the specificities of different antibodies in the products.

            We therefore urge that the BPAC accept the recommendations of the CBER staff to lower the potency standard for anti measles antibody in preparations of IGIV and IGSC.  IDF further urges the CDC to continue its surveillance program for outbreaks of wild type measles in this country.  Efforts must continue to determine whether patients with primary immunodeficiency are among the cases reported and, if so, determine the immunoglobulin replacement status of those patients.

            We're pleased that CBER is maintaining the current measles standard for the IM preparations and we feel that it would also be beneficial to our patient population if CBER could consider the feasibility of having available preparations of immunoglobulin that are manufactured, IGIV that are manufactured, to contain higher than standard titers of anti measles antibody and some other specificities as well for short term use by patients who need to travel to areas of the world where these infectious diseases are endemic such as Africa or the Middle East.

            We would also like to see continued and expanded research to more fully understand the roles of the various components of the immune system in protection against measles to help clarify the relative risk to patients with antibody deficiency, cellular immunodeficiency or combined forms of immunodeficiency.

            Also I forgot to say at the beginning that I personally have no conflicts.  But the Immunodeficiency Foundation does receive unrestricted educational grants from many of the companies that produce immunoglobulin.  Thank you.

            CHAIRMAN SIEGAL:  Thank you very much.  Is there anyone else who wishes to make a statement during the public part of the meeting?  If not, we'll proceed. Thank you very much.

            Now we need to address our questions.  You can all read them.  The first question is do committee members concur with the FDA proposal to lower the minimum measles antibody specification as described.  Is there discussion on this matter?

            MS. ELGIN:  May I?

            DR. SZYMANSKI:  I would like just to bring up a couple of issues.  We discussed here.  We learned that about 60 percent of patients who receive immunoglobulin receive it not because they are incompetent and the measles antibody I don't think matters in those cases.  So any level of measles antibody would be fine to treat those individuals.

            Now I think the Swiss presentation sort of was quite convincing that even if you lower the antibody level even more than it is proposed now the patients were not at the risk for measles in even incompetent patients.  So I think it seems to me that it does not present a great danger if you lower the level to 0.48 from 0.6.  I just wonder what anybody else is thinking.

            DR. EDWARDS:  May I?  On this same question, I have actually a burning question.  First of all, in answering the question, I felt that from the presentations and the literature that we've had so far that there is no reason why we shouldn't lower it to the 0.48.  But my question and I'm hoping that someone in the audience if not my colleagues here around this table might answer this question.  As we've seen, we're saying that we get better vaccine from those who have had the disease naturally and the question that keeps coming to my mind is that while we have seen less incidence here in the U.S. and therefore don't have the numbers here that have natural measles and therefore can't develop vaccine from that, why is that we're not talking about developing vaccine from those countries where we still see measles as a major disease there and occurrence in that population?  Is there any specific reason why we're not going outside of the U.S. for that herd immunity that we talk about?

            DR. GOLDING:  I think -- Well, the issue there is collecting plasma outside the U.S. and there is a whole host of problems for doing that that we only accept products that are made from U.S. licensed plasma because of the way that donors are deferred and infectious disease risk from those donors.  So I'm not saying it's impossible, but it is huge problem to ask for non U.S. plasma to be used.  What would have to happen is that in countries where they have high titer measles antibody you would have to have plasma centers that then could get U.S. licenses in order to collect the plasma and then ship it to the U.S.  It's not impossible but extremely difficult.

            CHAIRMAN SIEGAL:  Are there any other comments concerning this?

            DR. DI BISCEGLIE:  Just a question.  I don't see -- I'm in agreement with the idea of lowering the measles antibody specification.  But I'm not sure about the number, 0.48.  Is there some basis for that and why that?

            DR. GOLDING:  There's a lot of mathematical calculations based on what a protective  titer would be.  But starting from a protective titer of 120 IU/mL, what we found and what I presented is based on pharmacokinetic calculations.  You would expect that if you dropped the titer to 0.48 you dropped the lot release requirement instead of 0.6 to 0.48 of the standard, you would end up in practice of having immunoglobulin preparation that if you gave them at 400 mg/kg which is probably from a point of view of the standard the lowest dose you would end up with a trough level that's, if our calculations are correct, around 240 mIU/mL which is twice what we think is the protective level.

            Part of our thinking is that in the immune deficient population, we don't have data to know what is protective in that population.  We heard from several speakers that T cell immunity may also be important.  So we want to have a margin of safety here for that population.  So some of this is -- A lot of this is based on estimates because we don't have the data.

            We saw today from CSL with very high trough levels which we're going to ask, being a continued discussion with them and try to look at that data more carefully.  But based on what we knew going into this meeting, the 0.48 level seemed to us a reasonable estimate.  It also means that based on all the lots we've been looking at over the last few years that 100 percent of those lots would pass the lot release test.  So it ensures from the point of view of the FDA both having continued supply without problems of lots failing and at least double the protective level in the lowest dose that is used clinically.

            DR. DI BISCEGLIE:  A follow-up if I might.  Is that okay, Mr. Chairman?  Sorry.  So by choosing 0.48 given that the titers are failing, might we be facing a similar hearing five years from now to say we can't keep up any longer?

            DR. GOLDING:  I think that is possible and I think we can look into those calculations.  But I think there is the one way of addressing that which is saying you have to give higher doses.  But there's a problem with that because there's cost involved and there's also availability involved with higher doses.  So if the titers continue to fall, we could end up five years from now that 0.48 is not sufficient.  But we may be --

            DR. DI BISCEGLIE:  So it's incumbent on I think maybe both the agency and the manufacturers to prepare for that now by getting some of the data that might support saying we can go even lower or we cannot go lower.

            DR. GOLDING:  Well, I agree with you, but I think one of the things we have is in the question is to ask -- One of the questions is to actually do pharmacokinetic studies, asking the manufacturers to do studies to get actual data and to then compute that and then look at that in terms of the falling titers and see maybe there is a more realistic number for the next five years.

            MS. BAKER:  I had some questions for Dr. Baker and the other manufacturers.  You had mentioned that when some lots seemed to be in danger of failing that you have a policy to ship them overseas and I'm wondering -- I didn't hear you clearly.  If you could clarify.  Is this something that is currently occurring?  At what antibody specification do you make a decision to ship overseas?  How often has this occurred?  When did it start?  In what proportion of the lots has this occurred?

            DR. BAKER:  Sure.  I can answer that.  In terms of the lots that have failed, we have had one and it was marginal failure.  I think I took the question in a more hypothetical sense that if we have a large number of lots failing what could we do and in a hypothetical sense since we don't have a requirement that is similar to the measles antibody and titer we could divert those products to Europe or to use as European production.  But the reality is there has been a grand total of one and it was just at the margin.

            CHAIRMAN SIEGAL:  I have a question for the FDA actually.  Dr. Epstein perhaps.  I just want to know whether there's a absolute requirement that we use measles antibody levels for certification of this product in the long run or could that be changed and therefore sidestep the whole issue in the long run?

            DR. EPSTEIN:  Okay.  Well, the answer, first of all, the regulations require a titer for intramuscular immune globulin.  It has been a policy and consistent practice to apply the same titer and principle to the intravenous and subcut preparations but that's not actually in the regulations.  Whether we need to maintain that policy is up to us and the Director of CBER has discretion where to set the threshold for lot release if we maintain that.

            But I think your question leads to your suggesting do we need this at all which was your opening remark and I guess that's a question we could ask this committee.  Is there the sense that this is playing a protective role or not?  And I guess having heard Dr. Moss' presentation the question arose in my mind in the following way.  If you believe the monkey data that the natural history is essentially identical from an immune deficient to an immune competent subject as long as there's cellular immunity intact.  What does that suggest?  It suggests that if you didn't have this titer in the product you wouldn't be putting at risk the immunodeficient patients who have cellular immunity.

            Conversely, if you do have deficient cellular immunity, the question is whether given a replacement to achieve titers that are less than associated with sterilizing immunity, that is to say, prevention of infection plays any role at all and I think what we saw here is that although a large of proportion of subjects who get these higher replacement levels exceed roughly 1,000 mIU/mL or 1 IU/mL that at the projected lower titer, in fact, you don't expect very many to be anywhere near that level.

            So the point is in actual practice we're not giving patients enough product to get sterilizing immunity which raises the question of whether we're actually benefitting the people who are cellular immune deficient.  So I think what's really going on is that the PID population is being protected by the herd immunity of the general population and there's rather an open question whether the low level replacement compared to sterilizing immunity places any role, whatever.  In a certain peculiar way, that suggests to us that we can be a little bit less worried about lowering the titer because its punitive benefit may not be an actual one.

            CHAIRMAN SIEGAL:  That's clarifying.  Thank you.

            DR. EPSTEIN:  Sorry.  I know it was a little circuitous.

            CHAIRMAN SIEGAL:  No, it was very good.

            DR. EPSTEIN:  But I'm trying to assimilate a lot of results here.

            DR. CRYER:  It seems to me that with taking all the data today that we've heard that it's pretty clear that we could support a yes to No. 1 and not really worry about it again unless one of three happened and the three things would be that some of the donated units start falling below the 0.48 level.  The second would be that some of the people getting those units started getting measles.  And the third would be that the epidemiologic studies start to show penetrants into the population who have been immunized when there are some of these sporadic outbreaks.  So it seems to me -- I mean this seems pretty clear cut from a commonsensical point of view.

            DR. GLYNN:  But I think that also brings the question of travel in those patients.  So what is usually done when someone with immunodeficiency is going to be traveling.  Do you give them a dose just before they travel?  What's the usual practice?

            CHAIRMAN SIEGAL:  Well, in practice, you can simply up the dose.

            DR. BERGER:  I think if a patient with an immune deficiency who is maintained on immunoglobulin replacement is going to travel most of us would probably give that patient a dose before they departed.  But it also raises questions about how long they're going and can they get a dose while they're overseas and so on?

            DR. GLYNN:  And do you think your practice would change if we decreased the dose of the titer or you would just give --

            DR. BERGER:  Well, if somebody is going to -- It also depends -- It's not totally clear to me that if we vote to advise the FDA to carry out positively on question one whether we're also going to change the specification for IM.  Because if we don't change the specification for IM which is not indicated, then you may say if you're going to a measles endemic place, take an IM dose before you go.  So that possibility would remain open as would the possibility of giving a higher IV dose before they go or subcu and ask for a subcu dose or something like that.

            DR. GOLDING:  I just wanted to add, the IM, we would think might be used for normals.  But the problem with IM is the same.  We're going to have to deal with it separately.  We are going to have to deal with the titers are falling down in the IM as well.  So it's not necessarily going to be a solution.

            CHAIRMAN SIEGAL:  Last comment I hope.

            DR. FINNEGAN:  You're not going to like the comment.  I am very concerned that we are being asked to answer a question for which we have been given almost no scientific data for a problem that is still theoretical although it is approaching and for people who are significant risk of dying if, in fact, we guess wrong.  And I think we're setting a precedent that really concerns me.  I mean I have not heard good scientific data today I don't think.

            CHAIRMAN SIEGAL:  Further comments?


            DR. KATZ:  My only response to that is that IVIG in particular and "subcu" immunoglobulin are used for important things than measles now and to start losing lots over the risk of measles as somebody who has to ration intravenous immunoglobulin from our distribution hub pretty much constantly for several years I don't measles to be the reason that I have to tell somebody they can't some.

            DR. FINNEGAN:  But are there other ways of handling it besides dropping down to 0.48?  In fact, the woman for Immune Deficiency said can we have a higher level if we're going to travel.  Can you have a lower level that you just put on that does not work for measles?

            DR. KATZ:  I think that gets to question three which I hope we'll have time to discuss as a separate kind of --

            CHAIRMAN SIEGAL:  Well, I'd like to get a vote on this question first and I'd like to go around the room.  So I'm asking people whether they agree or disagree.  Let's start with Mel Berger.

            DR. BERGER:  I agree.

            EXECUTIVE SECRETARY JEHN:  So we'll go around the table here.  So Dr. Berger, you're a yes.  Dr. Ballow.

            DR. BALLOW:  Yes.

            EXECUTIVE SECRETARY JEHN:  Dr. Colvin.

            DR. COLVIN;:  Yes.

            EXECUTIVE SECRETARY JEHN:  Dr. Cryer.

            DR. CRYER:  Yes.

            EXECUTIVE SECRETARY JEHN:  Dr. Di Bisceglie.

            DR. DI BISCEGLIE:  Yes.

            EXECUTIVE SECRETARY JEHN:  Dr. Edwards.

            DR. EDWARDS:  Yes.

            EXECUTIVE SECRETARY JEHN:  Dr. Finnegan.

            DR. FINNEGAN:  No.

            DR. GLYNN:  Yes.

            EXECUTIVE SECRETARY JEHN:  Dr. Glynn, yes.  Dr. Quirolo.

            DR. QUIROLO:  Yes.

            EXECUTIVE SECRETARY JEHN:  Dr. Schreiber.

            DR. SCHREIBER:  Yes.

            EXECUTIVE SECRETARY JEHN:  Dr. Szymanski.

            DR. SZYMANSKI:  Yes.

            EXECUTIVE SECRETARY JEHN:  Dr. Whittaker.

            DR. WHITTAKER:  Yes.

            EXECUTIVE SECRETARY JEHN:  Ms. Baker.

            MS. BAKER:  Yes.

            EXECUTIVE SECRETARY JEHN:  Dr. Siegal.

            CHAIRMAN SIEGAL:  Yes.

            EXECUTIVE SECRETARY JEHN:  Opinion from Dr. Katz?

            DR. KATZ:  Yes.

            CHAIRMAN SIEGAL:  Let's proceed to the second question for which we need to vote as well.  CBER is considering requesting additional studies to confirm that primary immune deficiency patients will achieve trough levels of measles antibodies above 120 mIU/mL if treated with IGIV and IGSC products that meet the proposed revise potency standard of 0.48 times the CBER standard.  Do the committee members agree that this information is needed?

            DR. FINNEGAN:  I think a preliminary study before that is what exactly is the level that's needed to prevent infection because I don't think anybody knows.  It's somewhere between, it looks like, 200 and 1,000, but nobody seems to know what the real level is.  So I would say that a more basic step would be that.

            CHAIRMAN SIEGAL:  Mel.

            DR. ALLEN:  I think that data like the data presented by Dr. Zenker is achievable and so if we had data comparing the titer and lots that patients were given at least with the trough levels, if not, the formal pharmacokinetics of the whole pharmacokinetic curve, then it would be possible -- We would be on much firmer ground to make a mathematical extrapolation that any given titer in the product this and this trough level would be achieved.  So that's something that when we have to revisit this five years from now or if the data that she just talked about were available one could at least make a mathematical projection of what titer in the product would give a trough titer in the patient that would be satisfactory.  And that data is certainly available from patients being treated now.  You just need a sample of the lot they're given and a sample of their trough level.

            DR. GLYNN:  I think it would be really important to those data because everything we've seen are just simulations.  So I think we need to actually check that the numbers pan out the way we thing that they would.

            CHAIRMAN SIEGAL:  From what we've heard Dr. Epstein and from what we've been thinking about it, it strikes me that part of the problem is that the really susceptible population are the kids with combined immune deficiency and others with C-8 deficiency and things of that sort for which there are no data at all.  And that really probably what we need to do for populations like that is to provide sterilizing protective antibody immunity and it's clear that you need much higher titers than the FDA standard proposes to achieve that so that if we're going to look at that, we might be looking to do this with specialized immunoglobulin preparations that are exceedingly high titered.  You can't do that with the IM stuff because you just can't give enough.  So IM immunoglobulin was traditionally protective against measles because it modified measles in healthy adults really.  Isn't the genesis of the standard?  And that wouldn't apply to a kid with severe combined immune deficiency actually confronted with the virus I think anyway.

            But I personally agree that we should do -- we should find out what actual peak and trough levels are and that would be a useful and relatively simple study to do and it's already been partially provided to us.  Other comments?  If not, we can go around the table again.

            DR. QUIROLO:  I have just one question for you.  I don't give IVIG.  So on the label or in the insert, does the manufacturer state what the antibody levels are?  Is there some way to find out?

            CHAIRMAN SIEGAL:  I haven't read a package within 30 years.

            DR. QUIROLO:  Would it help you, would it help the clinician, to know because I noticed that in one of the papers there was a huge difference between the manufacturing processes as to how much antibody there were in each of these different products?  So would it help the clinician to know whether the titers were in these products?

            CHAIRMAN SIEGAL:  It would but it's never provided and, of course, as has been pointed in this meeting, there are other titers which would be much more helpful than the measles titer because measles hasn't been our clinical problem the way pseudomonas antibodies would be or other encapsulated bacteria antibodies and so on.

            All right.  So let's go around the table.

            EXECUTIVE SECRETARY JEHN:  Before we go around the table, I just want to summarize the first one.  It was 13 yeas and one nay.

            For question two, Dr. Berger.

            DR. BERGER:  Yes.

            EXECUTIVE SECRETARY JEHN:  Dr. Ballow.

            DR. BALLOW:  Yes.

            EXECUTIVE SECRETARY JEHN:  Dr. Colvin.

            DR. COLVIN:  Yes.

            EXECUTIVE SECRETARY JEHN:  Dr. Cryer.

            DR. CRYER:  Yes.

            EXECUTIVE SECRETARY JEHN:  Dr. Di Bisceglie.

            DR. DI BISCEGLIE:  Yes.

            EXECUTIVE SECRETARY JEHN:  Dr. Edwards.

            DR. EDWARDS:  Yes.

            EXECUTIVE SECRETARY JEHN:  Dr. Finnegan.

            DR. FINNEGAN:  Yes.

            EXECUTIVE SECRETARY JEHN:  Dr. Glynn.

            DR. GLYNN:  Yes.

            EXECUTIVE SECRETARY JEHN:  Dr. Quirolo.

            DR. QUIROLO:  Yes.

            EXECUTIVE SECRETARY JEHN:  Dr. Schreiber.

            DR. SCHREIBER:  Yes.

            EXECUTIVE SECRETARY JEHN:  Dr. Szymanski.

            DR. SZYMANSKI:  Yes.

            EXECUTIVE SECRETARY JEHN:  Dr. Whittaker.

            DR. WHITTAKER:  Yes.

            EXECUTIVE SECRETARY JEHN:  Ms. Baker.

            MS. BAKER:  Yes.

            EXECUTIVE SECRETARY JEHN:  Dr. Siegal.

            CHAIRMAN SIEGAL:  No.  I'm just being contrary.  Now the last question is please comment on the need for -- I'll change my vote by the way.

            Dr. Katz.  I'm sorry.

            EXECUTIVE SECRETARY JEHN:  He's not a vote, but it's just an opinion.

            DR. KATZ:  My guts tell me that we can talking about measles and IGIV in the United States, but I think it's hard to argue against getting this data because the PK data is relatively easy.  Trying to define the correlates of protection and immunity

I don't think we have a clue and I think while 120 correlates with something.  That does mean it's the cause.  So I'm not sure how far in a time of virtually zero incidents in the U.S. we can go toward defining what immunity really is.

            CHAIRMAN SIEGAL:  And again, in the Chen study from which that number is derived, that was done in healthy adults, not in kids without CD-8 cells.

            Okay.  So please comment on the need for and feasibility of any alternative strategies that CBER could consider to reduce the likelihood of failed lots of IGIV and IGSC based on potency testing for measles antibodies in order to ensure availability of product for primary immunodeficiency patients.  Mark.

            DR. BALLOW:  I have to assume that there is variability from lot to lot, that some lots have higher levels than other lots because from what we've heard there are lots of failed and they are either discarded or they are sent to Europe or elsewhere.  And I and my colleagues have been pushing actually to look another group of antibodies and that is antibodies to pneumococcal polysaccharides because this causes significant clinical disease in this group of patients.  And one day we hoped that the bottle would actually be labeled as to their antibody content with regard to some of these important antibodies again particularly pneumococcal polysaccharides but one could do it also for measles antibodies.  So therefore one can visualize on the shelf.  I know this will be distribution nightmare, but one could visualize that you would have bottles on the shelf where you know the titers of measles and you know the titers of pneumococcal antibodies and therefore you could utilize those particular lots for patients with primary immune deficiency disease where it's important to have appropriate antibody titers to protect those individuals and use the other lots for off-label.

            DR. BERGER:  I would also like to support this idea.  In the workshop, several examples were brought up not only about pneumococcus but about, for example, the problem of chronic Enteroviral Meningoencephalitis in Bruton's patients and so on and it's easy to see that the issue raised now about measles because measles is the one that's written into the law we're going to face the same issue with Varicella zoster for example and that's going to be much harder to control natural exposure because people will get Shingles unless there's incredibly high penetration of the new zoster vac.

            So I would suggest two things at least be considered some time in the future.  One is the idea of having some sort of agreed upon assays and labeling lots or product according to their antibody content against a variety of diseases and then the second issue was raised which Mark also touched upon is the issue raised by the tremendous use of IGIV for "off-label uses."  And it sounds very funny to say should we label some of the lots to be used only for off-label use but, in fact, we could label them for use in ITP.  Several of the products are labeled for ITP.  Of course, we have very little --

            I think one of the most impressive things out of the workshop and this session today is how little we know about IVIG or IGG products and how they work in the patients and however little we know about it in PID patients is a lot more than we know about it in the autoimmune and neurological diseases that actually constitute the majority of the use.  But at least an interim strategy or as a strategy at some point in answer to issue number three is to consider the potential of labeling lots as not for use in PID. Then those lots could still be on the market and could be used for other indications.

            CHAIRMAN SIEGAL:  I hope we're taking notes on this.

            DR. CRYER:  Yes, I have a similar comment.  I think if I have the process down right, then all of these units have to be measured anyway.  So it's just a matter then of recording the antibody levels for the various things on each unit.  I think what that allows is even if you didn't begin selecting out units for certain things at the beginning you would at least have a registry that allowed you to correlate the levels of individual antibodies with the outcomes in specific patients that you could then make generalizations on later about what you need to do.  If you're already doing it anyway, it's just a matter of writing it down and sticking it on the bottle or the bag.  It seems pretty simple to me.

            CHAIRMAN SIEGAL:  Dr. Szymanski.

            DR. SZYMANSKI:  We voted yes for the number two, but even it's difficult to do the study unless you know how much antibody you have.  So even for that purpose you had to have measured level in the bag to know how much to increase the titers.  So labeling is important.

            CHAIRMAN SIEGAL: I think one of the things we don't know at all, really, is how much variation there is in the repertoire from one batch of gamma globulin to the next except insofar as the subclass changes from one manufacturer to another which is documented in one of the papers that we received.

            DR. COLVIN:  As a small aside, something else from the FDA, if you look at how the labels are on bottles like this, that tells us exactly how much vitamin A.  It sort of makes sense to me that we would do the same thing in the case where it might actually have a real impact as opposed to drinking this.

            DR. DI BISCEGLIE:  A little off track, but I think perhaps important for the Agency to consider is one of the uses of I think the intramuscular preparation is post exposure prophylaxis of Hepatitis A and the Agency may know the answer and I don't need a response from them but I suspect that the titers of antibody to Hepatitis A in lots are declining as with measles and it's something that I think should be looked at.

            DR. YU:  We do have some data which is not yet published and the HAV levels indeed are a little bit low and also depends on type of plasma, if it's source plasma or versus recovered plasma.  So recovered plasma a little bit lower.

            DR. GOLDING:  Can I just mention that in reference to a previous remark that in the Audet paper that is part of the handout sheet, they studied 166 lots from seven manufacturers and the mean values or the standard deviation are given there and they are close to a threefold difference between the lowest levels of measles titer and the lowest -- lots with the lowest levels to the highest levels.  It's about a threefold difference.

            CHAIRMAN SIEGAL:  But we don't know the pneumococcal antibody titers for Type 3 Pneumococcus for example in those same lots, do we?

            DR. GOLDING:  No.  I thought you were talking about measles.

            CHAIRMAN SIEGAL:  I'm thinking in general about the heterogeneity of antibodies that ones find in a given pool and how that ends up in gamma globulin and how different each lot is with respect to that because we're really -- I mean gamma globulin is essentially a black box and for off-label uses it's certainly a black box unless we're talking about how much anti-big D there is or how much isoglutinin there is at random there.  But we don't even understand how it works as was pointed out, and for most of the off label uses.

            DR. GOLDING:  We agree with you and there was a paper published by the FDA by my group which looked at titers of H. flu and Strep pneumoniae among a large number of lots from different manufacturers.  So there was a paper last year where we looked at that, but we have been talking to the manufacturers to try and encourage them to develop their assays and to use those assays for PK studies to try and get to the point that I think you're aiming at and we have the same goal.

            DR. BALLOW:  One thing we haven't talked about is education.  So if we move forward with this, I think we have to educate at least those individuals who use gamma globulin and patients with primary immune deficiency disease to make them aware that there are circumstances like travel abroad or mini epidemics that might come along in certain geographical areas to be aware that they have to increase the dose or give extra doses of gamma globulin in order to protect our patients based on some of the data that we've heard.  I think a lot of my colleagues probably don't appreciate that at this point.  So there may have to be some education or maybe an addendum to the package insert of these products.

            CHAIRMAN SIEGAL:  One strategy that we could use as clinicians is just to send off titers for 14 serotypes of pneumococcus in our patients and see what we're getting.  All right.  Are there any other comments in this third question?

            DR. QUIROLO:  I think your statement underlies the fact that there should be labeling for the titers because the clinicians say who was in a measles epidemic would know which product to use.  If you have no idea what you're giving, how can you decide whether you're going give 400 or 800 mg of product that maybe has a low titer?

            DR. BERGER:  In all fairness certainly seeing a higher titer might lead you to use a certain product in a certain situation, but as we also see with measles, understanding the correlate of a titer done with any given assay doesn't necessarily directly translate into predicting the clinical efficacy of that preparation.  So this whole issue, I think, is a little bit more complicated than just measuring titers by ELISA and putting them on the bottle like the vitamin level.

            CHAIRMAN SIEGAL:  Anyone else?  All right.  Dr. Epstein, do you have any other comments or needs from us?

            DR. EPSTEIN:  No.  I wanted to make a very small comment in the current context because the question was asked about is 0.48 times CBER standard good enough for the future looking forward five years or ten years from now and we have a little bit of information about that which is the neutralizing titer of plasma pools in the birth cohort 1968 to 1972.  That's close to 40 years post vaccination and there is gravitation toward a level of 1 IU/mL or 1,000 mIU/mL in the pool which correlates with the level that Dr. Golding said is what you would need in order to end up with projected trough titer of 120 per mL in the recipient. So I think that suggest to us that it is in fact a level that would remain robust over time.

            But I couldn't agree more that if we have actual studies on administered dose and trough levels obtained, we'll be in a much better position to predict where things will end up.  But that's just a small comment in the larger context.

            I appreciate the deliberation of the committee and I think that FDA has obtained the feedback that we need to go forward.

            CHAIRMAN SIEGAL:  In that case I thank you all for coming and this meeting stands adjourned.  Off the record.

            (Whereupon, at 4:29 p.m., the above-entitled matter was concluded.)