This transcript ahs 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.





























Friday, June 20, 2003


8:30 a.m.













Hilton Gaithersburg

620 Perry Parkway

Gaithersburg, Maryland




Kenrad E. Nelson, M.D., Chairman

Linda A. Smallwood, Ph.D., Executive Secretary



    James R. Allen, M.D.

    Charlotte Cunningham-Rundles, M.D., Ph.D.

    Kenneth Davis, Jr., M.D.

    Donna M. DiMichele

    Samuel H. Doppelt, M.D.

    F. Michael Fitzpatrick, Ph.D.

    Jonathan C. Goldsmith, M.D.

    Harvey G. Klein, M.D.

    Daniel L. McGee, Ph.D.

    Paul H. Schmidt, M.D.



    Robert J. Fallat, M.D.



    D. Michael Strong, Ph.D.



    Liana Harvath, Ph.D.




III.  Discussion on Recovered Plasma


     A.  Introduction and Background

         Elizabeth Callaghan, MS, SBB (ASCP)              5

     B.  Presentation

         Robert Lunsford, ZLB Bioplasma                     10

     C.  Presentation

         Kay Gregory, AABB                                 18


Open Public Hearin

  Mary Gustafson, PPTA                                     46

  Paul Holland, M.D., Blood Source, BCA America            51


     D.  FDA Current Thinking and Questions for

         the Committee

         Elizabeth Callaghan                               78


     E.  Committee Discussion and Recommendations      84


IV.  Vaccinia Immune Globulin Intravenous

Current Thinking and Indications for



     A.  Presentation

         Dorothy Scott, M.D.                           133


     B.  Committee Discussion                         168


    DR. SMALLWOOD:  Good morning.  Welcome to the second day of our committee meeting.

    I am Linda Smallwood, the Executive Secretary.  Yesterday, I read the conflict of interest statement that applies to this meeting.

    In the interests of fairness, I would like to ask if there is anyone on the committee or any speakers or participants that would like to make a declaration at this time regarding any potential conflict of interest, please do so.

    If not, if you are speaking and if you do have such a conflict, please do so prior to giving your presentation.

    We will attempt to follow the agenda as printed.  Just a reminder to all speakers that we do have a timing device to assist you in your presentation.

    At this time, I would like to turn over the proceedings of this meeting to the Chairperson, Dr. Kenrad Nelson.

    DR. NELSON:  Thank you, Dr. Smallwood.

    The first item on the agenda is a discussion of recovered plasma.  To introduce and give background, Elizabeth Callaghan.

III. Discussion on Recovered Plasma

A.  Introduction and Background

    MS. CALLAGHAN:  Good morning.  In reference to Dr. Klein's comment yesterday, we are going to be asking the committee to advise us on several issues concerning the development of standards for recovered plasma, so be careful what you ask for.


    I would like to give you a little background on recovered plasma before we get into where we are now and what the questions will be.

    Recovered plasma is a byproduct derived from whole blood collection.  This is how it has been made routinely. It is distinguished from source plasma by the mode of collection and the requirements for testing, storage, pooling, dating, and labeling.

    Recovered plasma is not a licensed product.


    The storage and shipping conditions are dictated by short supply agreements between the recovered plasma manufacturer and the consignee of the product.  Because it is not a licensed product, and in order to be shipped in interstate commerce, the short supply agreements have to be in place.  That is in 21 CFR 601.22.

    Part of the short supply agreements include time to freezing.  This is an agreement between the manufacturer and the consignee as to what type of product and what kind of product they are willing to accept.

    The standard practice of industry is usually a product frozen within 8 hours or within 24 hours, and these are products that are usually used to make Factor VIII, or frozen within 120 hours, and this is used routinely to make IGIV.


    To emphasize the lack of regulations for recovered plasma, there are only four cites in the CFR that recovered plasma is mentioned.  One is in the Standing Operating Procedure section, which if you make recovered plasma, you have to have standard operating procedures to say how to do it.


    There is a section in the labeling that says in lieu of an expiration date, you must put the date of oldest product on the label.  There has to be a caution statement to distinguish products that are made for further manufacturing to injectable products or non-injectable products.


    For recovered plasma that cannot be made into a licensed product, you have to have the statement, "Not for Use in Products Subject to Licensure Under Section 351 of the Public Health Service Act."


    There are two cites under Records.  One says if you make recovered plasma, you have to have records as to how you did it and when you did it.

    Everybody's very best favorite, because there is no expiration date, records have to be retained indefinitely.  I have visions of people who have been making recovered plasma for many years having a warehouse of molding records forever, I can imagine.


    Because of the lack of regulations, there have been many compliance issues over the years regarding recovered plasma.  They include misbranding of the units, lack of shipping and disposition records, inadequate quarantine and destruction of unsuitable units, shipment of untested units, therapeutic units, and autologous units which do not meet all normal donor suitability requirements.


    Lack of short supply agreements, lack of product quality and consistency, that is, storage temperatures that are not correct, or preparation of the products are inappropriate, non-uniform labels, registered facilities who do not ship product over state lines do not have to send their labels to CBER for review, so these people are now making recovered plasma and because they are short supply agreements, they can ship it in interstate commerce, but we don't see the labels, so there have been some really novel things that have shown up including labels that are incomplete or inaccurate.


    In contrast, source plasma is a licensed product, and it does have a dating period, which is 10 years, and it has very specific regulations regarding the collection, labeling, storage and shipping.


    Irrespective of this, both recovered plasma and source plasma may be further manufactured into the same final products, Factor VIII, IGIV, and IVD products, et cetera.


    In light of there concerns, and the lack of standards, on June 13th of last year, we asked the committee if we should go forward with developing standards for recovered plasma.

    The committee voted unanimously in favor of developing standards for recovered plasma.

    After hearing several of the presentations from the industry, the committee also suggested that we find an alternative name that does not have a negative connotation, that being recovered plasma has a negative connotation.

    The committee also suggested that FDA find a way to allow FFP that was collected by apheresis to be converted to recovered plasma prior to the expiration of one year.


    So, where are we now?  FDA and industry have been working on developing standards all year.  We have had many meetings together and separately in order to do this.  You will hear two industry presentations as to what the basic standards should be.

    Recently, the plasma industry has proposed several standards, which has caused a lot of contention between the whole blood industry and the plasma industry, but I have heard as of yesterday, they have resolved this, so I am kind of happy we don't have to go into that today.

    After the industry presentations, I will give you the FDA's current thinking on this topic.

    DR. NELSON:  Thank you.


    That is the introduction.  Robert Lunsford, Director of Plasma Resources at the Plasma Protein Therapeutics Association.

B.  Presentation

Robert Lunsford

    MR. LUNSFORD:  I will correct that slightly.  I am with ZLB Bioplasma.  We are a member of PPTA, but I am not with PPTA.

    ZLB Bioplasma, Inc., provides a major source of intravenous immunoglobulin (human) - IGIV - and other specialty plasma-derived products in the U.S.  The company's focus is on helping the U.S. healthcare community improve the quality of life for patients by providing a steady supply of safe and effective immune-based therapies and related services.

    ZLB Bioplasma, Inc.'s affiliate, ZLB Bioplasma AG, develops and manufactures the plasma-derived therapies, using the plasma of U.S. donors, for its FDA licensed products.  ZLB Bioplasma AG, originally a laboratory of the Swiss Red Cross, has over 50 years experience in plasma fractionation.

    ZLB Bioplasma AG is a wholly-owned subsidiary of CSL Limited, a leading biotechnology and biopharmaceutical company founded in 1916 in Melbourne, Australia.

    ZLB would like to thank FDA for the opportunity to participate in this public discussion about recommendations pertaining to recovered plasma.  Manufacturers of plasma-derived therapies use as the starting material source plasma and/or recovered plasma to provide many lifesaving therapies, including, for example, IGIV, albumin, and coagulation factors.

    ZLB believes that recovered plasma which meets the current AABB standards and other equivalent regulatory standards is safe for use as a starting material for the manufacture of plasma protein therapies.

    However, ZLB supports FDA's efforts to develop regulations that will allow for the licensure of recovered plasma while continuing to support the constant supply of safe plasma for further manufacture.

    As such, the new regulations should not hinder the supply of safe recovered plasma by adding undue burden on the collection or manufacturing process.

    FDA currently has regulations in place that provide for the licensure of source plasma.  In the regulations, source plasma is defined as the "fluid portion of human blood collected by plasmapheresis and intended as source material for further manufacturing use."  FDA regulations do not currently provide a comparable definition for recovered plasma.

    Should FDA proceed in developing regulations pertaining to the licensure of recovered plasma, we strongly encourage the Agency to develop these regulations in harmony with existing U.S. and EU specifications already in place globally.

    FDA regulations for recovered plasma, if developed, should actually include all types of plasma for further manufacture.  In addition to source plasma, which is already a licensed product, new regulations should incorporate licensure provisions for recovered plasma, fresh frozen plasma, and concurrent plasma.

    Recovered plasma includes plasma separated from whole blood - that is in excess of the demand for fresh frozen plasma.  Any regulations should allow for specifications that are applicable to the finished plasma therapies.

    This includes plasma frozen less than 24 hours after collection, at a temperature of minus 20 degrees centigrade or colder, if cryoprecipitate is to be recovered. Some variation exists in accordance with current manufacturers specifications referred to in their short supply agreements.

    Recovered plasma also includes plasma frozen at a temperature of minus 5 degrees centigrade or colder within a period of 72 to 120 hours if cryoprecipitate is not recovered.

    Individual manufacturers have specifications for the temperature storage requirements written into the licensure for their finished products, for example, the requirements may be for storage at minus 5 degrees centigrade, minus 18 degrees centigrade, or minus 20 degrees centigrade or other variables.  To provide harmony with existing EU standards, we recommend that plasma be frozen and stored at minus 20 degrees centigrade.

    There is currently no clear specification as to how long recovered plasma may be held before manufacture.  At present, individual manufacturers have specifications written into the licensure for their finished products. Typically, the range is at least two years or greater.  ZLB defines the shelf life in our EU Plasma Master File as three years.  Therefore, new regulations should include provisions that account for this variability.

    Fresh frozen plasma is plasma frozen in less than 8 hours at minus 18 degrees centigrade or colder.  At present, regulations do not allow for the conversion of fresh frozen plasma to a licensed plasma for further manufacture.

    It is important to allow for fresh frozen plasma to be converted when all other requirements are satisfied, for example, the original fresh frozen plasma may have to be stored at minus 20 degrees centigrade or colder.

    Concurrent plasma is plasma collected from volunteer donors by apheresis during the collection of red blood cells or platelets.  The plasma is suitable for transfusion, for example, as fresh frozen plasma.  New regulations should also include provisions that allow for the licensure of concurrent plasma as plasma for further manufacture if the material satisfies the other requirements for collection and storage.

    Based on the use of U.S. recovered plasma by FDA    licensed U.S. and European fractionators, we encourage the FDA to seize the opportunity to harmonize U.S. and EU standards, especially with respect to freezing and storage temperatures and times.

    Thank you for your attention.

    DR. NELSON:  Thank you.

    Any questions?  Harvey.

    DR. KLEIN:  Is there any scientific reason outside of harmonization with EU to ask for minus 20 degree storage?

    MR. LUNSFORD:  The difference between 18 and 20 is extremely minor, but since there are already specifications in place at minus 20, it seems logical that we grab this opportunity to go and harmonize.

    DR. KLEIN:  Is the same thing true for the 3-year outdate, is there any reason?

    MR. LUNSFORD:  Not really, 3 years, 10 years, either one would be more than adequate.

    DR. ALLEN:  Not a question for the speaker, but for some of our blood banking colleagues.  Is there equipment in place, as best you know, at most blood collection centers for freezing and storage at minus 18 and 20, or would that changeover require a significant upgrade of equipment for processing?

    DR. STRONG:  No, we have equipment for that. That is really the routine.  Fresh frozen plasma is the routine for transfusion, and it is stored at those temperatures.

    DR. FITZPATRICK:  You mentioned a number of differences between manufacturers even up to minus 5 degrees C for storage and in length of time of storage.  In the application to FDA, there must have been data to support the efficacy of the products that are made with product that has been stored for those periods and at that temperature.

    Are there differences in the manufacturing processes that would account for a difference in efficacy? If one manufacturers wants it stored at minus 20, and the other at minus 5, is there a difference in the manufacturing process that the temperature makes a difference for, or was it a matter of convenience and efficacy be about the same because the manufacturing processes are about the same?

    MR. LUNSFORD:  To the best of my knowledge, there is no significant difference in the manufacturing process that would account for the differences in temperatures.  I think it has more to do with historic methodology that the fractionators established going back in case of ZLB, 50 years.

    DR. EPSTEIN:  This gets a little bit ahead of the discussion, but I think that whereas that statement may be true for albumin and immune globulin, the issue of time to freezing and potentially the storage period based on temperature of storage, is not comparable for labile factors particularly clotting factors.

    So, I believe you have heard a correct answer for albumin and immune globulin, but I think the chapter is not written for any hemophilic factor.

    MR. LUNSFORD:   I am sorry, I should have been more clear.  For coagulation factors, definitely the shorter freezing time, in most cases 24 hours, in some cases I believe it is actually 18 is required in order to preserve the cryoprecipitate.

    DR. NELSON:  The next speaker is Kay Gregory from American Association of Blood Banks.

C.  Presentation

Kay Gregory

    MS. GREGORY:  Thank you and yes, it's me again.


    At its June 2002 meeting, as Elizabeth has told you, the Blood Products Advisory Committee discussed issues relating to recovered plasma, and the blood bank representatives provided you with information about problems with the current process of managing recovered plasma.

    After hearing those presentations, the committee voted to recommend that FDA develop specific product requirements for recovered plasma.


    Following these BPAC recommendations, the AABB Interorganizational Task Force, with representatives from the American Association of Blood Banks, America's Blood Centers, the American Red Cross, Blood Centers of America, and the Armed Services Blood Program began formulating ideas and on June the 6th of this year, 2003, we submitted a proposal to FDA concerning license requirements for recovered plasma.


    Just as a reminder, recovered plasma is the only blood component manufactured by FDA-licensed establishments that does not have direct FDA oversight.  Instead, recovered plasma is regulated through short supply agreements signed between the supplier of recovered plasma and the pharmaceutical manufacturers of plasma therapeutics.

    The concept of regulation by short supply agreements was created many years ago when plasma was literally recovered from expired whole blood.  This indirect mode of regulation is out of pace with FDA's more recent and extensive applications of cGMP's to blood establishments.

    Likewise, recovered plasma is no longer obtained from outdated whole blood.  In short, both the terminology and the regulatory process is woefully out of date.

    In order to assure the highest quality plasma for plasma therapeutics, the collectors of blood and blood components believe that recovered plasma should be licensed and should be subjected to the same regulatory scrutiny as plasma for transfusion, and let me also add that AABB already has existing voluntary standards that apply to recovered plasma.  Again, we will be working with PPTA to resolve any differences that we might have on those issues.

    Let me now turn to the specifics of our proposal to the FDA.


    As I said, we propose these as licensing requirements.


    We propose that the product should be named "plasma for manufacture."  This name reflects the intent of the product and doesn't reflect the manner of collection.

    You have heard that FDA proposes to use the term "component plasma."  Our concern with that is that traditionally, we have used the term "component" to imply or to state that this product is going to be used for direct transfusion, and we think this would be introducing just further confusion, so we really prefer "plasma for manufacture."


    In terms of donor qualification, we recommend that these qualifications should be the same as allogeneic whole blood, so note that this would preclude use of autologous plasma, therapeutic plasma, et cetera, some of those plasmas that Elizabeth alluded to having had compliance difficulties with.  So, we are really talking about someone who meets allogeneic whole blood requirements.

    We are also interested in being able to use plasma that is collected concurrently with cellular products for transfusion by apheresis or collected simply by apheresis and intended for plasma for manufacture.

    There is an existing memorandum from the FDA that was issued in March of '95 that is called, "Revision of FDA Memorandum of August 24, 1982: Requirements for Infrequent Plasmapheresis Donors."

    We would note that these requirements we would like to have applied to any of our donors that would be collected by apheresis either concurrent or simply by apheresis.  The major difference is that this specifies donation only every four weeks.


    Again, the methods of preparation for plasma for manufacture.  First of all is what you probably are well aware of, separating plasma from a whole blood donation. Sometimes we separate that and turn it into fresh frozen plasma for transfusion, but if we have enough fresh frozen plasma, we may choose to go ahead and directly separate that and use it for plasma for manufacture.

    Secondly, as I have mentioned, infrequent plasmapheresis where we are doing automated collection of cellular products for transfusion, not unusual to do this in terms of collecting platelets for transfusion and collect plasma at the same time that we could convert to plasma for manufacture.

    We would also like to be able to include infrequent plasmapheresis that is being collected for the purpose of manufacture.

    Finally, we would like to be able to convert plasma that was originally collected or prepared for transfusion, for example, fresh frozen plasma, and we would be able to convert that into plasma for manufacture without having to wait for the product first to expire as fresh frozen plasma.


    Some additional details about the method of preparation.  If we are separating it from whole blood, we would like to be able to do that anytime during the dating period for whole blood.

    Again, this will depend on what the plasma is going to be manufactured into, so it is quite likely that most of it would be separated immediately, but we would like the option to not have to do it immediately.

    Secondly, plasma for transfusion that could be converted to plasma for manufacture, we would request that that conversion could occur anytime during the dating period and up to one year after the outdate as a transfusible component, because remember as a transfusible component, fresh frozen plasma has storage requirements that it must be stored at minus 18, minus 20 already.


    In terms of expiration date, we have proposed two years from the date of collection because it was our understanding that this would give the fractionator enough time to be able to pool the product and do something with it.  However, these are our initial proposals and if there is a reason to match the European Union requirements or do something else, we are certainly amenable to discussing those.


    In terms of testing for infectious diseases, again, we would like to have the same requirements as for whole blood with the exceptions that already exist, and that is, we are not required to have a negative result for core, and not required to have a negative result for anti-HTLV I/II.


    There are a number of labeling requirements.  First of all, the product name, which we have already said we would like to see plasma for manufacture.


    Again, on the labeling, we would like to have a statement of the freezing time, something like frozen within (blank) hours after phlebotomy, and that blank could be filled in depending upon when you had done it, depending on what the product was going for.  I will talk more about that in just a minute.


    The current caution statement, that is, "Caution: For Manufacturing Use Only into Injectable Products."


    We would also like to have included the product code, and this could be from the uniform labeling guidelines, ISBT 128, whatever is an acceptable machine-readable bar code, but that is the purpose of the product code, is to be able to read it with some sort of an electronic means.


    Again, the amount of the product, so this could be the total volume or the weight of the plasma.


    For whole blood-derived plasma for manufacture, that which we have obtained from a whole blood donation, we propose the name and volume of source material, for example, "From 500 ml CPD Whole Blood."


    If the plasma has been collected by plasmapheresis or apheresis, the total type and volume of the anticoagulant used.


    Again, on the label, the storage temperature, and have proposed minus 18 or colder, and that number is simply because that is the current requirement for fresh frozen plasma, and many of our freezers are what we call minus 18 freezers.  They probably keep things at minus 20, but the alarm system is set for minus 18.  Again, we are willing to talk about that if that is a critical matter.


    Again, on the label, the facility identification,  the name, address, and license number of the collection facility, and the name and address and license number of the institution where it is separated if it is different from the collection facility.


    The statement about the testing that has been done, which would be sort of generic, that is, just negative by FDA required tests.


    The collection date would include the month, the date, and the year.


    A statement about component retrieval, which would be the same as required by FDA for source plasma or recovered plasma.  What we are talking about here is there are differences between when we have to go out a unit of whole blood or a transfusible component back and attempt to do something as opposed to the FDA requirement.

    For example, for CJD, there are some different requirements, and we would like to be able to follow those that are applied to source plasma or to the product currently called recovered plasma.


    In terms of recordkeeping, we propose that we would keep the records for 10 years, however, if FDA really wants 10 years and 6 months, that is probably not going to be a real sticking point either.


    In terms of freezing, if you will notice, we have not proposed a specific time frame for freezing because all of these products are made into different things, and we think that what we really need is a way for the manufacturer to be able to determine what did we do with this product, so we are suggesting that the time frame in which it was frozen should be on the label, so that the fractionator can tell what we did, but rather than saying it has to be within X amount of time, it depends on what the fractionator is going to do with the product.

    We think it is better simply to fill in the blank of what time it was frozen.


    Obviously, short supply agreements should no longer be necessary when plasma for manufacture is licensed.


    Also, currently, if you noticed, I said that the collection date would be on the recovered plasma label, and the preference I understand is to continue this practice, but it would also be acceptable to require an expiration date instead of the collection date when an expiration date is established for plasma for manufacture.

    Currently, we can't put an expiration date on it because there isn't one.


    A couple of additional considerations for when the product would be licensed.  We would like to be certain there is a grace period to use up the existing inventories that were manufactured under our short supply agreements.

    Secondly, especially for those facilities that currently are unlicensed and are not used to meeting license requirements in terms of submission to FDA, we would like to make sure that there is an expedited review and that we help these people out to get licensed for plasma for manufacture.


    Working together, we believe we can make it happen, and I think we already have established a precedent that the fractionators, FDA, and the blood bank collection industries have been working together to make it happen.

    Our proposal is that we would limit this to plasma intended for use in injectable products because we believe that the current labeling regulations are adequate for non-injectable products.

    Finally, we have provided a starting point, but we are available to have further discussions and we are certainly interested in harmonizing with EU if there is a reason to do so.

    Thank you.

    DR. NELSON:  Thank you, Kay.


    DR. SCHMIDT:  Kay, sort of one-third of the way through, you were mentioning collection by apheresis, and you mentioned four weeks.  What was the significance of the four weeks, no more often than four weeks?

    MS. GREGORY:  No more often than every four weeks, and that is what is specified in the FDA guidance as qualifying as an infrequent donor.  We are not suggesting that if we were collecting more often than that, we should be able to do that.  If we wanted to do that, we should be required to get a source plasma license.

    So, we are saying we want to stick to our current requirements.

    DR. SCHMIDT:  Do you know what the logic behind that is?  I don't.  Why was it defined that way?

    MS. GREGORY:  I have no idea.  Jay?

    DR. EPSTEIN:  This is because of the issue of patient protection.  Under the source plasma license, you have to do an annual physical exam and at each collection, you have to do a total protein and periodic serum protein electrophoresis.

    The concept here is that if the donor is apheresed only infrequently, that those particular donor safeguards can be waived.  So, that is the linkage.  So, we currently do permit waiver of annual examination, total protein, and serum protein electrophoresis if you have a source plasma donor, but you apherese infrequently.

    DR. WILLIAMS:  Kay, were the system that you describe, if it were in place, could you comment on what proportion of plasma collected by apheresis would be collected as FFP and then either used as FFP or converted versus the proportion that might be collected directly into a label, plasma for manufacture?

    MS. GREGORY:  Celso or Paul, do you know an answer to that?

    DR. BIANCO:  Currently, only about 20 percent of the plasma that is collected or that is from whole blood is converted into fresh frozen plasma, because those are the patient needs, and the remainder is shifted to recovered plasma currently, under the current settings.

    Some of the plasma that is collected for apheresis is converted for plasma for transfusion, particularly jumbo units that are 600 ml that are used particularly for TTP patients and plasma exchanges, and all that.

    Certainly, the blood collection facilities would then collect more plasma as concurrent plasma if they were allowed to ship these for further manufacture.  Currently, that is not the big practice because there would not be a useful purpose for that collection.

    DR. HOLLAND:  Paul Holland, Blood Source, a large regional blood center in Northern California.

    Again, we take virtually all of the plasma from the whole units of blood and make it into what we now call recovered plasma.  For FFP, we actually make it all by infrequent plasmapheresis because they are jumbo units, and that is what we use as our FFP.

    One of the problems, as you have heard, is that if you don't use it or you don't need it, you make excess, you must keep it for at least a year and even then it is difficult to convert it into recovered plasma at that time.

    But certainly, as Celso said, we would probably prepare more concurrent and more apheresis plasma if we had a place to send it, that is, for further manufacture.

    MS. GREGORY:  I think, Alan, one of the things is it is unlikely that we would be doing apheresis specifically to collect plasma for manufacturing plasma.  It is that we are doing it to collect FFP, and if we don't need to use that FFP for transfusion, we want to be able to, even if we didn't collect it concurrently with some other product, we want to be able to use it for plasma for manufacture.

    DR. HOLLAND:  If you want a number, Celso just reminded me we were collecting about 500,000 units of FFP at the moment by pheresis--I am sorry--of platelets, and we could make all or certainly a portion of those we could collect concurrent plasma.

    DR. NELSON:  Can't you do that now?

    DR. HOLLAND:  Well, we can, but if we do, we cannot send it for further manufacture, therefore, we are sort of stuck with it, we outdate it, and then we toss it, so this gives us another avenue to produce more plasma, which is needed, as well as better use of our donors.

    DR. NELSON:  I guess I am still confused about the regulations that would prevent a unit collected for FFP to be converted into recovered plasma since it is a short supply agreement and there aren't temperature requirements.

    DR. HOLLAND:  But it is defined, and Jay can tell you even better, basically, it is defined as the plasma from a whole unit of blood, which is then converted over.  You cannot, by definition, us concurrent plasma or apheresis plasma for this purpose, it is just precluded.

    DR. EPSTEIN:  It is because the regulations were crafted based on the concept of the intention at the time of collection.  So,if the intention at the time of collection was to make a transfusible product, it would have been seen as getting around the intent if you could immediately convert it to a product for further manufacture.

    What has been argued here is that that basis for the distinction has become obsolete.  It has also been argued that the basis of the distinction based on apheresis is obsolete since we make now transfusible components, as well as products for further manufacture by apheresis, and even sometimes concurrently.

    I wanted to just push back a little bit, Kay, on your statement that you wouldn't directly make plasma for further manufacture from whole blood donors in any greater extent than you now do if you could immediately make it at the time of collection, because there is also the economic incentive that starts to enter the picture.

    It is my understanding that the economic value of the products currently sold as recovered plasma is higher, and if we were to become permissive, making a highly similar product from a whole blood donor, wouldn't that be an incentive for whole blood systems to make more plasma for manufacture?

    MS. GREGORY:  Yes.  What I think I was trying to say was I don't know that we would immediately rush out and start doing a lot of apheresis.  It is possible that we would, but--

    DR. EPSTEIN:  I think we shouldn't presume that people wouldn't.

    MS. GREGORY:  Okay, I would agree with that.  It is entirely possible that they would.

    DR. ALLEN:  Thank you for the presentation.  This has obviously been carefully thought through and will be interested in comparing it with the FDA's proposals.

    I have got just a couple of short questions for clarification on my part.  With regard to the expiration date, you say two years from date of collection.  That would be within that period of time, the plasma would have to be used for manufacture, whatever the outdating on the manufactured product.

    MS. GREGORY:  Yes.

    DR. ALLEN:  Okay.  The product name, you are proposing just a single plasma for manufacture, and it would not otherwise specify the source, such as from whole blood, concurrent, except that that would then be handled under the labeling as you require or the name and volume of the source would indicate where it came from.

    MS. GREGORY:  Yes.

    DR. ALLEN:  As far as your concern, there really isn't any reason for further distinction of the source of the plasma.

    MS. GREGORY:  This group did not believe so.

    DR. ALLEN:  Thank you.

    DR. BIANCO:  Just addressing the question that Dr. Epstein asked, there is an incentive to collect the concurrent plasma as an apheresis procedure is being performed.  The apheresis kits are quite expensive, the apheresis process is quite expensive.  So, the revenue coming from converting the concurrent plasma into plasma for further manufacture would be beneficial and an incentive.

    However, there is no real incentive for collecting just apheresis plasma for further manufacture on the part of whole blood collectors, because the value or the reimbursement that collecting facilities receive for that would not compensate for the costs of the apheresis and the kits, so there I don't see an incentive.

    The incentive there where people go after the apheresis plasma is for plasma that is very useful for transfusion like that AB plasma where you try to convert AB donors where the red cells are only a very small portion of the recipients are Type AB, and the plasma is very valuable, so as fresh frozen plasma, this is worth the investment into the apheresis process, but it wouldn't be economically smart to go and collect plasma by apheresis as would be source plasma.

    DR. KLEIN:  Before you leave, Celso, I guess I don't quite understand that.  There is an entire industry that collects plasma by apheresis for further manufacture. They actually pay their donors and seem to make a profit at it.  You are telling me that if you didn't pay your donors somehow you would lose money?  That doesn't compute.

    DR. HOLLAND:  Let me clarify it a different way. Plasma which is fresh frozen is certainly more valuable when you transfuse it as a transfusible component than it would be if you converted it and sold it as recovered plasma, however, if you make fresh frozen plasma now, that is currently, by apheresis or as concurrent as an extra product during the plateletpheresis process, if you don't transfuse it as FFP, you have to throw it away, so there is no reason to make very much of it, because you would be afraid to throw it away.  But, yes, you are correct, I mean certainly source plasma, individuals are paid, and it can be economically viable, but for us at the moment it is not.

    It would help us if we could make our concurrent plasma, the apheresis plasma, especially even before its one-year expiration date, to be sold as recovered plasma if we had extra.

    DR. KLEIN:  Paul, I understand that and I agree with that entirely.  I think Jay's comment was wouldn't you possibly start a new industry, and the answer to that is possibly.

    DR. HOLLAND:  Possibly, certainly for recovered because it is certainly easy to get occasional units of extra plasma from pheresis of platelet donors, but we are not going to go into in a big way because it isn't economically appropriate for us.

    DR. SCHMIDT:  It probably doesn't enter at all into the province of the FDA, but does anybody want to discuss the need to tell donors that this plasma is going to go that route instead of some other route, or are we getting into any problems relating to the FDA of volunteer versus paid?  I guess not, and maybe nobody wants to discuss that.

    DR. HOLLAND:  Could I answer that?  Actually, as you know, Paul, we make a big point of that in telling our donors that at least some part of their unit of blood will very likely be used.  If we accidentally or don't happen to need their red cells or their platelets, or they happen to outdate, almost always the recovered plasma, if it otherwise qualifies, can be used.

    So, we actually push that and tell the donors they are helping many patients in addition to their transfusible components, that their plasma may be also made into further derivatives, plasma derivatives.

    DR. SCHMIDT:  I was speaking to what Harvey was talking about, where you set up a program to intentionally do this.

    DR. HOLLAND:  I don't think it's a problem.  You certainly notify them.

    DR. EPSTEIN:  We are going to hear some more about proposals for these licensing schemes, but since we are already sort of diving into it, I just want to provide a little bit of overview about what the underlying conflicts are.

    Basically, what we are seeking is the organizing principle here, and the problem is that there are a set of different organizing principles and that they sometimes clash, so what are they.

    One organizing principle would be to define the products according to their manufacturing conditions, and the manufacturing conditions include such things as apheresis versus whole blood collection, time to freezing, freezing temperature, and storage period.

    A second organizing principle is the donor criteria, is the product different if you collected under the conditions that now prevail for source plasma versus the conditions that now prevail for whole blood, and should that distinction be preserved even if you end up at an endpoint where the manufacturing conditions are, in fact, identical.

    That is the problem that is posed by the donation of a product for further manufacture from a, quote, unquote, "whole blood donor" given by apheresis, what is the difference in the product there?  The only difference is how you selected the donor or how frequently you apherese the donor.

    The third organizing principle is the intent at the time of collection, and I think that the intent at the time of collection does hook this ethical issue of what is it that the donor expects, but it also hooks the issue of how did you get to that point, what are you going to make from the donor, what does the donor expect, how are you going to handle the product.

    So, whether or not we think that that is a useful current distinction or not, it is still one of the candidate organizing principles.  That principle also can be extended into the question of different uses for different products made different ways.

    So, for example, we have already touched on the fact that perhaps time to freezing should be part of defining the product because it may make it suitable to make some end products and not other end products.

    So, for example, should we or should we not distinguish the product and give them different product names based on whether they are suitable to make injectables or not, based on whether they are suitable to make Factor VIII or not.

    So, the issue that we have is that the current scheme has aggregated those things in a certain way, having linked intent at the time of manufacture, and condition of manufacture, so we have apheresis with intent for further manufacture, and then we have intent to make a transfusible product, which was silent on whether it was whole blood or apheresis.

    That boundary is now getting very fuzzy and what we are really looking for is a new organizing principle, but there are these candidates, and they sometimes overlap, and they sometimes don't, and they each have their merits, but they can't all be the organizing principle because they don't entirely overlap, so that is sort of the underlying problem.

    Just to touch for a moment again on the donor distinction, the distinction between source plasma, which is defined, not by the donor, but by the product, that was defined by the method of preparation and the intent.  It's apheresis plasma intended for further manufacturing use.

    Under that standard, because we allow frequent apheresis, we have added patient safeguards or donor safeguards, I keep calling them patients, but donor safeguards.  Those are the annual exam, the serum protein, the total protein and serum protein electrophoresis, but mind you, the product standard is also different because of further processing.

    So, for example, we don't require HTLV testing, the anticore test.  We don't exclude persons who have had five-year exposure in Europe.  We don't screen the donor for malaria risk, and the court has not yet spoken on West Nile virus screening.  You heard a little bit of that yesterday.

    In addition, we have a distinction which is not in the regulations, but is the current practice where the vast majority of source plasma comes from a paid donor, whereas, the vast majority of components for transfusion comes from the unpaid donor.

    Now, that can be either way because the reg doesn't require you to label the product as source plasma or whole blood based on payment.  It requires you to label payment based on something convertible to cash, and there are paid whole blood donors, and there are unpaid source plasma donors, but still it is a fact on the street that the vast amount of source plasma comes from the paid donor, and the vast amount of components for transfusion comes from the unpaid donor

    So, there are distinctions based on donor selection including frequency of collection, the donor safeguard, the product protections, the manufacturing conditions, the intention at collection, and the intended use of the products themselves, and it is that unfortunate mixture that we are trying to sort out here.

    So, when you hear the different schemes, you need to be asking yourself, well, which of these principles is operating, and is that the one we should land on, or if these principles are combined, what is the right combination to usefully distinguish the products.

    I am afraid it simply is complicated, and it is more complicated than it seems on the surface.

    DR. NELSON:  I guess it's a complicated question, but I wonder if any of these variations have really translated into problems with efficacy of the end product, and if they haven't, then--but it may be impossible to tell because it is so complicated, and the end product is a mixture of plasma, plasma derivatives that were obtained from many, many sources, so you don't actually know where it all came from.

    But I can see from the standpoint of regulation of the process, it is a nightmare, and I guess that's the issue.

    DR. STRONG:  There is one other complicating factor, to address Harvey's question about the economics, there is a significant--this is a marketing force--but there is a significant differential between what is paid for source plasma and what is paid for recovered plasma.

    DR. NELSON:  You mean by the manufacturer, and which is higher, the source plasma?  So, the other is we were going to throw this away, but if you give us a little money, you can have it.

    DR. STRONG:  Yes.

    MR. LUNSFORD:  The difference between the economic value of source plasma and recovered plasma is relatively small today.  At one time it was greater, but there is not a great deal of difference any longer.

    DR. NELSON:  I would like to move to the open public hearing.

    Mary Gustafson, Plasma Protein Therapeutics Association.

Open Public Hearing

    MS. GUSTAFSON:  The Plasma Protein Therapeutics Association appreciates the opportunity to provide comment in the open public hearing on the topic "Discussion of Recovered Plasma."  PPTA is the primary advocate for the world's leading source plasma collectors and producers of plasma-based and recombinant biological therapeutics.

    Providers of recovered plasma are valued partners in the production of lifesaving plasma protein therapies.  The medicines produced by PPTA members include bleeding disorders, immune system deficiencies, alpha-1 antitrypsin deficiencies, and albumin for burns and shock.

    PPTA supports regulatory standards that add value in protecting the safety of donors and assuring the quality of products.  PPTA, however, urges FDA to proceed cautiously in creating new product categories and redefining existing products.

    Any change to existing standards should be thoroughly considered to address possible risks and carefully designed to ensure that there are no unintended consequences.  Due caution is necessary recognizing the significant efforts that have been taken by the FDA and industry to assure the Congress, the public, and recipients/patients as to the safety of the Nation's blood supply and plasma derivative products.

    Consideration should also be given to the impact of any new U.S. regulatory requirements on the global regulatory environment.  PPTA encourages FDA to harmonize its requirements with other regulatory authorities whenever possible.

    Source plasma was originally licensed to include only plasma collected by plasmapheresis intended for use as source material for further manufacture into injectable blood derivative products.  Subsequent to the initial licensing, FDA, through formal rulemaking, broadened the definition to its current definition as stated in Title 21, Code of Federal Regulations, Part 640.60.  This regulation states, as others have said today, that source plasma is defined as the "fluid portion of human blood collected by plasmapheresis and intended as source material for further manufacturing use."

    The definition was changed to ensure that donors   were protected regardless of the eventual use of the plasma, that is, for use in injectable products or non-injectable products.  This definition and associated regulatory controls have served the industry for over a quarter of a century.

    FDA's issue statement discusses, and I quote, "the potential for inappropriate use of recovered plasma that is unsuitable for the further manufacture  of some products."

    No data have been provided to support this position.  Quality system requirements and controls within individual blood establishments govern management of critical processes such as donor suitability determination, viral marker testing, and release of products.

    Changing a name and licensing a new product will not overcome basic quality system deficiencies.  The naming of a product is very significant in terms of establishing its legal identity and intended use.  FDA should more carefully examine its position in considering product definitions and their impact on current regulatory programs. FDA must carefully evaluate its rationale for proposing any change to existing definitions and requirements.

    Additional consideration should be given to limiting product definitions to establishing legal identity and intended uses.  You have not yet been given your questions to the committee, but Question 2 states, "Does the committee agree with changing the definition of source plasma in the regulations to include the requirement for freezing immediately after collection?"

    Specifications for storage conditions are not appropriate for a product definition and may unduly limit other suitable and acceptable uses that are defined by user specifications.  Specifically, liquid source plasma is stored in the liquid state and is licensed and is manufactured for use in non-injectable products.  The plasma industry must have this licensing option.

    In addition, the proposed source plasma redefinition to include immediate freezing after collection is, in itself, problematic.  The current requirement for storage at 21 CFR 640.69(b) states that, "Immediately after filling, plasma intended for manufacturing into injectable products shall be stored at a temperature not warmer than minus 20 degrees centigrade..."  The ... mean there are multiple exceptions.

    Immediate freezing is an unattainable goal.  Over the years, FDA has been asked to interpret this and has provided various interpretations of "immediate" for practical application.  We urge FDA, in considering whether recovered plasma should have standards that address the time to freezing to make any requirements science-based, practical, and applicable for all plasma of the same intended use.

    As Jay just eloquently outlined, there are many ways to cut this pie, and we look forward to the opportunity to work with FDA and the blood community in developing requirements for plasma intended for manufacture that are reasonable and appropriate.

    DR. NELSON:  Thank you.

    Questions?  Thank you.

    Miriam O'Day from the Immune Deficiency Foundation.  Miriam O'Day?

    [No response.]

    DR. NELSON:  Paul Holland.

    DR. HOLLAND:  Thank you for the opportunity to speak here today.  I am speaking on behalf of my regional, not-for-profit community blood center Blood Source, a large center in Northern California.

    I am also representing BCA America, which stands for the Blood Centers of America.  It is a consortium of about 30 blood centers in the U.S., virtually all of whom are also members of AABB and AABC, but it works in a way to sort of coordinate its collections and use of those collections whether they are blood or blood components, as well as its plasma.

    I would like to say that we agree with the statement that AABB has proposed, but I would like to emphasize four points.  I also believe that it is really not very complicated.

    First of all, we do need a new and more appropriate name.  Plasma for manufacture would work fine, if you wanted to be more specific, it could be plasma for manufacture into injectables or PMI.

    Second, we really urge the FDA to license this material.  It is long overdue, and the era of short supply agreements should long have disappeared, so basically, it is time to license this.

    Third, we certainly believe we should continue to be able to use blood, that is, the plasma from whole units of blood which are currently acceptable into what we now call recovered plasma, but as we also collect plasma for transfusion as part of apheresis procedures either as part of a plateletpheresis or as a pure plasmapheresis procedure to make FFP for transfusion, there is no reason why this should not also be convertible to plasma for manufacture into injectables.

    Finally, there is no reason to have to keep FFP for a year before it can be used as recovered plasma or whatever we are going to call this.  It should be acceptable within its dating period of one year or at least a year or more beyond that dating period to be converted into plasma for manufacture into injectables.

    Thank you for your consideration.

    DR. NELSON:  Questions?

    DR. STRONG:  Paul, do you have any comment on the issue of time to freeze or freezing?

    DR. HOLLAND:  No, I think the time to freeze, you could have certain set ones and then, as Kay said, it would depend upon the manufacturer to choose and to pay you for what they think it is worth depending upon the time to freeze and their ability to make, you know, labeled components versus not being to make labeled components, such as Factor VIII.

    So, I think we should have defined ones, but they should be sort of stepped, you know, up to 8 hours, up to 24 hours, up to 120 hours, just so that there is some ranges, and if you qualified and you can label it as such, then, the manufacturer decides what he or she can do with it.

    DR. NELSON:  At what temperature do you keep fresh frozen plasma?

    DR. HOLLAND:  We keep it at minus 18, but I think it would be relatively easy to change that to minus 20.

    DR. NELSON:  Where did the minus come from?

    DR. HOLLAND:  That happens to be manufacturers' specifications for certain uses of their plasma.  We don't use that for transfusible components because we need minus 18 or colder for the labeled components to be able to store them for one year.

    DR. NELSON:  Would there be a problem to harmonize all plasma to minus 20, let's say?

    DR. HOLLAND:  I don't think so.  I think most of our freezers could make that.  I think if you make minus 18, you could probably make minus 20.  Making it to, say, minus 30 consistently would be a problem.

    DR. KLEIN:  Paul, do you have any idea how much more plasma might be made available if all of the various kinds that we are talking about were, in fact, licensed as a single component?

    DR. HOLLAND:  Not exactly.  As we tried to indicate before, we would just like to be able to use as extra material.  I don't think we are going to go into it a big way because we can only plasmapheresis people every 4 weeks anyway, and you are doing plateletpheresis, and you would just be doing it as part of a concurrent, so whether it would increase the supply by 10 percent or 20 percent or 30 percent, I would put it in that ballpark.  We are not going to double or triple our collection of plasma for further manufacture because that isn't economically feasible.

    DR. FITZPATRICK:  Paul, most of the discussion has revolved around fresh frozen plasma, which is frozen within 6 to 8 hours of collection, however, there is a very large collector who makes plasma frozen, which is frozen within 24 hours of collection, and I haven't heard that even addressed as a component here, and I don't know what the answer is.  Is that convertible to recovered plasma, or how that fit in to the milieu here?

    DR. HOLLAND:  My understanding would be at the moment it would not be unless it qualified as FFP, that is, you qualified it, and kept it for a year, at which time you then could do that.  So, again, it's this idea of why can't  you take a transfusible component even before it's expiration date and turn it into something else rather than having to wait a year.

    DR. FITZPATRICK:  Technically, do you feel there is a difference in labile factors between fresh frozen plasma and plasma frozen?

    DR. HOLLAND:  I personally believe there is, but you have to look at the studies to see.  We freeze ours within 8 hours.

    DR. NELSON:  You would propose that blood collection facilities that primarily collect components for transfusion would continue the current testing algorithm, that includes core, HTLV-I/II, and West Nile virus?  I would think it would be complicated if you had two testing algorithms and two streams in the same collection facility.

    DR. HOLLAND:  Well, you are right.  Basically, what we are saying is that the plasma we collect is FFP now, the plasma we collect is FFP by concurrent plasma, and that by plasmapheresis, all has to qualify as a transfusible component, so it has to meet all the requirements.

    We are able to then convert that if we have excess into recovered plasma, so, in fact, yes, there are more stringent requirements.

    DR. FITZPATRICK:  But the AABB proposal, though, proposes that units that test positive only for core, or test positive only for HTLV-I/II would not be a transfusible component, but could be used as plasma for manufacture.

    DR. HOLLAND:  Correct, but that is current policy, that is current permitted now, so it is no change.

    DR. NELSON:  So, it is not a risk, but if it were, it would increase the burden because we would convert these units into manufacture.

    DR. HOLMBERG:  Jerry Holmberg, Haemonetics.

    I don't believe anybody has mentioned the differences in the donor deferral as far as what source plasma currently the PPTA requires for a national deferral registry versus the independent donor or blood center deferral registries, how would that work?  Would there be some sort of more of a national deferral registry?

    DR. NELSON:  Isn't there now?  I don't understand.

    DR. HOLLAND:  I can partly answer that.  There is, PPTA has a national deferral register.  Each individual center and part of organizations have deferral registers.  We are currently in discussions with PPTA how to harmonize this.

    But the point is the material we are talking about now is currently eligible to be transfused without further inactivation, and it just seems kind of crazy not to be able to have that go into products which do undergo further manufacture and viral inactivation.

    DR. BULT:  Jan Bult, PPTA.  Just an additional comment.  Some of you mentioned it already.  We have this week a very constructive meeting with delegation of AABB, BCA, ABC, American Red Cross.  We have issued a statement on our web site, and will issue a further communication early next week that will further explain what the next step is, also announce the question about donor deferral.

    DR. STRONG:  The 8-hour time frame is a bit artificial, as well, and historical, because fresh frozen plasma really is no longer used for Factor VIII.  It is primarily a fibrinogen replacement protein component, so that 8-hour time frame was really developed many, many years ago because of the Factor VIII issue.

    DR. DiMICHELE:  I have a question actually that can be answered by anybody, maybe from the blood banking industry.

    Just relative to the current discussion, if, for instance, at this time, if you have a hepatitis B core antibody or HTLV-I/II antibody-positive donor, that donor would be permanently deferred from blood donation under the current regulations, however, on a one-time basis you would be able to use that plasma as recovered plasma.

    Were the regulations for recovered plasma to change, would that donor continue to be permanently deferred from volunteer blood donor collection?  I assume that that would still have to happen even though this person could now be a source for recovered plasma or whatever, plasma for manufacturing.

    DR. BIANCO:  I think I am responding for everybody.  Yes, those donors are deferred.  The FDA guidance allows at least for the donor to donate once more and upon the second hit with a core antibody, the donor is permanently deferred.

    This is done because the current assays that are used for core antibody have low specificity.  They have about 50 percent false positives.

    There is no intent to change that.  The reason why the core is shipped for further manufacture--and maybe Dr. Finlayson, that is sitting very quietly at the end row there may explain to us a little bit better--is because there have been many studies including studies done by Dr. Finlayson at FDA in which the core antibody, usually those donors also have antibodies to hepatitis B surface antigen, and they contribute to the safety of the final product.

    That is why the manufacturers have accepted the core units, but it is a small number and obviously, it is not continuous.  That donor is not going to continue donating because the primary purpose of those collections are the transfusible products.

    DR. STRONG:  Just to expand on that comment a bit, I think with the implementation of nucleic acid testing technology, that we potentially have the capability of re-entering some of those donors that have false positive anticores, but we have to work out an algorithm to assure that those are not, in fact, positive for surface antigen and therefore infective.

    DR. NELSON:  I understand there is some effort to improve the specificity of the anticore, as well, and I also understand that there are two assays by two different manufacturers that vary in the specificity, so that there may be hopefully, may be possible to improve that specificity.

    The core antibody was actually originally introduced as a surrogate, as you know, and now I think its more important value is to rule out people who may, in fact, be hepatitis B infected, but have a false negative surface antigen.

    DR. STRONG:  That's the biggest loss to blood donors as far as testing goes is the loss to core.

    DR. NELSON:  I understand that, mostly due to false positives.

    DR. FITZPATRICK:  On the 8-hour, though, for making cryoprecipitate, don't we still have to have an 8-hour freezing time for FFP?

    DR. STRONG:  It is still required.  I am just saying that it's an antiquated requirement because we don't use FFP for Factor VIII, and it makes no difference for fibrinogen.

    DR. FITZPATRICK:  A change to that is just a domino effect, if you change to 24-hour, then, FDA also has to change the cryo definition and purpose of cryo.

    DR. DiMICHELE:  We also use it for Factor V deficiency.  We still use it for Factor V deficiency, which is another labile factor.

    DR. STRONG:  But Factor V is not quite as labile and actually 24 hours wouldn't make much difference.

    DR. FINLAYSON:  John Finlayson.  Since I have been accused of the horrible crime of being quiet, let me absolve myself of that.

    One of the more difficult things that we have had to wrestle with over the last decade is the fact that recovered plasma covered such a multitude of products, so I would like to respond to a question that was asked by the Chairman earlier, does it make any difference in terms of the thing that you manufacture out of it.

    I would like to preface this by saying just because we don't know everything doesn't mean we don't know anything.  I think we all grew rather weary of having the tobacco companies say, well, there is no definitive proof, so I don't think we have to wait 40 years to grow out of that.

    Recovered plasma for a long time meant just that, it meant plasma taken off of red cells where the whole blood had outdated, and we do have a certain amount of information about that type of recovered plasma or analogous material.

    There certainly are numerous examples where we can demonstrate differences in the product.  For example, in the late 1970s, a number of you in this room will remember we had the hypotensive episodes caused by plasma protein fraction and even in a few cases by albumin, and it was a repeated phenomenon that one was much more likely to see these happen in PPF or even albumin made from recovered plasma than that made from source plasma.

    Why?  Because there was an activation of the contact activation system and one was much more likely to have pre-kallikrein activator that was generated and made its way all through into the final product.

    Similarly, it was observed and observed repeatedly and finally observed in a rather dramatically controlled set of experiments by James MacIver of the Massachusetts Department of Public Health that the stability of immune globulin--and I am talking about the intramuscular product--was dramatically different when made from recovered plasma of that sort versus that made from source plasma.

    Now, to answer another of the Chairman's questions, could that be compensated for by a manufacturing change, and the answer is yes, it could.  Dr. MacIver demonstrated that.

    Now, would a manufacturer tailor the manufacturing process to the starting material?  I seriously doubt it.  The manufacturer would be more likely to choose the one that would give the best product and use that all the time.

    Nonetheless, I could ramble on and on, you see Celso has pulled the plug now, and give more and more examples, but the one lesson that I can bring to the table after about 45 years is the starting material makes a difference, so whatever we end up with, let's define a starting material that will give us a decent product because there are lots of things that we know even though they haven't necessarily been carried all the way to a controlled clinical trial with the final product.

    One of the things we know is that when plasma sits as a liquid, the contact activation system can be activated. Another thing that we don't know, well, we do know, but it doesn't get very much publicity, is the fact that when these contact activation factors are activated in plasma, they are activated into an ocean of inhibitors, but these inhibitors and their corresponding enzymes have association constants, and those association constants tend to decrease with temperature.

    So, it again makes a difference.  Again, my plea is let's not just dismiss this because we don't have the clinical studies at the end to show that it makes a difference when the starting material is different.  It does make a difference.

    DR. NELSON:  Thank you.  That is an important contribution.  I hope you will be here and comment further when we either decide or don't decide on some sort of standard because I agree.

    The point I wanted to raise is I think the critical issue should relate to the efficacy or quality of the end product rather than just harmonizing these very disparate collection, storage, and other process.  If these are important, then, it is important to improve the quality.


    DR. KLEIN:  What John I think is talking about is that we are currently using materials that are probably less quality starting material than many of the things that have been suggested, and it seems to me that the schemes that we have before us as proposals for licensure simply define the conditions of these materials rather than excluding something we are already using, or excluding something that has been proposed because it didn't exist in the 1950s.

    I am wondering, John, you may want to comment on this, whether you would be satisfied with further definition of these materials, or are you asking the committee to consider removing some of the materials that have been used for the last 30 years even though they may not be of the quality that we would like.

    DR. FINLAYSON:  Now you have really done it, Harvey.  Let me tell you a little story and then I will answer this.  I would almost call it a parable although that might be considered presuming above my station.

    Back in the '50s, everybody knew that there was going to be a nuclear holocaust.  I mean that was a fact of life.  The Russians were going to shoot something at us, and then we were going to shoot something back, and if they were still alive, they would going to shoot something else, and I am not going to tell that story because that has already been spelled out by that wonderful science writer Art Buchwald published in the scientific journal of the Washington Post.

    However, one of the things that we knew was going to happen was there were going to be a lot of people in traumatic shock of one sort or another, and we also somehow knew that our transportation system was going to work very well, so that we could get some sort of a plasma volume expander into these people, and the Department of Defense had been very forward-looking in the early '50s and stockpiled vast quantities of dextran.

    The only problem was that some of it started turning bright yellow with time, and some of the rest of it started beginning to look like these little paperweights that you would invert and you would see the snowstorm falling on the igloo.

    So, they decided to go over to albumin.  Well, in those days, unlike what is the usual practice today, to store albumin at room temperature not exceed 30 degrees Celsius with a dating period of three years, the more popular thing was to store it at approximately 5 degrees Celsius with a dating period of five years.

    Well, the Defense Department said, hey, how about if we take this vial and we then vial the vial, so to speak, by putting it hermetically sealed in a metal can.  Now, we should be able to get a 10-year dating period.

    So, they did, and I can't say the generosity of the FDA, because it wasn't the FDA that regulated biologics in those days, it was under the NIH.

    Guess what.  The Russians didn't send that thing up, so what happened?  Ten years went by.  Now, all the Department of Defense has all these vast stockpiles of outdated albumin.  What do they do?  They came to the regulatory authorities and said hey, can we rework this stuff, and for reasons that I was not involved in, the answer was yes, provided that it can pass the release tests.

    Well,  so, it was reworked.  Now, what did this reworking consist of?  It usually consisted simply of popping the top, doing a sterile filtration, and bottling it up again.  Of course, you got the extra 10 hours heating at 60 degrees Celsius.

    When this was subjected to the release tests, invariably, if it would go through the sterile filter, it would pass the release tests.  Then, this kid came along and started to put some of it on DEAE cellulose, which I might say immodestly he synthesized himself, and the answer was it didn't look an awful lot like the albumin that was being made from fresh citrated plasma, and depending on the starting material, which if you remember in the Korean War there had been irradiated dried plasma for reconstitution and administration.  It was probably an efficacious product, at least it was efficacious in transmitting hepatitis.

    Much of that was fractionated into albumin.  Could you tell the difference when you used some of these tests other than the release tests?  You absolutely could.  Now, one can always take refuge in the question does it make any difference in the clinic.

    Well, many years later, Dr. Shrake showed that just what you would predict in terms of osmotic effectiveness was what you found when you did laboratory tests.  So, I would say there is certainly the potential to have less efficacy and certainly if you have a fragmented immune globulin where the fragments can be excreted and/or metabolized in 24 hours, it can make a difference in efficacy.

    So, now let me get to Dr. Klein's question.  You thought I could never get there, did you.  I think one of the things that we should find out from the plasma-producing organizations is just what is the current practice and what is the range of practices, because it is my personal opinion that if some of these more conspicuously unfortunate starting materials are still used, they really ought to drop out of the picture.

    In other words, I don't think that, for example, starting plasma that was taken off of whole blood that had sat for 42 days and then the plasma itself sat at room temperature for X period of time, really ought to be used to make injectable products, for the simple reason that we can do much better and I think we can do much better without being particularly burdensome on anyone.

    So, I think what would be useful would be to find out what are the current practices are and then I believe it was Dr. Holland that said maybe we can have sort of groupings of this in terms of time to freezing rather than simply having 6-hour, 7-hour, 8-hour, 9-hour, 13, 14, in other words, have some defined increments, but not have increments that are approaching infinity.

    DR. BULT:  I want to express some concern to you from the side of PPTA.  The agenda item for today is the issue of recovered plasma.  There has been extensive discussion about elements of recovered plasma.  To our surprise, one of the questions includes the question to redefine source plasma.

    I have not heard a single question about source plasma.  We have made a statement that the focus of the discussion is recovered plasma only.  As Jay said earlier this morning, the issue is extremely complex and we should not undervalue that statement.

    What is we know is that source plasma in the United States is well defined.  What we also know is that plasma for fractionation is well defined.  There is a European monograph and human plasma for fractionation that gives you all the technical details, some are the questions that you asked are all written down in that requirement and currently applied by the manufacturers of recovered plasma, as well.

    The inclusion of a changed definition for source plasma, as I mentioned before, came to us as a surprise, and that is the reason why we didn't come prepared to help you understand the complexity of this particular issue and, in our view, requires further investigation.

    Why?  Because only with that further investigation and information, you will be able to make a balanced decision because factors that need to be considered are, first of all, is it correct to include in a definition, a technical requirement.

    We have an enormous amount of regulations.  I mentioned to you the monograph that cover an enormous amount, not just freezing, but much more.  The inclusion of a technical requirement, a simple technical requirement, as it seems, does it create a loophole that we want to avoid. If you don't want to create a situation that use that simple requirement can lead to a situation that you only focus in that particular area, not take into account the full spectrum of regulations that need to be considered.

    Are we only talking about plasma for fractionation?  There is an important factor that you should consider.  There is source plasma currently being collected that is used for the preparation of diagnostic reagents, and that plasma is not immediately frozen, so if you include that technical requirement, it creates a problem for the development of diagnostic reagents.

    The issue of temperature harmonization, it seems so simple, but whether it is minus 18, or 20, or 30, what is the temperature deviation going to do?  What are the regulations in that regard?  We would like to have an opportunity to explain with an expert what harmonization temperature could do and what benefit we would gain or not.

    In our view, the current regulations for source plasma, as defined in the U.S.A., are sufficient.  We do believe that the technical requirements, as written down in the monograph, are totally sufficient, however, we are willing to reconsider the need for a new definition if there is appropriate time to bring in all the elements and have a consideration for the multiple aspects that need to be covered, and we believe that just the answering of this simple question do we need a redefinition is too simple.

    DR. EPSTEIN:  Dr. Bult raises a fair point why were we tinkering with source plasma, but it comes back to my earlier comment of what should be the organizing principle.  If the organizing principle, in defining the product, is not the donor standard, then, it's the product standard or the intended use standard.

    The concept that it was the product standard led to the question of what distinguishes source plasma from the process point of view, and the main thing that distinguishes it is the source plasma intended to make injectables is currently frozen rather promptly, you know, putting aside the moment of how immediate is immediate.

    Operationally, that is different, because the vast majority of plasma that is collected in the whole blood donor setting has delayed freezing on account of the need to remove red cells and to prepare platelets.

    So, there may not have been a need at the moment to change the definition of source plasma, but if we are trying to harmonize the schemes rationally, and if the organizing principle is the mode of processing, that's what led us to ask should we define source plasma in terms of immediate freezing.

    Now, again, I am not saying that that is the only way to look at the problem, but that's the logic that led to that change, and it is really no different than saying should we now distinguish, you know, go back to an antecedent regulation and distinguish source plasma to make injectables from source plasma to make in vitro products, because you wouldn't argue with me that source plasma to make injectables is not frozen essentially immediately, it is.

    I think that is the main point I wanted to make there.  Other issues will come up later.

    DR. NELSON:  Celso.

    DR. BIANCO:  I enjoyed Dr. Finlayson's points, but I want to just say that historically, things have changed very much and that today, recovered plasma as it is prepared is very well defined in the short supply agreements with the manufacturers, that is, even if the regulations don't exist for recovered plasma, these old, 42-day plasma is not used for fractionation.  The manufacturers have much stricter standards.  As Bob Lunsford just presented, they are defined by the manufacturers in order to get the best product they can get, and the collecting facilities comply with those.

    These products don't exist because of market forces.  They probably should be removed, I agree, from whatever licensed product is there for the plasma.

    DR. NELSON:  That's reassuring.

    DR. EPSTEIN:  Just another dimension here.  So, what we are talking about now is the suitability of plasma to make in vitro products and ways to distinguish that from the material that is used to make injectables.

    What you basically heard is that under the current source plasma scheme, source plasma can go down either pathway, however, the collectors do label the product based on its suitability to make injectables versus non-injectables as the intended use label.

    One important distinction, though, is that under the source plasma scheme, those are licensed products whereas, currently, we have unlicensed products under recovered plasma used both to make injectables and non-injectables.

    So, another question on the table, and this was sort of a subtle point, is should we be licensing what is now recovered plasma under some new nomenclature and set of standards, both to make injectables and to make non-injectables, or should we allow that plasma, which is unsuitable to make injectables, to remain unlicensed.

    It is a very subtle point, but under the AABB proposal, that plasma would remain unlicensed.  FDA is going to put on the table that that should be licensed, but licensed under a different name.  For argument's sake, let me call that reagent plasma at the moment.

    So, again, one of the distinctions here is if we are really going to harmonize the scheme, right now source plasma to make non-injectables is a licensed product, if we move to licensing, the thing that is now recovered plasma,  you have a question whether that part of it, which is unsuitable to make injectables, should be distinguished, but should that also be licensed.

    DR. NELSON:  Further comments?

    Why don't we take a break at this point and consider all these issues, and come back about 20 to 11:00.


    DR. NELSON:  Given that everything is absolutely clear, Elizabeth Callaghan is going to present us with some test questions on what has just been presented or some questions that we need to resolve.

D. FDA Current Thinking and Questions for

the Committee

    MS. CALLAGHAN:  Next slide, please.


    In light of all the information you have heard, I would like to tell you what FDA's current thinking is concerning this product.  FDA is considering renaming recovered plasma, "component plasma."

    It would be defined as plasma that is collected manually or by apheresis, either separately or concurrently with other blood components, from donors who meet all whole blood donor suitability requirements.


    In order to distinguish source plasma from this component plasma, FDA is considering moving the requirement for freezing source plasma immediately after filling the final container from elsewhere in the source plasma regs into the definition.

    This would make source plasma a distinct product frozen immediately after collection, which is what is in the regs now as opposed to component plasma, that would be plasma regardless of its collection method, but frozen within a specified time frame, such as within 8 hours, within 24 hours, within 120 hours as a labeled component.


    Considering the "time to freezing" standard, should we define it for component plasma used for the manufacture of labile plasma products, such as Factor VIII.

    Should only products frozen within 8 hours or 24 hours be used for labile factors?

    While the actual definition of such a standard is beyond the scope of the current discussions, FDA is seeking committee comment on the need for such a standard and for labeling categories that would indicate whether the intended use of the product component includes labile products.


    What I tried to do here was to make a comparison of the three presentations that you heard this morning.  I probably should have put "ZLB" instead of "PPTA."  I was unaware of a PPTA statement until this morning, so just think of that as ZLB instead of PPTA.

    I did this so that you could see that we are not all that far off in what we think this product should go to. Again, the name of the product FDA is considering component plasma.  AABB wants to call it "plasma for manufacture," and PPTA did not give us a name.

    As far as donor suitability, both AABB and FDA consider donor suitability to be the same as that for a whole blood donor.  PPTA feels that we should harmonize with EU standards.

    How the product and from where the product should be manufactured, all of us agree that it could be manufactured from whole blood.


    From concurrent, infrequent plasma, and from non-concurrent, infrequent plasma, that is, plasma collected singularly as fresh frozen and decided to be made into component plasma because you have too many A-positive fresh frozen plasmas in inventory without having to wait for the entire year.


    Expiration date.  FDA is considering 10 years to be consistent with source plasma, which has a 10-year dating period.  AABB has proposed two years, and PPTA's is two years or greater.

    Infectious disease testing.  AABB and FDA both agree that it should be the same as for whole blood donors.  PPTA has said they would like us to be consistent with the EU standards.

    As far as the units being negative for anti-HBc and anti-HTLV-I or II, AABB and FDA do not think that is necessary because that is the way it is now, and PPTA said we should conform to EU standards.


    FDA is considering the product to be frozen within a certain specified time, such as within 8 hours, within 24 hours, within 120 hours depending on the product to be made. AABB has proposed just having a blank and the time filled in on the label at the time of freezing.  The PPTA proposal was to freeze products between 12 and 24 hours if they were to be manufactured into heat labile products and to be frozen within 72 to 120 hours for non-heat labile products.

    For storage temperatures, FDA is considering minus 20 degrees, which is what we presently have for source plasma.  AABB is considering it minus 18, which is the standard right now for fresh frozen, and PPTA has considered minus 20 to minus 30 or colder.


    As far as shipping temperatures go, we are again trying to be consistent with source plasma, which requires a minus 5 Celsius or lower.  AABB is considering minus 18, which is what fresh frozen has to be shipped at, and PPTA has proposed minus 20 to minus 30 or colder.

    Record retention.  To be consistent with FDA and source plasma rules, we are saying 10 years and 6 months. There is a reg on the books that say you have to keep the records 6 months after the product expires, so, hence, you have 10 years and 6 months if we have a 10-year dating period.

    AABB has record retention for 10 years, and there wa no recommendation in the PPTA submission.

    As far as the expiration date, everybody agrees that there should be one on the label, and as far as licensing the component, we are all in agreement.

    So, now comes the good part, you get your questions.


    Does the committee agree with defining a new licensed component called "component plasma," which will include the products currently called recovered plasma, as well as apheresis plasma collected from allogeneic whole blood donors, converted expired and unexpired FFP collected by automated apheresis method, and plasma collected concurrently with other apheresis components?

    Do you want me to go through all the questions and then go back?

    DR. NELSON:  Yes.


    Should a different name be applied to plasma intended for manufacturing only into non-injectable products, for example, the name could be reagent plasma?


    Does the committee agree with changing the definition of source plasma in the regulations to include the requirement for freezing immediately after collection?


    Should the dating period for component plasma be uniform at 10 years or specified on the basis of freezing temperature?  If you freeze at minus 18, should it only be good for a year, something along that line.


    Should FDA limit the use of component plasma to make injectable products based on the time to freezing?

    We are back to should we use product that is frozen within 8 hours or 24 hours only to make products that are like Factor VIII where products that are frozen at times of minus 120 only to be made into IGIV.

    DR. NELSON:  Can we go back to Question 1?

    MS. CALLAGHAN:  Can we go back to the first question, please.

E. Committee Discussion and Recommendations

    DR. NELSON:  I think that probably rather than vote without discussion, perhaps it may be more important to discuss without voting.  I think we have various degrees of expertise that varies rather widely with regard to this subject.  I think we could ask questions and get clarification, hopefully, from some of the experts in the audience, as well.

    DR. SCHMIDT:  There is a little story I guess behind what Kay mentioned about component plasma.  The nonprofit blood centers used to be very strict about you referred to blood components and blood fractions, so when you got into trouble with the local county commissioners who wanted to do something about closing down, "plasma centers," you said, "Oh, they do fractions and we do components."

    Well, the FDA has kind of put everything together as products, and again we have got this is a blood products advisory committee.  So, that creates a problem with state laws, and the reason for the getting out of the implied warranty that there isn't a virus in the blood is that--I am sorry--the reason of getting out of it is that the blood banks are not selling a product, they are providing a service.

    So, this is why the distinction is important between a component and calling it something else.

    DR. KLEIN:  It just seems to me there are two issues here.  One is the definition, and the other is the name, and I don't know how strongly the FDA feels about the name.  Obviously, the blood banking community is concerned about some confusion there.

    Is there any problem, I wonder, with the name "plasma for manufacture," and we will deal with the definition secondly.  I would ask representatives from the Agency whether there is problems that they foresee with that particular selection of a name.

    DR. EPSTEIN:  Well, ultimately, no.  I don't think there is a perfect name offered around the table here.  First of all, component plasma is intended to hint at what you make from whole blood donors.  On the other hand, legally, source plasma is a component.  So, you know, that is not so perfect.

    Plasma for manufacturing has the same problem in reverse, because currently, the definition of source plasma says that it's apheresis plasma intended for the manufacturing use, and if we call this product plasma for manufacture, then, it begs the question of whether it is captured by the source plasma regulation.

    So, I am not sure we have got the perfect name, and I agree with you that the issue really is how do we define it, and we may need to do further work on the best name.

    So, I don't know that we have a reason to object to the term "plasma for further manufacture."  I am not sure there is a good reason to object to "component plasma" either.  Neither is perfect.

    DR. NELSON:  There is another issue, too, and that is that you are giving this a name, but it also includes a wide variety of products in terms of how they were collected, frozen, stored for how long, and all that kind of thing.  As you mentioned, they are labile components and then there are other uses, you know, do we need two names.

    Currently, you know, the project gets married in the middle, it changes its name.  It starts out as fresh frozen plasma and then becomes recovered plasma after it gets old, like it gets married, I guess, it is changed, it has got a married name or whatever, and the names change.

    I don't know of that is a problem.

    DR. EPSTEIN:  This comes up in one of the later questions, but one of the options would be to have subcategories according to time to freezing and/or temperature freezing.  So, in effect, we are really talking about multiple products with multiple names.

    So, were we to go the route of component plasma frozen within 8 hours, component plasma frozen within 24 hours, et cetera, those really would be different product names.

    DR. NELSON:  But I guess, irrespective of the name that AABB has proposed, which makes sense to me, is that there be some specifics about when the product was collected, when it was frozen, how it was stored, and how old it is, and that this judgment could then be used.  I am sure that the manufacturers are interested because they want a product that has some quality, standard quality, and that may vary by all of these parameters.

    But the issue I guess is how should FDA regulate this process differently than they are now.


    DR. BIANCO:  I will try.  I don't know if I will help.  Maybe in thinking a little bit about the name or the name that was proposed for AABB, I think that when we discussed within the blood banking organizations, we were still married to the issue of intent, and maybe what I am realizing today, particularly after what Elizabeth and Jay presented, is that maybe intent is the obstacle here, it is not really what is helping us to get there.

    The product really is plasma and is the same essentially if it is collected from a unit of whole blood or if it came from a concurrent plasma collected during a platelet apheresis that will be the two.

    So, couldn't we just call it plasma?

    MS. CALLAGHAN:  Yes, but there is a licensed product called plasma, and it is for transfusion.

    DR. BIANCO:  So, you need to distinguish the plasma for transfusion from what you are calling component plasma.

    MS. CALLAGHAN:  Exactly.

    DR. BIANCO:  So, I didn't help.  I tried.

    DR. ALLEN:  What's in a name.  My thinking on this, I could be satisfied with either of the two proposed names.  I think that component plasma is perhaps more descriptive of what we are dealing with here although if one makes the argument that components are intended for transfusion, and fresh frozen plasma is a component, then, to call this component plasma that is intended for manufacture may be somewhat confusing.

    I think, however, the descriptiveness of it as a source may be more important.  With regard to the concept of plasma as a product, yes, it is, but in terms of plasma for manufacture, it is also really considered, if one is looking at other manufacturing, you know, non-blood industry manufacturing, it is really more of a raw material than it is I mean since it's the source that is then used to manufacture other products, final products, I mean it really does get very twisted.

    I personally come down perhaps slightly in favor of the term "component plasma."  I think if you use "plasma for manufacture," your source plasma is also plasma for manufacture, so that, to me, is not very helpful.  I think it could go either way, and I suppose I would argue that the committee ought to make a permissive recommendation on this. I don't think that it is really important for the committee to make a final recommendation.

    Let me make one other comment with regard to some of the discussion earlier in the day with regard to suitability requirements, that is, the hepatitis B core antibody status and the HTLV-I/II status.

    This definition states that the donors for component plasma must meet all whole blood donor suitability requirements, which would indicate that if blood banks intended to bring donors back primarily to plasmapherese them for plasma, but not for other blood components, that they still would have to meet all the whole blood requirements, and you couldn't bring back somebody who is no longer, because they are core antibody-positive, would not be capable of donating whole blood, but could donate plasma.

    I am comfortable with that, and I think, to me, the definition is important in terms of the name here that is recommended.

    DR. DiMICHELE:  I think one way to potentially distinguish this from source plasma might be to call it volunteer plasma for manufacturing, because you can't call it transfusible plasma for manufacturing if you are also going to include the core antibody or HTLV-I/II antibody-positive plasma.

    I just wanted to clarify just with the FDA and also with the Chair, because there has been two issues that have been brought up, one is are we really talking about plasma for injectables only at this point, or are we talking about injectables and potentially reagent plasma, as well, because if we are talking about injectables, then, I think we need to clarify the name, as I think was suggested by BCA, as maybe volunteer plasma for the manufacturing of injectables.

    DR. FALLAT:  Being a non-blood banker, I will add yet another--rather than using volunteer, since I understand there can be volunteers even in source plasma, what you are really talking about is derived plasma.  It seems to me you could call it apheresis-derived plasma, whole blood-derived plasma, and then you could add "for injectable" or "for reagent."  So, now you have defined everything and it is very clear, it seems to me, being a non-blood banker.

    DR. NELSON:  Except, I guess at the time of collection, it is not all clear what they are going to do with the plasma.  They will collect some as fresh frozen, but it depends on the demand, and if the demand isn't there, or they anticipate a higher demand and then collect, and then they store it, and then eventually, as I say, it gets married and changes its name, which I guess is okay if it always meets all the important criteria with regard to its performance and this kind of thing.

    But I do like the AABB proposal that all of the qualities be labeled as such, so that you know, because this component plasma, if you will, is still pretty heterogeneous or could be heterogeneous.

    But if the FDA makes very stringent criteria, then, a certain amount of collected plasma will not be used, and whether or not that would lead to a shortage or not, I don't know,  but there have been shortages.

    DR. SCHMIDT:  Since Jay has suggested that they might rethink this business, I think we might get off the naming problem.  As I remember, that name has to be spelled out on the label, and if you start spelling out what you said there in equal letters, you know, it gets to be that long.

    DR. NELSON:  It gets to be like a Thai last name.

    Do we need to make any more comments about this question?

    DR. FITZPATRICK:  I have a comment on the definition.

    MS. CALLAGHAN:  What we had conceived component plasma to be defined as is, "plasma that is collected manually or by apheresis, either separately or concurrently with other blood components, from donors who meet all whole blood donor suitability requirements."  That is the actual  definition that we were considering.

    DR. FITZPATRICK:  My comment to that is that it does lump source plasma into that definition, because it doesn't make the distinction of frequent or infrequent donor, and that has been the distinction between the products.

    DR. NELSON:  These donors, by this definition, have to meet all whole blood donor suitability requirements, which is the testing, the source plasma, so this would still differentiate component plasma from source plasma.

    MS. CALLAGHAN:  No, whole blood donors also have a malaria restriction and a CJD travel restriction, which source plasma doesn't, so there is a slight nuance.

    DR. FITZPATRICK:  But as far as the definition of the product, source plasma is from frequent donors, and there are different criteria that apply to those donors, and that gets back to Jay's comment, if you change, to me, this muddies that water because now you don't have that distinction between frequent and infrequent donor.

    DR. EPSTEIN:  I think the distinction over frequency of collection is important to retain, but it is not currently part of the definition of source plasma.  It is the practice that source plasma donors are frequently apheresed, and that has led to FDA defining certain donor safeguards, but those criteria are not part of the definition of source plasma.

    DR. ALLEN:  How often can platelet donors come back, plateletpheresis donors return?

    MS. CALLAGHAN:  They can be pheresed twice a week, but they can only do 24 collections a year, but they are all volume limits that go along with that.  There was also if you are going to collect concurrent plasma along with it, there is a limit, I think it's 15.5 ml, 5 liters of plasma in a year if you are collecting it concurrently with like the pheresis.  So, there are limitations for plasma donors and concurrent plasma collection.

    DR. ALLEN:  Would that need to be included somehow in the definition?

    MS. CALLAGHAN:  It could be.

    DR. FITZPATRICK:  My second problem is with concurrent, because it goes back to Jay's comments about categorization and intent.  The intent when you collect whole blood is to collect a product for transfusion, and recovered plasma has been considered a byproduct of the red cells essentially.  It wasn't needed for FFP and couldn't be used, but we don't want to waste it.

    The most offensive thing you can tell a donor is that you have thrown away the product that you collected from them, so, that's, as Dr. Holland said, usually a good thing, that you can tell the donor that even though we might not use your red cells, we are going to use part of your blood for something.

    But concurrent collection, to me, has a different intent.  The blood center that is doing concurrent collection is collecting plasma from that donor for the intent of selling it for manufacture in order to offset costs for dollars, and it comes down to dollars on a lot of this.

    So, I think adding concurrent plasma and lumping it into everything is okay as long as the intent is made clear to the donor at the time of collection, that we are collecting your platelets and, oh, by the way, we are also collecting plasma, not necessarily for fresh frozen plasma, but to sell for manufacture into factor concentrates for hemophiliac or some other product, but that the intent of that collection is still for transfusion, but to also help offset costs and make some more money.

    So, I think the concurrent element adds a little different twist there.

    I had tried to make a table to sort this out, but you already did that.

    MS. CALLAGHAN:  Sorry.

    DR. FITZPATRICK:  That's okay, thanks.

    DR. KLEIN:  Mike, that may or may not be so.  You may be collecting red cells and plasma by apheresis or platelets in plasma.  They may not at that point be intended for further manufacture, it might be intended for transfusion.  A week later, it might be sent for manufacture.

    So, again, that hasn't traditionally been part of the definition, and put into the definition whether it's volunteer or whether you have gotten informed consent about selling it.  I think that is an issue that has to do with your operating procedures and really shouldn't be in the definition.

    DR. FITZPATRICK:  No, I wasn't suggesting we put it in the definition.  I was just saying that there is--I agree, Harvey, if you are going to increase FFP production and you do that, fine, but there comes a breakpoint in cost analysis where centers are going to say okay, I have got this donor, I don't necessarily need the FFP, but I can collect more plasma and sell it, and that is going to help offset my operating costs of doing this plateletpheresis, and that becomes a business decision at that point, not necessarily a decision to collect more FFP for transfusion.

    DR. SCHMIDT:  Is it possible to table this discussion and request the FDA to consider all of these comments and come back to us in September, or will it throw off the rest of the questions?

    MS. CALLAGHAN:  Next June, plasma, the third sequel.

    DR. KLEIN:  Mr. Chairman, I don't think this is all that complicated.  I mean I think we can recommend fairly easily to the FDA that they can use a term that is either "component plasma" or "plasma for manufacture," even a third one if they find something that sounds a little bit better, and I find this definition quite acceptable.  I don't see that there are any big problems that require us to either table or to prolong the discussion unless there are some issues that I haven't heard raised.

    Unless some issues are raised, I would make that in the form of a motion.

    DR. NELSON:  Well, I guess we were asked to vote. Does anybody object to this idea?  I mean we may have different ideas for the name, but other than the principle of changing the name and including all of these products under that name.

    DR. EPSTEIN:  If I could comment, I think it was stated earlier, I think by Harvey, that the important point here is not the name, but the definition, that's correct, but the idea is that the name may hint at the basis for the categorization, whether it is really based on processing or it is based on the donor population, or it is based on the intent at the time of labeling, et cetera.

    That is really what is in the name, as well as trying to pick a name that reduces confusion, so that the purchasers know what they are getting sort of transparently upfront, but I don't think it is important for the committee to select a name by voting.  I think what we were looking for was how do you react to these names, what are they communicating to you, and do they, rightly or wrongly, hint at any distinctions that ought to be important here, mainly the distinction from source plasma.

    I also want to just come back for a moment to Donna's question, are we talking about plasma only to make injectables, or are we also talking about plasma to make in vitro reagents.

    The answer is that both issues are on the table, and the proposals are, in fact, different.  The AABB proposal, if you read the fine print, is that plasma for further manufacturing is only plasma intended to make injectables, and under that scheme, you would still have an unlicensed product, which wasn't given a name, but is possibly still recovered plasma which would be used to make injectables.

    Under the FDA proposal, we would incorporate plasma to make non-injectables under a licensing scheme potentially as a subcategory of component plasma or given a new name.

    So, the issue is on the table, but the proposed resolution is not the same from different speakers.

    DR. ALLEN:  Without trying to suggest what a possible name might be, I would be more in favor of a separate name simply to avoid potential for mixup or confusion.  I don't feel that strongly about it, but I think a separate name probably has some merit.

    DR. KLEIN:  Having heard Dr. Epstein's comments, then, I would modify mine previously and say that perhaps we should accept the suggestion by the FDA of component plasma, because the plasma is going to be collected primarily for component, I believe, as it has been in the past, and then eventually turned into manufacture.

    So, that would give us a better idea of what the source is and perhaps clarify what the distinction is between source plasma.  So, I would fall on that side, I guess slightly, and as I said previously, I think the definition is perfectly adequate.

    DR. NELSON:  Okay.  I don't think we need to vote, do we?

    DR. SMALLWOOD:  If you were voting, are you going to vote--oh, you are not voting, this is just the consensus on the discussion.

    DR. NELSON:  We could either vote or we could even have a hand vote.

    DR. EPSTEIN:  I see no harm in getting the sense of the committee, but I think it needs to be understood that these are early steps towards eventual rulemaking, and that we don't want to sort of get locked in at this stage.

    We envision having a workshop to follow this discussion.  This is an opening foray.  To me, the discussion is as valuable as anything you might vote at this point, and voting, you know, potentially could constrain us.

    I mean if there is a really strong sentiment that you know the answer, that is up to the committee, but I think it is the discussion that is helpful to us.

    DR. HOLMBERG:  Jerry Holmberg, Haemonetics.

    Dr. Klein, would you also throw in the definition with the reagent plasma, is that what you are saying?

    DR. KLEIN:  I look at this as sort of the first step.  I mean this is kind of the general overall look at what this stuff is and how we define it.  So, I don't think we have gotten that far down, and just to sort of look a little further down the pike, when we are going to start talking about freezing times.

    You know, we haven't had any data presented to us today about time to freezing, stability of proteins, quality of components, and so anyone who is going to define a freezing time today is either extremely knowledgeable or a fool.  So, I think right now we are just drawing out the broad category and yes, I think I would include both under this broad category, and then we will further define that as we get down the pike.

    DR. HOLMBERG:  Thank you.

    DR. NELSON:  The second question?

    MS. CALLAGHAN:  Could I have the second question, please, the next slide 1(a).

    Should a different name be applied to plasma intended for manufacturing into non-injectable products?  An example could be reagent plasma.

    DR. NELSON:  Well, I don't know, I think it should, but it seems like that the products may well have different characteristics that may be rather grossly different as opposed to difference between 18 degrees and 20 degrees, and there may be quite a bit less stringent requirements, et cetera, when you inject something and when you use it to manufacture a reagent.

    On the other hand, reagents are important, too, with regard to the QC.

    DR. FITZPATRICK:  Like Dr. Klein said, this is a step, so as you make the determination in the life of a component, because we modify components frequently, we irradiate blood, we split red cells, so there ought to be a way for clarity of labeling a component that is being sold to a supplier for a non-injectable, different from an injectable, so that there is clarity and you reduce the risk of something getting mixed up.

    So, at some point in the life of the product, I would support there being a name that differentiates it as a non-injectable or for manufacture of non-injectables.

    DR. BIANCO:  I want to support that, but I think that we have the beginnings of a hierarchy here, that is, the first thing that was defined with Question 1 in your discussion was the definition of what the product is and where it came from, and now, as both Dr. Klein and Dr. Fitzpatrick presented, what is the product going to be used for, and many of those requirements will be made actually by the manufacturers that will make reagents, will make all those.

    But there are some basic characteristics that we will have to define for those products after they come.  So, I think that if we layer it in terms of the modifications of the product or the characteristics of the product, for the intended use after we defined what the product is, is probably the path that we should follow.

    So, yes, I would say that obviously, plasma that is collected with the intent as, for instance, I know that some centers were collecting plasma from people that had been immunized against smallpox to prepare potentially preparation of IGIV with specific antibodies to smallpox, so that would be for injectable products, but would be a special product with different characteristics and a different definition.

    I think that we should focus today on the basic characteristics of the products and then later the modifications that we will make for each one of the intended uses.

    Again, I don't know if I helped, but I see this as one of the modifications that you could have.

    DR. KLEIN:  I feel much more comfortable now knowing that the discussion is more important than voting on this question because that makes it a lot easier.

    I think, yes, it would be very valuable, I think, eventually to be able to label something for injectable and have a licensed product, but clearly, something that would qualify for human use, might be used as a reagent, and something that has no longer value as an injectable or for human use, might also be a reagent.

    So, in theory, yes, but I think we now are going to have to--not now--but we are eventually going to have to define what those characteristics are for a product that is going to be suitable for an injectable, and once we have done that, then, we can sort of define everything else plus those that are suitable as potentially labeled as reagent use.

    I think it would be valuable to have such a category.  I don't know that we yet have the science to be able to do that, and certainly not today.

    DR. NELSON:  Can you give us the next question?

    MS. CALLAGHAN:  Definitely.  Can I have the next slide, please.

    Does the committee agree with changing the definition of source plasma in the regulations to include the requirement for freezing immediately after collection?

    DR. NELSON:  We have heard that this would be a problem for the plasma industry in that some of their product is not used for injection, but rather used for reagents.  I don't know how much of that is known beforehand and what intent there is at the time that it's collected.

    Maybe you could clarify.  I don't know much about this industry.

    MS. CALLAGHAN:  If I can make it a little clearer. In the CFR now, there is a requirement that source plasma be frozen immediately after filling the container.  That is already in the regs.

    Further down in the regulations, there is an exception for modification of source plasma, which allows you to have liquid plasma, which is stored at refrigerator temperatures, so we would not change anything other than moving the requirement for source plasma.  It's the requirement for freezing source plasma immediately up into the definition, but there would still be the exception for liquid plasma if you so wanted it.

    DR. FITZPATRICK:  This gets back to the other comments previously about immediately and the problem with the definition of immediate, and even though the CFR says that currently, there has been an exception made to have liquid and then source, and I think this confuses the issue, not to mention the fact that--I don't want Dr. Klein to think we are fools--because we haven't seen any data on the need to make this a requirement.

    So, I don't think I would be able to support that.

    DR. NELSON:  I guess immediately could mean you draw the blood in a freezer somewhere.

    There was a comment from PPTA?  Yes.

    MS. GUSTAFSON:  I think we do object to having technical specifications in a definition.  A definition identifies the product, and I think you can get it too cluttered if you start putting storage conditions and other technical specifications.

    I think I would like to reiterate what Dr. Epstein has said, that is kind of a baby first step, and as suppliers of 12 million liters of plasma a year, I think that we would be primary contributors to their task group or a workshop to try to work out--you know, it looks straightforward, but it is fairly complicated.

    You have got two laws under the Food, Drug, and Cosmetic Act, and the Public Health Service Act, which require products to have suitably descriptive names and have defined intended uses.  Then, you have a regulatory scheme that right now we are trying to fit certain characteristics into a regulatory scheme that may be piecemeal and we may want to look at the entire regulatory scheme.

    With the regulations, you have subparts of the regulations that have products defined, and under those definitions, you have suitability of the donor, processing characteristics, storage characteristics, and shipping characteristics.  The testing has all been consolidated in another area of the regs.

    So, I think there is a lot of considerations.  Besides regulations, there is a lot of guidance documents, which Elizabeth has mentioned, certain things from guidance documents.  There is also instructions to inspectors for inspecting these facilities, there is compliance programs, compliance policy guides, and I think we need to look at the entire regulatory scheme.

    I would very much support doing this within a task force or a workshop environment.

    DR. SCHMIDT:  The original requirements for plasma centers, where they needed to have a physician on the premises, and as I remember the way this was handled, I don't know if it was with NIH or the FDA, was the definition that appeared elsewhere, but not in the regulation, that the physician could be constructively on the premises, and that was defined as 10 minutes.

    So, the original regulation said, you know, something that got handled very nicely, differently.

    MS. CALLAGHAN:  That was from the platelet guidance document back in 1998, that constructively available.

    DR. NELSON:  They are not going to redefine a physician, are they?

    DR. EPSTEIN:  I just wanted to restate what I said earlier.  Why is there any tinkering with source plasma in this dialogue if what we are trying to fix is recovered plasma?  But the reason is if you are trying to define recovered plasma based on a certain principle, what is that principle, is the principle the donor selection criteria, is that the lead issue?  Is the principle how you make the product?

    If the principle is how you make the product, then, the thing that most distinguishes source plasma is the condition of rapid freezing, as well as at the temperature, although that is easily harmonized.  So, that is what led to the issue of whether that distinction should then carry through to source plasma.

    But I also want to comment that currently, source plasma can go either to the route of make injectables or to the route of making non-injectables, and it does get labeled as such later in the process although both of those products are still source plasma, and what would be on the table here in essence is that what is now liquid plasma under the source plasma exception for freezing, would no longer be called source plasma.  It would get a different name.

    Now, again, whether there is any need to tinker with all of that really comes back to whether we are reorganizing the distinctions among these products and on what basis.

    DR. NELSON:  So, what is now source plasma is frozen immediately?

    DR. EPSTEIN:  Source plasma which is intended to make injectable products is still, in fact, frozen extremely rapidly.  Perhaps someone can correct me, but I am not aware that manufacturers are accepting source plasma made under liquid plasma exception to make injectables, I think they are not.

    DR. BULT:  The last comment, Jay, was absolutely correct.  At the same time, we should not forget that the current definition of source plasma covers both area, as you correctly identified.

    As everybody has realized, all the parties in the room are absolutely willing to work together to find a solution, to do something, to have no waste especially in the recovered plasma area, but a change should not lead to a risk of creating a loophole when we include this definition of source plasma or create a potential waste of plasma for reagents.

    So, therefore, we absolutely support the idea to have a workshop and give our experts a chance to talk about the specific requirements.  The issue is so complex that we should not rush to a conclusion here.

    DR. DiMICHELE:  I just want to add that my impression is, in terms of the discussion that centered around Question 1, that relative to the possibilities that Dr. Epstein discussed initially, that we sort of have come to maybe an unstated sort of conclusion that the definition should primarily include donor characteristics and the intent of the collection, I mean based on the discussion that focused around Question 1.

    I think part of the focus of that discussion also indicated that the details of manufacturing and how that product was ultimately going to be used may result in subcategorizations of the plasma in general.

    I think if that is the case, then, I think Question 2 really would fall back into that category as some of the comments from the floor would indicate.

    I guess what I am trying to say is relative to your initial panel of potentials, Jay, and where this Question 2 fell in, I don't think we are discussing on the basis of manufacturing process.  I think we are discussing on the basis of donor selection, you know, labeling this product and licensing this product on the basis of donor selection and intent.

    DR. ALLEN:  I would halfway agree with that conclusion.  This obviously is extremely intricate and there are existing standards.  If I were to be asked to vote on this right now, I couldn't because I am not looking at the whole definition.  I would have to abstain.

    I agree with the concept of putting in certain requirements, and certainly, if one is only talking about plasma that is to be used for manufacture into injectables, there are different standards than plasma used for non-injectables.  I don't think we begin to have enough information before us today to make some of these requirements.

    I certainly think that the definition needs to be looked at very carefully.  The question of whether there should be two separate names for the different--or different names, I won't even say how many--for the source plasma lines of production.

    Certainly, one wants to be as efficient as possible with the use of valuable products, one wants to assure that donors who come in, whether they are paid or not paid, are treated fairly and equitably, and that their time and their donation of human material is used appropriately.

    On the other hand, I think product safeguards are extremely important because we have got end users who will be receiving these.  So, my sense would be to put more emphasis on the processing standards and the product standards than on the donor selection criteria in the definition, but obviously, that is also extremely important because it has to do with the standard of the end product.

    I am not sure whether this needs to be, this issue of immediate freezing, which is not a defined term, one has to define in a regulatory environment what immediate means. So, I am not certain that it needs to be in the initial definition, but it clearly needs to be prominently addressed and appropriately addressed in the total regulations at some point.

    DR. NELSON:  Currently, how is immediate defined, within 8 hours?

    MS. CALLAGHAN:  I don't know.  I have copies of the CFR although it is an old one, sorry about that, but I did steal it from somebody.

    Under Source Plasma, under General Requirements, it says Storage.  "Immediately after filling, plasma intended for manufacturing into injectable products shall be stored at a temperature not warmer than minus 20."

    Then, it goes on, "except for plasma that is collected, provided, 640.74--."  But they require that you put it in the freezer immediately.

    DR. NELSON:  So, it doesn't say in any more detail than that what that means.


    MS. GUSTAFSON:  Over the years, there had been attempts at defining it, and we were looking in a checklist instructions from 1990, and it said that immediate should be without undue delay.  So, that is very helpful.

    I think, and I don't know where exactly this had come from, but in recent years, it was thought of to be perhaps 30 minutes.  Now, what has happened is, I don't know that that was scientifically determined, and with attention to quality systems, we have auditors who--I mean there is very elaborate systems now in plasma centers to make sure that you freeze this plasma within 30 minutes of collection, and I don't even know that this has any scientific basis, but it is measurable, so we measure it.

    DR. EPSTEIN:  I don't know that it needs to be in the regulation.  There are standards and guidance documents, for example, there is a European standard of achieving an end temperature of minus 30 within one hour of collection, so I think the general concept is a target temperature within a specified time.

    We have not yet specified that in the FDA standard, but I don't think that it is such a difficult task.  What we would settle on may have a lot of controversy, but the concept of what you need to do to define immediate is simple enough.  It is just target temperature within target time.

    DR. NELSON:  That brings up another issue, and that is the PPTA and the plasma manufacturers also set a goal to harmonize U.S. with European requirements, and other than that temperature requirement, in what way are they now not in harmony, or what would that require?

    My guess is that the plasma manufacturers probably try to meet EU standards particularly if they want to sell the product in Europe, but I don't understand what the discrepancies and differences are at the moment.

    DR. BULT:  As we mentioned today, the issue is extremely complex.  We learned about this question less than 48 hours ago, so I hope that the committee appreciates that that isn't a lot of time to get prepared, and I fully understand the questions that you are asking for, but if you look at the differences, the difference between minus 18, minus 20, now we hear minus 30, we heard already minus 5, you have to look at the shipping conditions, how many deviations are allowed, how many are not allowed, and what are the conditions under which this has to be done.

    We are perfectly happy in this workshop that is suggested to come back and give the precise answers, and identify what the discrepancies are and how we feel that we can make a contribution here.

    DR. KLEIN:  Mr. Chairman, again, I think that conceptually, it would be very nice to have some kind of additional definition, I absolutely agree, but as has been pointed out, no one is prepared to talk about such things today in any kind of detail.

    We haven't heard any data on this today, so I think it would behoove the committee to say that conceptually, that might be a nice idea, but we would like to have a lot more information both from the industry, who has pointed out the complexities, and perhaps from the scientists, as well, before we address this issue.

    MR. LUNSFORD:  Part of the difficulty in harmonization between U.S. and EU specifications has to do with donor deferral.  The folks at Blood Systems, Incorporated, a member of BCA, have prepared a gap analysis, and we would be happy to share that with the committee and the FDA very soon, future date.

    DR. NELSON:  Thank you.

    DR. ALLEN:  Just looking at the table that was presented in the slides and in the handout materials, there certainly are several areas where the EU standards are listed.  Donor suitability is one area, infectious disease testing among them, and I concur, I think it would be helpful to have that information available and presented to us for consideration.

    DR. NELSON:  Okay.  Can you move to the next one?

    MS. CALLAGHAN:  The next question.

    Should the dating period for component plasma be uniform at 10 years or specified on the basis of the freezing temperature?

    DR. ALLEN:  Again, as Dr. Klein has pointed out, we really haven't been given any data.  I am curious why the AABB selected an expiration date of only two years versus the FDA of 10 years.  I am not sure that I personally--and I won't speak for the rest of the committee--have enough information to really be able to vote in any way on this or even give much in the way of a sense of direction.

    Certainly, unless there are reasons otherwise, a tendency towards uniformity makes it easier to apply, but that should be based on data and intended uses, and again, probably is an issue that could be addressed in the workshop assuming that there will be one.

    DR. NELSON:  I interpreted the AABB two years as if harmonizing, if you will, with the updating of fresh frozen plasma of one year, and allowing another period after that for it to be converted into material for injection.  The 10 year, I am not sure where that came from.

    MS. CALLAGHAN:  Source plasma has a 10-year expiration at minus 20.

    DR. EPSTEIN:  I think part of the again embedded issue here is minus 18 versus minus 20, and are we going to call for data to make a distinction between the 10-year period and the 1- or 2-year period, or do we go another route.  There are two other alternative routes.

    One is we accept 10-year dating for the minus 18 degree stored product.  The other is that we harmonize the storage temperature for fresh frozen plasma to minus 20, and then we have no reason to say that the dating period ought to be different than for source plasma unless you think time to freezing is a big variable.

    The reason we are posing this question is to beg the question of whether it needs to be data driven, because it won't be easy to get these data.

    DR. NELSON:  Intuitively, I would suspect the time to freezing probably makes a difference, you know, from what John told us before, and my guess is that it does.

    DR. KLEIN:  There are some data, there are some data that exist for fresh frozen plasma and for other frozen plasma preparations.  They are not ideal, but they do exist and have been looked at over the years for different proteins.

    I don't think that we need to get a lot of new data to make this decision, but what I do think is that if it's relatively easy to go to minus 20, and from what I have heard today, it is, and there is a fair amount of data at minus 20, then perhaps what we need to do is to have that put together, and then to select that period of the longest reasonable period of time supported by the data for which you have a quality product.

    If harmonization comes into it, then, that's terrific, but it seems to me that there are some data available.  We have already heard that minus 18 is probably not going to be an issue.

    DR. NELSON:  When you label something fresh frozen plasma, is there a time to freezing requirement on that?

    MS. CALLAGHAN:  Yes, it's within 8 hours.

    DR. NELSON:  I don't know if that's immediately.

    DR. KLEIN:  Again, there are some data.  It is primarily dealing with Factor VIII as has been said earlier, although there are some data with other coagulation factors and some other proteins, as well.

    DR. ALLEN:  Certainly, as we heard, there were three time periods - the 8 hours, 24 hours, and then the 24 to 120, and presumably anything over 120 would not be used for manufacture of an injectable, but I guess even that was open for question.

    I think all of these need to be looked at and defined, and whatever data are available, should be brought to the fore.  Since I don't think it's addressed otherwise, but it was in the table, the issue of the shipping temperature and I guess duration of shipping needs to be addressed.  The FDA is proposing minus 5 degrees or colder. It is not addressed apparently in the AABB or the PPTA, although I thought your slide was different on that.  Maybe I just looked at it very quickly.

    So, I don't know if it's not only the initial freezing time and temperature, but whether the shipping time, the duration of shipping and temperature may also be important for consideration.

    DR. BULT:  I think it also adds to the value of having this workshop because we can talk about a 10-year time frame as a technical requirement, but to my knowledge, no company is using any material that has a 10-year time frame.  I think it is less than 3 years.

    The underlying concern is what testing technology is used on materials in question, how do you ensure that we are up to date and that we don't use old materials that may have not been subject to newest technology.

    DR. NELSON:  I think we have discussed this.  Next question.  This is the last one, right?

    MS. CALLAGHAN:  Yes, this is the last one.  You are off the hook after this.

    Should FDA limit the use of component plasma to make injectable products based on the time to freezing?

    DR. KLEIN:  Again, I hate to sound repetitious, but we really haven't heard very much data about this.  My feeling right now is that the initial step ought to be that suggested by the blood collecting organizations, and that is, that you label the component as to the time to freezing. That allows the manufacturers to determine whether it's acceptable for the intended manufacturing use, whether it's for albumin or whether it's for cryoprecipitate leading to Factor VIII.

    Eventually, I think we will want to define the time to freezing, but again without having any data presented to us, I don't see how we could conceivably do that today.

    DR. NELSON:  I agree.  In the current short supply agreements, under which recovered plasma is manufactured into injectables, do those agreements require the specifics, in other words, time to freezing and temperatures, that kind of thing?

    DR. BIANCO:  Yes, they do, they are very specific and the time to freezing, and transportation conditions, and those characteristics.

    DR. FITZPATRICK:  There is two different purposes. One, when you are labeling for FFP, previously, you were labeling a product to treat a bleeding disorder.  When you are selling plasma to a manufacturer, the manufacturer wants to have the most product available in that plasma, so that when they fractionate the product, they get the highest yield possible, so the freezing restrictions are practical and economic and efficacious in order to get the highest yield.

    From a fresh frozen plasma standpoint, you want the highest yield, but there were practical considerations because of mobile collections, time it takes to spin down and remove the plasma, and so there were both practical and efficacy issues involved there in small numbers of units to single patients as opposed to large number of units in a pool to create a factor concentrate.

    DR. NELSON:  I was just trying to find out if all of these data on this product were, in fact, available currently under these agreements, and hopefully, that was the case.  Apparently it is.  I can see the value of having some regulations or something, having a licensed product and having the FDA being able to monitor what is going on, too.

    DR. EPSTEIN:  I think what the FDA was trying to sort out is whether we ought to take the current practices and then codify them into the product specifications when we license them, or whether we ought to stay neutral and just apply the label as to time of freezing, but not link it to what anybody might do with that product.

    So, the issue of do we need more data comes down to whether we want to take a position on the product  standard and its intended use, or leave that open to the manufacturer and whatever we might approve in a final product.

    There are sort of two fault lines.  One fault line is we don't think anybody makes injectables from products that have been frozen at a time longer than 120 hours post-collection.  Would it not be reasonable simply to enshrine that as a minimal standard.  One could always have a voluntary, more stringent standard, but that would be a minimal standard.

    A more provocative question is whether we should take a position on a minimum standard for time to freezing if you are going to make clotting factors.  That issue gets down to the question of whether it's okay or not okay to blend source materials of different quality as long as you achieve the desired end product.

    Right now we are completely neutral.  The fractionator can fractionate whatever material they deem suitable, and we concern ourselves with the end product standard, but as Dr. Finlayson has pointed out, sometimes that can trip you up in terms of having an effect on the product quality, and so the question is should the FDA raise the bar at least for fractionation pools that are intended to make AHF.

    So, there are sort of two different fault lines here, one of which is current practice, the other of which is raising the bar.  Now, we don't have to decide either today, but what we are asking about is the principle, in other words, should we care about the ultimate use of the product as part of the product standard under regulation, or is it just enough to label it for its processing condition. That is really what we are asking you.

    We are not asking you where do we draw the lines. That would require looking closely at the data.  We are asking you should we apply this principle.

    DR. KLEIN:  Jay, again, I hate to be wishy-washy on this issue, but I think you should probably care, but again without seeing some of the data that John referred to, and some of the information that I am sure the manufacturers have and would give us in great perfusion should we ask for it, it is hard to know whether it's very important to do that of minimally important to do it.

    So, I think, yes, you should care, but it may end up that you don't actually define it that way because it may not make a difference, but, yes, you should care.

    DR. FITZPATRICK:  Given that question, Jay, I would support the AABB position of labeling the source material as to time of collection and time of freezing, and not codifying what goes into the factor concentrate by putting limiting factors on the source material, but my mind-set, can you not codify what source material goes into the end product, in other words, if you want to raise the bar on factor concentrate, can you not require the manufacturer to use source material frozen within X number of hours, and then they select from what is provided to them to fractionate as opposed to putting the onus on the other end from the supplier of that source material.

    DR. DiMICHELE:  I would just like to comment from the standpoint of these Factor VIII products, which I am more familiar with than blood banking components, but I think the issue comes really down to the factors are these concentrates, have we found problems with these concentrates in kind of not regulating the source material.

    One of the things that is becoming very obvious is as we are developing different assays, for instance, for measuring Factor VIII, is that products do measure differently depending on whether you are measuring it by chromogenic assay, by one-stage clotting assay, and plasma products look different than recombinant products.

    Among plasma products, there are differences in the profiles that have actually been published and discussed in, for instance, the Factor VIII/Factor IX Subcommittee of the ISTH, and interestingly enough, some of these differences are differences in whether the source material has been recovered plasma or whether it has been source plasma.

    Ultimately, however, the final point becomes do these products look differently when they are transfused and infused into patients, and unfortunately, that end sort of product analysis has so far not looked that different although there are subtle differences, the question is whether it makes a clinical difference.

    I think you can actually address this problem on many different levels, and the data required to answer the question of whether you should regulate the source material, I think can be answered on very many different levels.

    I think right now there probably are differences and whether they are clinically significant is I think yet to be determined, but assays are changing, and I think if at any time as we begin to maybe more precisely assay hemostatic efficacy of products, and we notice that there are differences, maybe these issues would have to be addressed from the source.

    DR. NELSON:  The other side of the equation, this is really very complicated because I am sure that requirements at a  certain level might lead to not having enough product available or shortages, or that kind of thing, and obviously, that's a patient safety issue, as well, and where to draw the line is really complicated.

    As I echo Harvey Klein, no data have been presented to date to evaluate any of these issues, but I guess, as a committee, we are very concerned about the efficacy.  We are also concerned about availability, I would think, for this critical group of patients.

    DR. NELSON:  Have we answered this question?  By raising five more questions.  Is that the last one?

    MS. CALLAGHAN:  Yes, that's it, you are off the hook.

    DR. NELSON:  Strangely, we are on time.  We will reconvene at 1 o'clock.

    [Whereupon, at 12:00 Noon, the proceedings were recessed, to be resumed at 1:00 p.m.]

A F T E R N O O N  P R O C E E D I N G S

     [1:00 p.m.]

    DR. NELSON:  This afternoon, the topic is Vaccinia Immune Globulin Intravenous: Current Thinking and Indications for Use, that will be presented by Dr. Dorothy Scott.

IV. Vaccinia Immune Globulin Intravenous:

Current Thinking and Indications for

Use - Informational Presentation

Dorothy Scott, M.D.

    DR. SCOTT:  I just want to let you know that I will be talking about monkeypox at the end, so at least there will be some exciting information coming up.


    First, briefly, I am going to talk about some of the issues that have come up with vaccinia immune globulins. I am going to start out talking about the manufacturing issues and things related to that, and go on to some of the clinical issues, then, finally, the monkeypox.

    The vaccinia immune globulins are used or historically, have been used to treat complications of the smallpox vaccine.  All of these products now are under IND and they are all manufactured from source plasma of donors that had been vaccinated at least once before with the smallpox vaccine and then are recently vaccinated for the purpose of harvesting high-titer plasma with anti-vaccinia antibodies.

    The source plasma typically has been collected approximately 10 to 30 days post-vaccination, and I will show you why.  This is kind of an interesting timepoint in a regulatory sort of way.

    The newer products are manufactured using solvent detergent treatment and nanofiltration steps for viral clearance.  Again, that becomes important.


    These are the complications of smallpox vaccination.  I actually will be adding a few at the end of this talk.  The ones that I have here in yellow are the ones that vaccinia immune globulin is felt to be effective for. When I say that, it is because mostly what we have to go on is published studies and historical controls.

    Eczema vaccinatum is one of those situations where vaccinia immune globulin is felt to be effective.  This occurs in people with eczema.  Sometimes even the eczema isn't active, but people with a history of eczema can get it.  These people, when vaccinated, have vaccinia spread to their skin in a widespread fashion, and this condition used to be fatal I think in about 20 percent of cases without VIG.

    Progressive vaccinia is a different kind of lesion.  It usually begins at the vaccine site, and this is a failure of the host to be able to clear the vaccinia virus, and usually, these are expanding necrotic lesions.  It used to be 100 percent fatal prior to the use of vaccinia immune globulin.

    Ocular vaccinia, especially blepharitis, conjunctivitis, there is a use for VIG in those conditions. It is felt that keratitis should not be treated because of some animal experiments which suggests that vaccinia immune globulin could increase corneal opacities.

    Generalized vaccinia is a question.  This is rather broadly defined, but some people do seem to develop rashes and high fevers and are rather prostrate, and it is thought to be due to a generalized spread of the virus, and vaccinia immune globulin has been used in those cases, but there isn't really a good definition of what constitutes severe generalized vaccinia.

    Then, there are other reactions to the vaccine - hypersensitivity reactions, encephalitis, which is quite rare, and recently, a mild pericarditis has been described.


    These are some of the challenges in the development and use of vaccinia immune globulin.  I put IV because all of our newer products are formulated for intravenous use.

    It is very difficult to determine what would be the optimal clinical study to show efficacy because, of course, real treatment studies are not possible in a pre-event scenario, in other words, not a lot of people are being vaccinated and there is an extremely low rate of the complications that are likely to be treatable with vaccinia immune globulin.  I will actually show you some numbers closer to the end of this talk when we are in the clinical section.

    There is also an interesting scenario with the current vaccination blood donor deferrals and their relationship to collections of plasma for vaccinia immune globulin.  There is a question of whether or not it can be used for post-exposure prophylaxis of people who were accidentally vaccinated and actually have contraindications to vaccination or even develop a contraindication after being vaccinated.

    There is a question of whether it could prove useful in other complications particularly the myopericarditis.  I will tell you about what the current feeling about that is, but we will know more information in a couple of weeks, not about vaccinia immune globulin, but about aspects of this disease.

    Then, of course, recently, how can one help but wonder if it could possibly be of use in monkeypox prophylaxis or treatment.


    First, I am just going to go on to the strictly regulatory aspects of licensure of vaccinia immune globulins.  This is a section of a talk that I actually gave to the Advisory Committee for Blood Safety and Availability last year, in 2002, in February.

    So, therefore, it is a review, but I know that this committee has not seen this information.  However, it was decided some years ago that licensure would be based on pharmacokinetic equivalence and safety data.  The pharmacokinetic parameters have to be not inferior to vaccinia immune globulin given IM.

    I would be glad to answer questions about how these studies can actually be done.  It is quite complicated and I would say that we are doing the best we can with what we have, I think all of us.

    It is complicated because there really isn't available VIG(IM) to give, so therefore, a theoretical curve needs to be generated to compare the real data to.  The curve is based, of course, on historical information, what we know about the pharmacokinetics of IM products.

    Human surrogate markers for efficacy are not required.  They are encouraged prior to approval.  An example of this would be the influence of VIG(IV) on the take of a vaccine, for example, lesion size or frequency of take.  This would give you some pharmacodynamic parameters.

    An accelerated approval designation was, and still is, considered desirable.  This would expedite availability of product.  Also the accelerated approval designation also lends itself to Phase IV commitments to human surrogate marker studies or even actual studies for efficacy.

    Mind you, I don't think this regulation was written with the scenario in mind that we have now, and that is that we have these anti-counterterrorism products that we have really no way of testing unless we have a widespread outbreak of a disease for which they are intended or involved.


    The scope of the accelerated approval is for biological products that have been studied for their safety and effectiveness--I would underscore this--in treating serious or life-threatening illnesses and that provide meaningful therapeutic benefits over existing treatments. Approval may be granted on the basis of adequate and well-controlled clinical trials establishing that product has effect on surrogate endpoint that is reasonably likely to predict clinical benefit, or on the basis of an effect on a clinical endpoint other than survival or irreversible morbidity.


    The approval requirements include that the applicant studies a product further to verify and describe clinical benefits, especially when there is uncertainty as to relation of the surrogate endpoint to clinical endpoint. Post-marketing studies are expected to be designed and underway promptly, need to be carried out with due diligence subject to post-marketing recordkeeping, and those requirements would no longer apply once FDA determines that the post-marketing studies have verified and described the product's clinical benefit.

    Again, interesting challenges for these kinds of products.


    In 2002, we also told the Blood Safety and Availability Committee that new product indications or indications for the new VIG(IV)s would be limited to treatment of historically vaccinia immune globulin treatable vaccine virus complications, however, things have happened since then, and there is a potential for considering post-exposure prophylaxis possibilities.

    For example, is this something that you may wish to have an indication for treating people who are accidentally vaccinated, who are immunocompromised or who have eczema or other exfoliative skin conditions.

    I would note that there was an indication in the previously licensed Baxter product for post-exposure prophylaxis for exfoliative or inflammatory skin conditions including eczema, but not limited to eczema.  Of course, like all of the rest, these were not based on controlled studies, but rather on retrospective studies.


    Our current thinking is that we encourage a study of animal models and of human surrogate efficacy markers, and trying to understand those, and that licensure requirements may change as a result of animal and human studies.


    Now, I am going to go into the manufacturing issues, followed by the indications for VIG use or at least how it has been used and what has happened in the recent smallpox vaccination efforts, and finally monkeypox.


    After the development of vaccinia immune globulins, at least after we received some INDs, we published a blood donor deferral guidance to do with smallpox vaccination and blood donor deferral.  That was in January of 2003.

    Among other things that suggested or recommended a deferral for vaccinees for 21 days after vaccination or until the scab falls off, whichever is longer.  The rationale for that was that there is a possibility of viremia in normal people who are vaccinated, and I will go into what little data we have in a minute, and that the consequences to a recipient of receiving vaccinia injection intravenously could potentially be severe especially when you consider that some transfused people are immunocompromised.


    This is some data that we received, which I have permission to show in the form.  This is just a donor response to dryvax vaccine, and this is an average of multiple number of donors, so this is not just one person.

    These are antibody titers.  They are actually in the form of units.  I will tell you now these are high titers.  This is the kind of plasma that a vaccinia immune globulin will be made from, and this is time after vaccination.

    All I can indicate to you, and I am grateful to have this data to show at all, is that these time periods here, and certainly here, are likely to fall within the donor deferral criteria.


    I would point out that VIG products historically have been made from plasma collected early post-vaccination. The reason is because that is where you get your highest titers.  Also, in vitro studies, to look at whether or not these are infectious, at least if not indicated, any sign of infectivity.  In other words, they don't have plaques in plaque assays, and there is not other evidence of live virus in the products.


    What are the chances that somebody who was vaccinated, who is otherwise normal, is going to have viremia?  Well, nobody knows.  In 1930, and I have this paper that was kindly translated for me by Robin Biswas, I think I should give him attribution, a group did actually look at normal children after vaccinated, took their blood, and titered it for vaccinia by a bioassay in rabbits, which was then passed along through some other organ, and basically, they were able to find viremia in 8 out of 17 of these children.

    How those experiments were done, what level of caution was taken, it is really impossible to know, but I would also point out that this is a European strain.  People were vaccinated with strains from different European cities, so they would have a Dresden strain and strains from all these cities, but typically, the older strains are thought to have been hotter strains, as it were, and perhaps are more likely to give you viremia.

    This is what they reported.  They noted viremia in a range of days from 3 to 15 post-vaccination, but mainly around day 6 or 7.  There is where your antibody response is just beginning to come up.

    It was also reported in a 1953 German journal, and we weren't able to get access to that.


    Kempe, in his Pediatrics article, reported that they had looked in over 100 normal patients after vaccination, and were not able to find evidence for viremia, however, the data wasn't shown.

    At FDA, we have plaque assays in progress to look at some study samples to find out whether or not there is evidence of viremia.  So far as I am aware, there have been no positives, but I can't give you the details.  These are being done in Dr. Indira Hewlett's lab, and I am sure she will report these when they have their final conclusions. They are also developing PCR assays.

    I am aware that in industry, as well, that these studies are being done, as well as in other government agencies.  I will point out, though, there is one limitation, and that is typically, these samples are collected to look at antibody and CTL responses, and they are not collected on an extremely frequent basis, so that if viremia is quite transient, it still could be missed in studies like these.


    Now, if you did have accidentally a little bit of vaccinia virus in your vaccinia immune globulin, what is the likelihood it would be inactivated?  Well, first, you would argue that it is likely to be neutralized by the antibodies.

    Let me tell you a little bit about vaccinia virus. It's enormous.  The orthopoxviruses are the biggest viruses there are.  Apparently, they can be seen under certain conditions by light microscopy.  They are enveloped DNA viruses.


    There have been some published studies about the clearance of vaccinia viruses during plasma fractionation using fairly standard types of viral validation methods. I am just going to show you two because these relate to the products that we have at hand.  There are other methods that have been studied.

    This is from a study by Roberts, I think, from BPL in Biologicals 2000.  A number of viruses were looked at for the purpose of this paper, but in this case, vaccinia virus was looked at in the context of solvent detergent treatment of a Factor VIII intermediate, so this was after cryoprecipitation, but prior to further purification.

    I am just showing you three viruses that were studied, so that you get a sense of what vaccinia is like.

    Here is vaccinia.  The treatment was TNBP 0.3 percent and Triton-X 1 percent, and so we don't have any robustness studies as a part of this paper.  This is the time of S/D treatment.  So, it goes all the way up to just 2 hours, which is kind of on the low side compared with what usually occurs in manufacturing typically at least, 4 hours of S/D treatment.

    This is just a quarter of an hour after exposure and this is the logs of vaccinia virus clearance.  You can see, as one might expect, that it is going up over time, but in this study, they never got complete clearance of everything that they added, whereas, if you look at HSV-1 or Sindbis virus, you can see that they are much more rapidly cleared.


    This is a study of S/D treatment of Fraction II precipitate using TNBP and Polysorbate 80.  There aren't very many details in this paper, so it was very hard to tell, impossible to tell whether this is a 60 or 180 minute treatment.  We don't have kinetics.

    Again, here is the virus vaccinia compared to HIV-1 and VSV.  This is how much was added.  This is how much was recovered from the spike, and this is how much was recovered after solvent detergent treatment, and here you have your reduction values and your clearance values.

    You can see here that the reduction of vaccinia is not exactly impressive compared with HIV and VSV.


    All of our recently manufactured new IND products have 2 viral inactivation or clearance steps that are expected to have an effect on vaccinia.  One is solvent detergent treatment--this is actually two--is nanofiltration.


    This is my final slide on this topic.  Just pointing out what we are thinking now about this issue, that donor exclusion for 21 days plus, because some people, the scab falls off later, post-vaccination would result in a loss of high-titer plasma for this product.

    Our working assumption is that viremia is likely to be infrequent, rare and/or intermittent if it's present at all in normal vaccinated donors, but it still could be there, there is no doubt about it.

    Testing for post-vaccination viremia while it's ongoing may not give us the answer for sure, in other words, we still could be missing something if it's transient.

    Viral clearance studies suggest that vaccinia can be inactivated by solvent detergent treatment, but it's relatively resistant compared to other enveloped viruses, at least in the studies where we looked.

    Of course, in validated studies from these manufacturers, we would expect to have somewhat different conditions and somewhat did matrix, so they have higher or better viral inactivation.

    I would point out that we think process-specific validation would provide an enhanced assurance of safety for this product.


    Now, I am going to switch to potency aspects for vaccinia immune globulin.  As I mentioned, it is not possible to determine the efficacy of VIG for its probable indications, so potency testing becomes an important surrogate of efficacy.

    The product potency is routinely tested by in vitro plaque reduction assays.  FDA has requested that we have bioassays rather than ELISA assays to assess potency.

    Also, we have developed an in vivo model of potency in severely immunocompromised mice.  These, of an in vivo assay, while we certainly are not requiring it of manufacturers, is useful to us because it can reflect neutralization of forms of the virus that are not easily cultured, in particular, the extracellular envelope form of the virus, which is probably important in spread in vivo.

    It also enables in-house comparison of neutralization activity for different products, and the project that we started doing this, I mean a SCID mouse is really the worst case, has now expanded to look at the efficacy and the mechanism of action effects in the immune globulins in CD4-deficient and hopefully eczema vaccinatum models, also to look at pre- and post-exposure prophylaxis.

    I am just going to show you one example of a prototypical experiment that we have done.


    I am only going to show you one of these, don't worry.  This is just to show you how the assay works that we have done.  We have tested all of our products that are in-house including the very old vaccinia immune globulin using these assays.

    This is injection of 6 SCID mice with a mixture of virus and vaccinia immune globulin.  So, it is not pre- and post-exposure prophylaxis, it is simply doing a neutralization in a test tube and injecting it into mice. It is sort of a mixture of an in vitro and in vivo test.

    This is the proportion of mice that survived and that is the time after injection.  These are mice that received virus alone, and typically, they die in about 30 days.  They have really got no defenses other than NK cells.

    Here, you see the dose-response curve.  These are mice given a total of 5 mg of VIG(IG), 1.25 and 0.3 mg.

    So, we are able to see a dose response and we are able to get a sense of where our products are.


    I also want to mention that we have developed an interim VIG standard.  This was manufactured by Massachusetts and kindly everybody has allowed us to have a portion of this lot and to supply it.  Of course, it was manufactured under GMP conditions.  It was aliquotted and frozen.  We have done two freeze-thaws, and it doesn't lose potency.

    It has been tested in three different labs with three different assays, well, three plaque reductions, 1 beta-GAL, and the SCID mice, and all of these tests have good agreement, and it is available from us at CBER for anybody who is doing research or development.


    Now, I am going to switch to the clinical issues with the use of VIG.  First of all, I want to point out that since we have started the vaccination of first responders, our designated teams of responders in the states, and a large portion of the military, that to date no cases of progressive vaccinia or confirmed eczema vaccinatum have occurred.

    This just gives you a sense of the denominators, and these numbers I got yesterday at CDC, so I think they are pretty up to date.  No such cases of either of these complications in about 450,000 military vaccinees, and none in the 37,000-plus civilian vaccinees.

    However, VIG has been requested for a couple of things.  One is for prophylaxis against eczema vaccinatum and a recently vaccinated burn patient, so, in other words, this is someone who got his vaccine, got some terrible burns,  and was felt to be at risk of a condition similar to eczema vaccinatum.  He did well.

    One case of ocular vaccinia and some cases of post-vaccination discovery of pregnancy.


    Now, with regard to the use of the vaccinia immune globulin products in pregnancy, the CDC has pointed out that the estimates, well, there is such a thing as fetal vaccinia.  I should say it is extremely rare, but it is a vaccinia infection of the fetus and it can be fatal to the fetus, however, the frequency of this is very low, and so the question is whether or not you would prophylax for this, what are your chances of really accomplishing anything.

    I would also point out that the inadvertent vaccinations of people who are pregnant that have occurred in the past year are mostly due to very early pregnancy that couldn't be detected on pregnancy tests or to conceptions fairly soon after vaccination.

    CDC has advised that women should contact their healthcare provider regarding use of vaccinia immune globulin, and CDC's Advisory Committee for Immunization Practices does not recommend preventative use of VIG for pregnant women.

    However, they have established a pregnancy registry for follow-up of vaccinated pregnant women.


    We have a new complication of smallpox vaccination, newly recognized at least, and that is an inflammation of the heart muscle and/or lining of the heart, myopericarditis is the name currently for this disease.  Some people have one, some have the other, and some have both.

    This is the rate of cases that have been seen in the Department of Defense vaccination effort, and the civilian vaccination effort.  Fortunately, there have been no fatalities, and the etiology is thought to possibly be immune mediated, in other words, is not currently believed to be vaccinia infection of the heart or of the pericardial sac.

    Publication of these cases and analysis of these cases is expected within the next couple of weeks, so keep your eyes out on some weekly journals.

    VIG use would certainly have to be carefully weighed in this context because, of course, you wouldn't want to enhance any immune or inflammatory response.

    There is ongoing follow-up of these cases to see whether they have long-term sequelae, such as cardiomyopathy.


    I was in Atlanta just a couple days ago, well, yesterday, and I just want to convey what is happening with the smallpox vaccine effort among civilians.  The Advisory Committee was concerned about the new complication of myopericarditis, naturally voted unanimously to recommend no current expansion of the existing state voluntary vaccination programs.

    The existing vaccination programs were to vaccinate sort of clear-cut teams of first responders and then to go on and more widely vaccinate people that might be first responders like firemen, policemen, and so forth, and they are not too keen on that right now.

    However, other aspects of preparedness should continue, that is, hospital readiness, and so forth.


    I am going to go on to monkeypox virus, which is recently emerged disease.  We certainly are thinking a lot about it in the Office of Blood in the context of blood donors.  Monkeypox is thought to have been brought to the U.S. in a shipment of 800 small mammals from Africa.  The most implicated animal now has been the gambian giant-pouched rat.

    You wonder what is the difference between this and a normal rat, and the difference is these are really big rats, but they clearly have a following.  They and/or some of their compatriots, such as doormice-infected prairie dogs, and that is where most of the infections have come to people.

    Now, monkeypox virus is another orthopoxvirus like vaccinia and small pox, it has got very close nucleotide sequence homology to smallpox, and studies in Africa have shown epidemiological studies that pre-existing immunity to smallpox or pre-existing smallpox vaccination I should say, well, actually, smallpox itself.  It seems to confer significant protection against monkeypox.

    The case fatality rate for this disease in Africa has been reported to be 1 to 10 percent.  Right now there are 87 cases under investigation in the U.S., as of yesterday, and I should point out that while most people have recovered there has been one case of encephalitis, and this is somebody who had to be intubated.  It was a 6-year-old child, and it is quite clear that this disease can be extremely serious and certainly that would get you up to your 1 percent fatality rate if she were not given the tertiary medical care.


    This is just a picture of monkeypox lesions.  You can see in this case they are vesicular, however, more subtle lesions have been described, and CDC has just revised their case definition essentially to include rash of any type and in any distribution, so they can be much more subtle than what you see here.


    What about monkeypox and the use of vaccinia immune globulin for prophylaxis or treatment?  VIG use, if any, is under discussion now with CDC, and I would note that they have recommended smallpox vaccination for people who are likely to have been exposed to monkeypox, so they are certainly thinking along the lines of using anti-smallpox strategies against monkeypox.

    In this case, the smallpox vaccination is still contraindicated for certain immunocompromised people who have been exposed to monkeypox.


    I just want to finish by acknowledging people who did a lot of the vaccinia research.  I only showed you one out of quite a number of graphs and interesting things that we found out, and the people who have worked especially Chris Anderson and Hana Golding on the vaccinia immune globulin interim standard.

    Thank you.

    DR. NELSON:  Thank you very much, Dr. Scott.


    I know when this expanded, the vaccinia program for bioterrorism was proposed, one of the concerns was the supply of vaccinia immune globulin to treat the potential complications based on a calculation from the data in the '60s where there was intensive surveillance to try to estimate how frequently VIG might be needed, but the current supply I guess is much more adequate than it was a year or two ago, is that correct?

    DR. SCOTT:  I would say it's more adequate and I think it also is useful to point out that the screening now as compared with the 1960s is probably much, much better.

    DR. NELSON:  It is, but we have got much more HIV now and other things, too, than we had then, so the hazard--I mean the program, the estimate was that 500,000 people would be vaccinated, and so far, 37,000 have been.  It is not widely accepted as to what the real risk is.  Were it to expand, I think we might have some issues.

    DR. ALLEN:  Just a question with one of your early slide on the complications.  Do I recall correctly that generalized vaccinia does not have nearly as high a fatality rate as progressive vaccinia?  It is in that variable category about whether VIG is useful, is that because there hasn't been much experience or it just doesn't occur frequently enough that anybody really has looked at the issue?

    DR. SCOTT:  I think it hasn't been well defined enough, but you are absolutely right that for what was called generalized vaccinia, which appears to be generalized rash often in children who looked otherwise healthy and were running around, it was extremely low and my understanding is that VIG was only used for children or people who were prostrate with fever and had very extensive rashes, which is less than 1 in 10 of these generalized vaccinia cases.

    DR. KLEIN:  On the mouse dose-response slide, you have got a couple late deaths at the highest neutralizing titer.  I was surprised we didn't go beyond 120 days because you wonder whether that's just delaying or is that actually preventing?  Do you have any data on that at all?

    DR. SCOTT:  Well, this is why we need money for research, but I would also point out one of the problems with these experiments can be that sometimes it is difficult to tell if you have got 1 out of 6 mice sick at all, or if you got 6 out of 6 sick, because the incubation period is about 14 days to pox, and so if you get something that is delayed--well, in this case it is 1, but if we got more, we wouldn't know if that 1 gave it to the others, because we know that can happen, we have done those experiments.  We have put infected mice in with uninfected mice and watched the incubation period, and they all get infected, but if you have individual cages, which cost $30,000 a rack, you can avoid that problem.

    That doesn't answer your question.  In the higher doses of VIG(IV) that we use, we on occasion will see 1 out of 6, more often than not, we see zero out of 6 ever get pox, and we followed at least one group of mice probably for about half a year.

    If you consider the model, which is a SCID mouse, it has no immune defenses, I think it is pretty good.

    DR. NELSON:  Comments?

    So, do you know what the supply of VIG is now, is that cataloged somewhere?

    DR. SCOTT:  Well, I do, but I think you would have to ask the CDC officially how much they have in their hands, but it is quite adequate for now, but that has to be taken into context.  I think if something happened tomorrow and there were a mass vaccination, possibly our complication rates would be higher because it would be less controlled circumstances.

    The people who were vaccinated were very carefully screened as a rule, and many of them, at least in the civilian sector, were already healthcare providers and had a clear understanding of how to avoid contact vaccination of other people, and how to avoid complications.

    DR. NELSON:  I am not too clear how or why the supply of VIG increased.  Maybe it was related to the current vaccination effort.

    DR. SCOTT:  Absolutely, and the potential vaccination effort.

    DR. NELSON:  I know that the supply of vaccinia was increased because one company was found to have had a whole bunch of it in the freezer, and then there were studies were to show that you can dilute it and still get an adequate response, and now there is this big contract for a new smallpox vaccine or what have you.

    So, I guess we are well prepared even for monkeypox maybe.

    DR. BIANCO:  Dorothy, is FDA contemplating any measure regarding monkeypox, something that could affect us?

    DR. SCOTT:  It's under discussion, Celso.

    DR. ALLEN:  Not directly on VIG, but on the smallpox deferral recommendations that came out earlier this year, any comments or adverse comments from people or organizations with regard to those, or they have been pretty well accepted?

    DR. SCOTT:  I think it is always desirable when we can to release a draft guidance and then go to final guidance depending on the circumstances, so the comments we received were in terms of constructive ones about how it might be possible to refine the donor questioning and to make things in a sense easier and still accomplish the same outcomes.

    I think also, as you all know even better than I do, I am sure, adding yet another donor question is always perceived as a burden.

    DR. NELSON:  Fortunately, I think at least for smallpox and other poxvirus infections, most of the cases are clinical, so we wouldn't need to worry about somebody who happened to have petted one of these huge, big rats and might be a subclinical carrier if he or she didn't have any symptoms, but maybe we don't know that.

    DR. SCOTT:  That isn't at all clear.  For smallpox, there is Variola sine eruptione.  There might be cases where people are transiently viremic, nobody knows for monkeypox.

    The likelihood that monkeypox has a viremic phase like smallpox does is there, and they develop a prodrome for monkeypox, at least the people have gotten sick with it, which is quite impressive apparently, with high fevers and severe backaches, but whether or not somebody is viremic the day prior to that is entirely unknown.

    DR. NELSON:  Other questions or comments?  Yes, John.

    DR. FINLAYSON:  I would just like to answer a question that Dorothy already answered, which was did the bioterrorism threat result in the much larger supply of an immune globulin, but I would also like to point out that one of the reasons that this program could get off the ground so fast is that there was already, before the bioterrorism threat, yet another rationale for having an immune globulin present.

    That is, that vaccinia is a fairly popular carrier in the biotech world, and so there were physicians conducting clinical trials with such vaccines in which the vaccinia was not the antigen, but the carrier, who just simply wanted to have some vaccinia and immune globulin present.

    Of course, for 20 years, we had thought that vaccinia and immune globulin was a product without a disease, so naturally, the supply of the intramuscular material had been allowed to dwindle, and that was the initial stimulus for the preparation of an intravenous product.

    DR. NELSON:  Some of the HIV vaccines were constructs where the vector was vaccinia actually.

    DR. DiMICHELE:  My question is then if the issue of potential vaccinia, you know, viremia contamination of this immune globulin has not been settled, are you still going ahead and collecting it?  I mean is there still ongoing collection from, for instance, vaccinated donors or whatever?  I guess I am a little confused by that.

    I am a little confused about the current product that we have.  I mean it was collected in the same way, right, made and collected in the same way?

    DR. SCOTT:  Yes, that is correct.  Of course, it is an IND product, so it is administered with informed consent, and so forth.  However, for purposes of licensure and additional assurance, viral validations seems a wise choice.

    DR. DiMICHELE:  Is there still collection going on?

    DR. SCOTT:  Yes.

    DR. DiMICHELE:  Donor collection

    DR. SCOTT:  To my knowledge, I believe there is.

    DR. NELSON:  I think initially, there had been no particular effort to remove viruses, you know, vaccinia that were in there, hoping that the immune globulin would neutralize them or whatever, but is it still the same procedure as it has been for 40 years or however long, for collection and preparation of VIG?

    DR. SCOTT:  I would say markedly improved and more well controlled.  Compared with what existed before, this is many generations ahead in terms of safety parameters, sophistication, and so forth.  In fact, there has been no historical belief or observation that these kinds of products have ever transmitted vaccinia.

    In other words, beginning quite a few years ago, in the regulation of these products, it was not perceived as a potential problem.

    DR. GOLDING:  Could I just add to Dr. Scott's answer?  In terms of the safety, what we are looking for is actual viral titers during the period of time when these people are donating, and also looking to see what kind of viral inactivation steps are in place and whether the highest viral titers, viral loads that could possibly be in the product would actually be removed by the inactivation steps.

    So, it's the usual paradigm for viral inactivation, but we aren't there yet, and the information is being gathered partly by the FDA and partly by the industry that are completing the study, so hopefully--not hopefully--before any of these will be licensed, I think we would have to have all of that in place in order to get licensure of any of these products.

    DR. SCOTT:  I would also point out I did show you what S/D information is available.  I certainly didn't show you any nanofiltration, but I did show you the slides of this virus, which is enormous, and even more standard filtration, of which there are many in plasma fractionation manufacturing, should remove it.

    DR. NELSON:  They could probably do EM studies of the product and see the virus that was there, right?  I don't know if there was virus.

    The other intriguing thing that you mentioned was about the myopericarditis.  I guess the implication was that we don't know the pathogenesis of this, but it might well be an immune-mediated phenomenon, so therefore, the vaccinia immune globulin treatment would not be appropriate.  There probably isn't any good data on this.  I don't know if any of the cases occurred or had to had vaccinia immune globulin and then developed the myopericarditis.

    DR. SCOTT:  The answer to that latter question is no.  There are some case studies in the literature that are very old, which have also indicated that this occasionally occurs.  Autopsy reports have reported some inflammation and inflammatory infiltrates.

    There will be a case report coming out in the next couple of weeks, and I am sorry I am not at liberty to tell you more, but we were involved in this case, at least peripherally, because the question of using VIG came up, and I think people will be pleased to see the amount of data that came out from an extremely thorough workup of this case, but it does definitely point to an immune inflammatory response rather than a direct infection.

    DR. NELSON:  Very good.  Again, this was informational, it was very good and interesting current important information.  There is no question here that we need to ponder.  When we get a lot of data, we don't get a question.

Committee Discussion

    DR. FITZPATRICK:  Can we move back to white particulate matter for like five minutes?

    DR. NELSON:  Sure.

    DR. FITZPATRICK:  After some discussion and thought from last night, I wondered if you would entertain a motion that we recommend that FDA rescind their current recommendation for extended inspection because of the data they presented yesterday that indicates that there doesn't seem to be concern.

    Even though they want to collect more data, I understand their desire to collect more data, they didn't provide data that supports the continued necessity of the extended inspection.

    DR. NELSON:  Are there any comments?  Dr. Strong.

    DR. STRONG:  I will second the motion.

    DR. NELSON:  That seems reasonable.  I have been advised that we won't have a voice vote, but maybe we could just have a hand vote.  No?  I guess we can't do that.  Maybe a consensus recommendation?

    DR. SMALLWOOD:  The procedure is that we have to deal with the issues as they come up on a particular day. Because of the public involvement and we are going back and those that are not present today, that were present yesterday would not have the benefit of that.

    So, what I have advised the Chairman is that if that is a consensus recommendation, we take it as such, but you do not vote whether it's verbal or hand raising.

    DR. KLEIN:  Could I just ask a question about that?  I have no problem with that and I have no problem with either voting or not voting or getting a sense of the committee, but since public discussion was through, and then it is really the deliberation of the committee, I don't see why the public with an interest being present or not being present makes any difference.

    The public already had its opportunity to comment, is that not correct?

    DR. SMALLWOOD:  The issue was not up for voting. It was only a committee update.  So, therefore, I have to follow the procedure as stated originally.

    DR. ALLEN:  Would it perhaps be helpful, but not out of order, if we went around and everybody made a simple statement, declarative statement, as to where they stood on the position?

    DR. NELSON:  I have voted in an awful lot of elections that didn't seem to make any difference in the outcome.  In fact, that is the usual case.

    Maybe I could ask if there is anybody that disagrees with Colonel Fitzpatrick's recommendation that the committee advise the FDA that, to this extent, that this requirement could be removed, unless there is another compelling reason that we don't know about that might require its continuance.

    Is that okay?

    DR. FITZPATRICK:  That would be fine.  Just so we get something in the record.

    DR. NELSON:  Any discussion?

    [No response.]

    DR. NELSON:  Okay.  The vote was unanimous.

    DR. DiMICHELE:  I actually have to abstain since I wasn't here for the presentation.  I will abstain from whatever just happened here.

    DR. SCHMIDT:  The same statement here.

    DR. NELSON:  Very good.  We accomplished a lot.  We will see you again on September 18th and 19th.

    Thank you.

    [Whereupon, the proceedings were adjourned at 2:05 p.m.]