ATDEPARTMENT OF HEALTH AND HUMAN SERVICES

> FOOD AND DRUG ADMINISTRATION
>
> CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
>
> **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.**
>
> **BLOOD PRODUCTS ADVISORY COMMITTEE MEETING**
>
> **76th MEETING**
>
> Friday, June 20, 2003
>
> 8:30 a.m.
>
> Hilton Gaithersburg
>
> 620 Perry Parkway
>
> Gaithersburg, Maryland
>
> PARTICIPANTS
>
> Kenrad E. Nelson, M.D., Chairman
>
> Linda A. Smallwood, Ph.D., Executive Secretary
>
> MEMBERS:
>
> 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.
>
> CONSUMER REPRESENTATIVE:
>
> Robert J. Fallat, M.D.
>
> NON-VOTING INDUSTRY REPRESENTATIVE:
>
> D. Michael Strong, Ph.D.
>
> TEMPORARY VOTING MEMBER:
>
> Liana Harvath, Ph.D.
>
> [C O N T E N T S]{.underline}
>
> **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**
>
> **Use-Informational**
>
> A. Presentation
>
> Dorothy Scott, M.D. 133
>
> B. Committee Discussion 168
>
> [P]{.underline} [R]{.underline} [O]{.underline} [C]{.underline}
> [E]{.underline} [E]{.underline} [D]{.underline} [I]{.underline}
> [N]{.underline} [G]{.underline} [S]{.underline}
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.\"
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> Questions?
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> As I said, we propose these as licensing requirements.
>
> \[Slide.\]
>
> 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.\"
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> The current caution statement, that is, \"Caution: For Manufacturing
> Use Only into Injectable Products.\"
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> Again, the amount of the product, so this could be the total volume or
> the weight of the plasma.
>
> \[Slide.\]
>
> 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.\"
>
> \[Slide.\]
>
> If the plasma has been collected by plasmapheresis or apheresis, the
> total type and volume of the anticoagulant used.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> The statement about the testing that has been done, which would be
> sort of generic, that is, just negative by FDA required tests.
>
> \[Slide.\]
>
> The collection date would include the month, the date, and the year.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> Obviously, short supply agreements should no longer be necessary when
> plasma for manufacture is licensed.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> Paul.
>
> 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.
>
> Harvey.
>
> 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.
>
> \[Break.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> Should a different name be applied to plasma intended for
> manufacturing only into non-injectable products, for example, the name
> could be reagent plasma?
>
> \[Slide.\]
>
> Does the committee agree with changing the definition of source plasma
> in the regulations to include the requirement for freezing immediately
> after collection?
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> Celso.
>
> 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. CALLAGHAN: No.
>
> 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]{.underline}
>
> \[1:00 p.m.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> \[Slide.\]
>
> 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.
>
> Questions?
>
> 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.
>
> \[Whereupon, the proceedings were adjourned at 2:05 p.m.\]