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
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 R O C E E D
I N G S
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
[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.]