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Blood Safety Transcripts
DEPARTMENT OF HEALTH AND HUMAN SERVICES
FOOD AND DRUG ADMINISTRATION
ADVISORY COMMITTEE ON BLOOD SAFETY AND AVAILABILITY
WHAT HAS CAUSED THE CURRENT SHORTAGES
OF PLASMA DERIVATIVES
AND WHAT CAN BE DONE TO CORRECT THIS SITUATION?
Tuesday, April 28, 1998
8:24 a.m.
Holiday Inn Georgetown
2101 Wisconsin Avenue, N.W.
Washington, D.C.
PARTICIPANTS
Arthur Caplan, Ph.D., Chairman
Stephen D. Nightingale, M.D., Executive Secretary
MEMBERS
Larry Allen
James P. AuBuchon, M.D.
Michael P. Busch, M.D., Ph.D.
Ronald Gilcher, M.D.
Edward D. Gomperts, M.D.
Fernando Guerra, M.D.
Paul F. Haas, Ph.D.
Keith Hoots, M.D.
Carolyn D. Jones, J.D., M.P.H.
Dana Kuhn, Ph.D.
John Penner, M.D.
Eugene R. Schiff, M.D.
Marian Gray Secundy, Ph.D.
John Walsh
EX OFFICIO REPRESENTATIVES
Mary E. Chamberland, M.D.
Richard J. Davey, M.D.
Jay Epstein, M.D.
David Feigal, M.D.
Paul R. McCurdy, M.D.
Jane A. Piliavin, Ph.D.
C O N T E N T S
Page No.
Introductory Remarks
Dr. Arthur Caplan 4
America's Blood Centers Perspective
James MacPherson 12
American Red Cross Perspective
Christopher Lamb 32
Food and Drug Administration Perspective
Dr. Mark Weinstein 65
Public Comment Period
Tom Moran 92
Cory Dubin 98
Sandra Brandley 101
Patrick Robert 102
Donald Tankersly 110
Committee Discussion 116
R O C E E D I N G S
DR. CAPLAN: Let me ask everybody if they would
take their seats.
What we are going to do is we have got two
speakers who kindly agreed to be put over until this
morning, James MacPherson from America's Blood Centers and
Christopher Lamb from the Plasma Operations, the American
Red Cross. We also have Mark Weinstein on this morning, and
then we have two people in the public comment period who we
will hear from.
At that point, we are going to move into
discussion of some of the things that this committee would
like to see happen as a result of the testimony that we have
heard. I want to begin thinking a little bit about some of
the directions we could go in.
I am just going to put some issues on the table,
not for final form. They are really just things to be
thinking about based on what we have heard so far that I
think we may want to say something about, and there may be
other things that we want to say things about, but this is
just in the service of getting us moving today when we get
to our discussion period.
One thing seems clear to me from listening to
yesterday's testimony. To some extent, some of the shortage
that has come up with IVIG arises because people in the
manufacturing side are not watching one another's production
plans, and so there is a shortage of data and a shortage of
someone having access to that data to allow or trigger
concern if it looks like production is not going to keep up
with demand.
So, one thing we may want to think about is giving
authority to some agency minimally to have access to the
requisite information to make sure that this vital supply of
blood products is not subject to market failure, inadvertent
market failure if you want to describe it as such, because
one company doesn't realize that another company is going
off-line or isn't making enough product or inventory is
slipping and no one is watching it in toto, and it does seem
to me there is a problem here about having an outside party
-- I am not sure who that might be, maybe the FDA, maybe
some other agency -- with the authority to at least get the
numbers.
We made a good start yesterday towards seeing some
numbers for the first time about IVIG supply. I was pleased
personally to see that this is going to happen on a
three-month basis from now on, but I am still concerned, the
whole area, because so many Americans rely on it, that we
get timely information about what is going on, so that if
there is a problem emerging, it can be flagged without
violating various business laws and practices, and so forth,
that companies have to operate under.
A second issue that came up for the long run that
I noticed was this issue of off-label and growing use for
various purposes of IVIG. It does seem to me that there is
an issue here about what medicine and clinical positions and
pharmacists need to be told about what to do both in
circumstances of general use and under circumstances where
there is a shortage.
We heard that people were battling one another for
the right to access the supply, and at the same time some
people came to us yesterday and had some very clear
explanations, and I thought amazingly for some of them, even
without access to an ethicist, had made up some very good
principles about how to distribute the supply according to
prioritization, about need, and so forth, and I think those
are great, and I was very impressed with those, I hope you
were, too.
There were some remarkable attempts to struggle
with scarcity, but we want to make sure that if this
scarcity is being driven in part by let's call it less than
vital use of blood products, such as IVIG, that messages go
out, from the NIH, from all federal agencies, that if we are
in scarcity, and tomorrow morning, let me remind you, we
will be in scarcity, that when we leave here we are still
going to have an inadequate supply of that substance, it is
not going to get fixed tomorrow morning, that we may want to
issue some recommendations about what to do now with respect
to off-label and non-approved uses, or areas where there
isn't data to show efficacy.
That may also come in the form, I was even
thinking potentially of a note from this committee to
medical journals about what to do in the time right now
shortage, so maybe workshops or information to practitioners
and pharmacists letting them know that there is this
shortage and what they should be doing and then continued
efforts to make sure that the demand for particularly IVIG,
or whatever the blood product is, is consistent with what is
known about efficacy and appropriate use.
So, that is a second area. If demand is driving
things, we may want to say some things about what to do
about that in the short run, in the long run.
A third issue that came up yesterday, which I
wasn't so happy about getting light shed on it completely,
but if there is shortage, we heard some talk about the blood
supply being something that Americans have to take seriously
as a responsibility to try and manage as a community, and
the rhetoric pricks up my ears of donor and donation as all
through the collection process.
People donate if they think that the supply is
short, there is an issue about where is that supply going,
is it going overseas, is it going elsewhere before it is
used in the United States, if we are the source of all the
plasma for the world, if there are markets distributing, is
the burden of shortage being handled equitably around the
world.
It seems to me I am not quite sure yet how that
burden is being distributed, but it is something the
committee may want to say something about in terms of again
response to scarcity.
The last point I will make, just to get you
thinking again, is that we did hear some about products that
might be emerging, that might be risk-free. This interest
in recombinant factors is very interesting as one way to
solve some exposure problems.
We want to push hard there and say that if some
nations are moving very fast, Canada and the UK, toward the
use of recombinant, we might want to make sure that
obstacles to access here are removed and that we push hard.
Paul McCurdy said yesterday the NIH was going to
do a consensus conference --
DR. McCURDY: We are thinking about it.
DR. CAPLAN: -- think about it, well, maybe they
should think harder about it. We should tell them to think
harder about it and sooner about it. That was well said -
there is 30 years of experience, we are thinking about it.
[Laughter.]
DR. CAPLAN: But we may want to urge steps to both
see this area developed aggressively with requisite research
and discussion about when it is ready to go on line, and
then to make sure that whatever obstacles, financial or
supply, might be out there, are minimized and make sure that
Secretary Shalala understands that there is an attractive
option, other nations are pursuing it, and I would hate to
see us come up with a supply of recombinant and then be
selling it overseas, but not having our own citizens have
access to it.
So, there may be ways to relieve some of the
burden of disease and help the safety issue if we can move
more to synthetic manufacture of some of the crucial blood
products that are out there.
Again, those four points are merely to get you
thinking when we move toward the area of discussion about
things that we might talk about or recommend. I am sure
that you all will have others.
As I think about the overall picture -- oh, I
forgot one other thing, I was looking down at Marian there,
she reminded me -- if we do have an emergency reserve, who
is that has a handle on the accountability of the
distribution of that emergency reserve.
It may be all right to leave that in the private
sector, but it may need some oversight, particularly with
patient and user input into how the emergency reserve is
distributed. If anybody can call up as a physician and
order the entire emergency supply from a private entity,
that may not be the best use of the emergency reserve, and
so I think we may want to say something there about what
kind of accountability or oversight or who should be
handling that. If we are going to have that, that may be an
area.
I know FDA and others have mentioned to me that
they have encountered problems with shortage in some other
places, and they may have things to say about systems that
they have used in the manufacture of drug that sometimes
become short for handling that, but I am a little nervous
about the accountability there as a fifth point with respect
to what we are doing with this emerging notion of keeping a
reserve on hand and who is controlling it, who has access to
it, what's the equitability of that, and is that being used
in any way in the spot market that we have heard about which
seems to be driving up prices when scarcity does exist, when
people take advantage of that.
We have heard that they do. Many people have come
to us saying that they can get supply, but they have to pay
two, three, or four times, where they have to agree to take
on other product - where is that coming from, what is that
all about, and what can we do to make sure that we are not
auctioning this scarce supply to the highest bidder as the
mode of distribution, or if we are happy with that, at least
we should say so, I suppose.
So, those five points are ones that I thought of.
As I said, you may have others that you want to put on the
table, or you may want to modify or think about these, but I
am hoping we can maybe get at some of those points, and you
can divide it this way.
We have some issues to deal with because of
current scarcity that will not end tomorrow morning. We
have some issues, then, to deal with about what to do about
scarcity to make sure we don't get in that situation down
the road. Both of those I think deserve the committee's
reflection.
Any other comments, any the panel would like to
make before we get underway? Dr. Guerra.
DR. GUERRA: If this is an opportunity to add to
your list, I would like to consider adding to that the use
of the IG, the immune globulin for intramuscular use, which
I think comes out or can come out as part of the
manufacturing process.
Perhaps a shortage in that arena, which is
primarily the public health shortage, is an even greater one
in terms of the thousands of people that at times need to
benefit from that in terms of post-exposure for a variety of
conditions, whether it is after a bite incident or whether
it relates to hepatitis or other conditions.
I wonder if it would be something to add to our
list for consideration.
DR. CAPLAN: A little personal anecdote here.
About a couple of weeks ago I went to Costa Rica just for a
camping trip. Before I left, the doctor said would you like
a shot of IVIG, and I thought, gee, I thought we were short
in the world of this, how come I can get all I want if I
promise to go to Costa Rica, but maybe I can't get what I
want if I sit here.
So, that may be an area where the two supply
streams intersect, and that is certainly something we ought
to be thinking about.
Other comments before we turn to our first
presenter?
All right. I want to say we have our work cut out
for us, but we have things to do, I suspect we will get back
to that, but also there are other issues we have to complete
hearing about.
Jim MacPherson is here from the America's Blood
Centers. Jim, if you would.
MR. MacPHERSON: Thank you.
DR. CAPLAN: Thank you, by the way, for agreeing
to let us hold you over.
MR. MacPHERSON: Not a problem. I preserve fairly
well.
I am not sure I am going to shed a whole lot of
light on your difficult task, but at least I will color in a
little bit of the piece of the puzzle.
I am Jim MacPherson. I am the Executive Director
of America's Blood Centers. I want to thank the committee
for this opportunity to explain where the independent
community blood centers within this important issue of the
availability of plasma pharmaceuticals.
ABC represents the independent, not-for-profit
community blood centers that provide nearly half the
nation's blood supply. Our members also provide nearly one
million liters of plasma, which FDA classifies as "Recovered
Plasma," for manufacture into pharmaceuticals.
Starting in the 1970s when plasma derivatives,
like antihemophilic factor and albumin, began to replace
plasma components that were provided by blood centers, the
independents attempted to have their plasma fractionated
into volunteer donor pharmaceuticals to be furnished to the
hospitals they served.
Unfortunately, the costs were high, and the market
at that time placed on premium on volunteer donor plasma
pharmaceuticals. Because of their not-for-profit status,
the community blood centers did not have the financial
resources to withstand the price and availability market
cycles, as well as recalls.
Subsequently, the independents began to sell their
excess plasma outright to willing pharmaceutical companies.
This practice continues to this day, but changes in recall
procedures and market preferences have had a profound effect
on where and how our plasma is used.
In the early 1990s, the independents began to see
an increased demand for their plasma. There are two reasons
for this. First, the Europeans place a high quality premium
on volunteer donor plasma pharmaceuticals, so that both U.S.
and European manufacturers began fractionating plasma into
volunteer donor products for European consumption.
Second, nearly all recovered plasma comes from
donors who give three or fewer donations per year.
Consequently, this plasma has a higher concentration of
plasma proteins than from paid donors, who often donate as
much as twice a week. So, it is viewed as a richer raw
starting material.
In the mid-1990s, plasma began to be recalled due
to the potential infection with CJD, as you all know about,
and like the Red Cross, pharmaceuticals made from ABC member
plasma became especially susceptible to recalls from donors
who subsequently came down with CJD. The main reason is
because many of our donors are over the age of 60, about 25
percent actually are over the age of 50.
In addition, community blood centers have very
close ties to the hospitals they serve, so when cases of CJD
occurs, the hospitals kindly let us know, so that we can
check to see if the patient was a donor, and occasionally,
that has occurred.
Nearly all the CJD recalls have involved volunteer
donor plasma, which I am sure you are aware of. Because
volunteer donor plasma became a business liability, all the
U.S. commercial manufacturers, namely, Alpha, Baxter, Bayer,
and Centeon, stopped using it. As a consequence, nearly all
one million liters of our members' plasma goes to Europe,
most of it to the ZLB -- which is part of the Swiss Red
Cross -- Central Laboratory in Switzerland and Immuno for
manufacture into plasma derivatives.
Much of the plasma derivatives made in Europe do
not come back to the U.S. except for immune globulin, and I
should probably clarify that. We were told by the Swiss
that about 90 percent of the paste made into immunoglobulin
does come back to the U.S. as finished product, so although
most of the albumin and Factor VIII and other things do not
come back, the immune globulin does.
It has been proposed that the Central Laboratory
in Switzerland fractionate plasma only from donors younger
than 55, however, both they and us have resisted age
restrictions for plasma donors because of ethical concerns.
On the other hand, reality is forcing us to review those
options.
Plasma derivative shortages may worsen, at least
in the short term. The recent ramp-up for production of
solvent/detergent-treated plasma has tied up perhaps 100,000
liters or more of volunteer donor plasma. The Red Cross can
address that more directly since it is their plasma being
made into S/D, and worse, the S/D process has a plasma loss
of somewhere between 30 to 35 percent. So, the process
itself will potentially consume hundreds of thousands of
liters of plasma each year. That presumes that S/D plasma
replaces fresh frozen plasma.
In addition, the independent blood centers are in
the process of quarantining about 100,000 additional liters
of volunteer donor plasma to be released as Fresh Frozen
Plasma Donor Retested for transfusion use when the donor
returns and is requalified as a donor.
The net effect of these occurrences is that
temporarily, many hundreds of thousands of liters of
volunteer donor plasma will not be available for manufacture
into derivatives, neither here nor in Europe. The situation
will ease, but will not disappear, when the ramp-up for
these two new products are complete.
Finally, it must be said that the independents
have been discouraged that our plasma cannot remain in the
U.S. If we had the financial flexibility -- and we are not
whining here, we are just stating the fact -- if we had the
financial flexibility to invest in manufacturing plasma
products in the 1970s, we may have earned hundreds of
thousands of millions in profits over the last 20 years, but
because we are not-for-profit blood centers, our mission is
to serve the patient first, and protecting our bottom line
has been, up until now, a distant second. I said up until
now.
We also recognize the risk of such an endeavor.
So, like the Red Cross, we would have been subjected to
hundreds of millions in direct product losses due to the
recent CJD recalls. We cannot afford to take such risks at
the expense of the American public.
While we are pleased and honored to have the
Europeans as our partners, we find it disappointing that
U.S. citizens cannot benefit more from the fine plasma
donated by nearly half of its citizens. We continue to
evaluate our options for the future and recognize much,
although not all, of the fate of the plasma rests within our
own hands.
I thank the committee for allowing me to share
this perspective. I also offer ABC's sympathy to the tens
and thousands of those whose lives depend upon plasma
products. We are community-based service organizations
whose bottom line is our neighbor. We share their confusion
and anxiety and frustration, and do what we can to help them
obtain the safest product they need and deserve.
Thank you.
DR. CAPLAN: All right. Why don't we go right to
questions. Jim, if you can just stay up for a second, I
will open the floor to the panel.
Keith.
DR. HOOTS: Does any of your source plasma go to
manufacturing in the U.S. or does all -- I guess we heard
yesterday their capacity is pretty well filled with their
own paid donors -- so all of the ABC goes to Switzerland as
far as for processing?
MR. MacPHERSON: Yes.
DR. GOMPERTS: I wonder, Mr. MacPherson, if you
could, for the committee, perhaps give a list, just run down
the actual manufacturers in Europe that might purchase your
plasma.
MR. MacPHERSON: The two primary ones are the ZLB
Laboratory of the Swiss Red Cross and Immuno. There are a
lot of smaller Italian and Austrian manufacturers, but they
are pretty much less than 10 percent. So, the vast majority
goes to those two.
DR. GOMPERTS: So, there is no plasma that would
go to the Swedish Corby facility or the two British
facilities?
MR. MacPHERSON: The British, thus far, no. I
don't know if any goes to Sweden at this point.
DR. GOMPERTS: The French, Dutch, Belgium?
MR. MacPHERSON: Not to my knowledge.
DR. GOMPERTS: Okay.
DR. CAPLAN: John.
MR. WALSH: Is it your impression, Mr. MacPherson,
that there is a market need for your plasma here in the
U.S.?
MR. MacPHERSON: Well, as I said, before CJD,
there was a premium placed on it, partly because it had that
white hat of volunteer donor, but also, as I mentioned,
because our donors only come back two or three times a year,
it is a richer starting material, so it was very rich in
both the components that are replaced normally, but also
especially in the immune globulins.
So, we think that there would be a big demand here
even in the U.S., and we have talked to the fractionaters
who said, sure, we would buy your stuff if it wasn't for
CJD.
DR. CAPLAN: Dr. Guerra.
DR. GUERRA: Suppose that ABC were willing to take
a big leap and make a major capital investment in
establishing a manufacturing plant, have you done some
modeling to see what that would cost and what the benefits
of that might be?
MR. MacPHERSON: Yes, we are just starting to look
at that, and we have been having some preliminary
discussions with the Canadian Government, because the
Canadians are interested in building their own fractionation
plant, but they have so very little plasma actually to
maintain it.
So, there are possibilities, but it is too
preliminary to really give you those figures, but, yes, we
are looking at it, because we recognize that for the last 15
years, we have just sort of given it away, and it's a
potentially rich resource that we could utilize better.
DR. CAPLAN: I think I understand this, but could
you just go through again why the CJD liability issue is
leading to this supply going overseas completely?
MR. MacPHERSON: Because of the recalls. I mean
if they --
DR. CAPLAN: Is this something that would be
handled by labeling, as our committee has talked about
sometimes?
MR. MacPHERSON: Potentially, sure, but again, if
you take a unit of plasma and you pool it with 50,000 or
100,000 other donors, suddenly, that becomes the subject of
the recall. You have seen the recalls over the years. I
mean they astronomical. So, I just think that as a business
decision, the manufacturers in the U.S. have just said they
don't want to.
DR. CAPLAN: The other reason I am headed in this
direction is you remember yesterday, we heard that the first
batch of emergency stock was from a recalled unit that was
negotiated out to be allowed to be put there.
MR. MacPHERSON: Right.
DR. CAPLAN: And I am wondering, you know, the
difference between what your practice is and what seems to
have emerged in another area we found a use.
MR. MacPHERSON: I guess maybe to state it this
way, we sort of go with the flow here at this point. We are
not in control of how the products are used or where they
are used. All we know is that the only market for this
product has been overseas, and the Swiss, up until this past
year, had not had a lot of recalls, just serendipitously, I
guess, and now they have had a lot of recalls and they are
having to reevaluate what they want to do, as well, because
they are finally suffering the hundreds of -- or at least
tens of millions of dollars in recall and product loss.
DR. GOMPERTS: When the Swiss withdraw in the
United States, do they also withdraw in Europe?
MR. MacPHERSON: Yes. They follow the regulations
of the highest regulatory authority over the product that
they make, so if the FDA says you recall that product, then,
they recall it everywhere. That is pretty standard practice
at least in the European countries.
DR. CHAMBERLAND: Actually, that was similar to my
question. Do you or does anybody else know if European
countries themselves have any regulations or requirements
for withdrawal when donors' diagnosis of CJD is subsequently
identified?
MR. MacPHERSON: I am not an expert on this, but
there are guidelines that are published by -- and I am
blanking on the name of the organization -- the CM Medicinal
something. They do have guidelines for CJD, but there is no
-- it is up to individual countries. I don't believe that
there is any, but maybe somebody else can answer that
question better than I can.
DR. DAVEY: I believe the British experience, it
is a bit ironic. They do withdraw for -- and correct me if
I am wrong -- the new variant, but actually they do not
withdraw for classic CJD, as we do here. I am not sure of
the other countries.
MR. MacPHERSON: The French do not, to my
understanding. The Swiss do primarily because they are
following FDA regulations or guidelines.
DR. BUSCH: Just to follow up on that, that is my
understanding, as well, is that for the most part, they do
not recall, similar to the U.S., and so if a donor, let's
say, in the U.S., a volunteer donor whose plasma was
exported to the Swiss, subsequently was diagnosed with CJD,
do you know what happens, is that notification passed on?
MR. MacPHERSON: They are recall, because they are
FDA-licensed products.
DR. BUSCH: Does the recall strictly apply to the
IVIG that is exported to the U.S., or will that recall also
apply to the other derivatives?
MR. MacPHERSON: Again, I am not the best person
to answer. My understanding is if they make a product, and
it's a licensed FDA product, they will recall it.
Otherwise, they will follow whatever the requirements are
for the individual countries.
DR. CAPLAN: Larry.
MR. ALLEN: Excuse me, sir. Are you saying that
none of the manufacturers in this country will buy your
plasma, is that what you are saying?
MR. MacPHERSON: Correct.
MR. ALLEN: And the specific reason is what again?
MR. MacPHERSON: CJD recalls.
MR. ALLEN: Because you have had so many in the
past?
MR. MacPHERSON: Because there have been so many,
well, because of the high association of recalls with
volunteer donor plasma, that is correct.
DR. DAVEY: I think that as Jim pointed out, it is
interesting, I think roughly 80 percent of the U.S. plasma
market is in the commercial side, 20 percent volunteer, but
the recalls are almost entirely reversed, 80 percent of the
recalls are volunteer, 20 percent are from the source plasma
side approximately.
I think, as Jim indicated, some of the thinking is
that in the volunteer sector, where there is a close
relationship with the donors, their families, and the
hospitals, that the post-donation information comes back
much more vigorously in the volunteer side.
We hear much more about whether a relative or a
former donor or a son who might have gotten growth hormone
or some shot 30 years ago, that information comes in the
volunteer side, we feel, although I don't have data to back
this up, much more frequently.
So, the recalls come much more heavily in that
side of the market.
DR. CAPLAN: Let's go to Jane and then we will go
to John.
DR. PILIAVIN: I just want to draw out what I
think is the obvious conclusion from what is being said
here. We know that at least historically, there have been
more markers for a variety of disease entities in the paid
plasma sector than in the volunteer sector notwithstanding
the fact that this seems to be getting a lot better in the
paid plasma sector.
If you are thinking about emerging diseases, it
seems that we should expect to find it more in the plasma
sector than in the volunteer sector, and we are saying that
one of the reasons for our vigilance is not specifically
because of CJD, but because of possible other kinds of
emerging factors.
It seems, therefore, totally ironic that most of
these recalls are happening in the area where we have more
confidence in the blood supply in other ways. I think this
just underscores what a number of people have said in
previous meetings regarding the CJD issue.
This is that doing these recalls provides a false
sense of security with regard to the entities that are
probably there in the plasma. In other words, if the reason
why we are having the recalls in the voluntary sector is
because of better communication with the hospitals, and, of
course, because we have got people who are older in the
volunteer sector, those two things together, it is very,
very likely that these entities are present at least as much
in the paid plasma sector. We just don't know it.
I think that is like the ostrich with its head in
the sand, you know, that because we don't have the
information, we say, well, this stuff is fine, and the
volunteer plasma is not fine.
Well, probably along the lines of all of the other
things that might be in there, that we just don't know about
yet, the opposite is true. I really think we have to
seriously consider changing our attitudes towards the CJD
issue, possibly by doing this kind of labeling, but the
labeling still carries some sort of stigma.
I think part of the problem here -- I know I am
rambling -- has to do with people's lack of understanding of
probability theory, and that the simple likelihood of
somebody undetected having CJD being in any pool of plasma
is pretty close to 1. Nobody quite understands what that
means, I think, and it is sort of if you can't see it, then,
it's not there approach.
All of these recalls for CJD are there for, you
know, just as we have said before, the tip of the iceberg,
but the iceberg is there and it's in everything, and the
only way to get rid of it is to just not use the plasma.
Obviously, that is not a choice.
I don't know what the bottom line here is. It's
just that I wanted to make sure that the conclusion came out
in terms of what is being said here about the relative
proportions of recalls.
DR. CAPLAN: I think Jane was rambling a bit until
she got up to the call that we understand probability
better, and then she lurched to optimism.
John.
MR. WALSH: I will try to be brief, but maybe I
lost something yesterday. We are all concerned about
safety, and we had a hearing on the CJD issue, and we made a
recommendation to the Secretary with regards to that, which
seems to address some of the perception or reality that you
are experiencing with the manufacturers.
I am not certain that I heard yesterday -- and
maybe I missed anything -- any of the manufacturers saying
to us that they have a limited supply or a shortage of raw
product to produce plasma derivative products.
MR. MacPHERSON: That's right.
MR. WALSH: So, if we are looking at a shortage,
you know, availability of plasma derivatives, you know, for
life-threatening diseases, and if the plasma is so
plentiful, all of your plasma is going overseas, production
seems to be the issue.
Does anybody on the committee hear anything
different than that?
DR. CAPLAN: Jim, do you want to get in on it?
DR. AuBUCHON: That is what I heard yesterday, as
well, John, however, if the manufacturers are producing as
much IVIG as they can, if they are running as many liters
through their plant as they possibly can, by shifting away
from volunteer plasma and slightly higher immunoglobulin
levels, they may reduce their final yield somewhat.
Now, that is probably only a couple percentage
points, my guess, but it seems like all of the things that
have affected the supply have only been a couple percentage
points, and, in aggregate, they have created a large
shortage.
DR. GOMPERTS: Can I just correct a misconception
here? The handling of the donor, whether it's volunteer or
paid donor, from the point of view of questioning,
evaluating is essentially identical as I understand it.
The major issue in this particular circumstance,
Dr. Davey, is a number one. In other words, when a
volunteer donor contributes a unit of plasma, the amount of
plasma collected is about 200 milliliters. With a source
plasma situation, it's 800, so you get four donors to one
donor from the point of view of going onto a phoresis
machine.
Secondly, the individual volunteer donor goes into
the blood bank once or twice a year. The source plasma
donor is there, can be as frequently as twice a week. So,
when you work this all out, the chances of an individual
donor coming in and having a predisposing condition that
might suggest a possibility of CJD, a slightly higher risk,
it's a numbers game.
Now, the actual yield of immunoglobulin and
albumin from a volunteer, a recovered plasma situation, is
higher, so there is an advantage in using the recovered
plasma, but the disadvantage is the frequency of recalls,
not from the point of view of safety, the issues of concern
out there for patients receiving albumin, immunoglobulin
factor, whatever, this is a major issue.
DR. CAPLAN: Let me take one more question, but I
wanted you to have a chance to comment.
MR. MacPHERSON: No, I would agree with what has
been said, and just to reemphasize the fact that it is true
that we are probably not talking about a shortage of plasma
in this country, because as our plasma has been going to
Europe, the paid sector has been increasing their output to
make up for the loss of plasma.
DR. CHAMBERLAND: Just to follow up on something
you stated earlier, you indicated that the Europeans, the
Swiss Red Cross had experienced more recalls this past year.
Are you hearing any sense from your Swiss Red Cross clients,
they are potentially rethinking about buying recovered
plasma from the United States because of the liabilities and
the recall issue, hearing that they have to withdraw a
product from both the U.S. and European markets, and that
would further chip away, as we heard yesterday, the Swiss
Red Cross, through Sandoglobulin, does come back to the
United States, are you hearing any indication that they are
rethinking buying U.S. recovered plasma?
MR. MacPHERSON: No, not really, because actually
they just built a second factory, and it was to accommodate
the huge increase in flow in the U.S. I suppose if the
economics worked against it, they would probably do it, but
at this point, we are their biggest client.
DR. CAPLAN: Thank you.
MR. MacPHERSON: Thank you.
DR. CAPLAN: Sorry, Paul, one quick one.
DR. McCURDY: Ed made a comment that I would like
to follow up on a little bit, because I think there is an
absence of data where it might be useful perhaps to have
data. The screening program for the volunteer and paid
donors is essentially the same.
We do know, however, there are data that indicate
somewhere in the neighborhood of 5 percent of volunteer
donors, at least in some of the centers where this study has
been done, have deferrable risks that they own up to on
anonymous questionnaires administered after the donation,
but do not on the face-to-face interview.
There are no such data for the paid -- at least I
am unaware of any such data -- in the paid sector. Nobody I
think has -- I mean there have been a lot of assumptions
made, but it is not clear why the marker rate, as Jane said,
seems to be higher among paid donors than it is among
volunteer donors, although they are coming closer together.
But I think there is an absence of data here
rather than data on which to base firm conclusions.
DR. GOMPERTS: I can talk anecdotally around that,
but one set of data is pretty clear. The source donor group
tend to be younger, there is no doubt about that.
Obviously, we have debated the issue of age cutoff certainly
from the point of view of CJD. I think that is a major one,
but also, the potential for exposure to growth hormone in
the seventies, sixties, is, of course, higher in the older
individual, as well.
DR. CAPLAN: One happy note for those of you
exchanging anecdotes about this particular subject is that
we will get back to the issue of donors probably in the next
meeting. That is what we had, if you recall that far back,
looking forward backwards, that is where we are going to
take a look, so we may actually get back into this data
issue there.
I was going to ask Paul, do you think that for
CJD, this issue of donor deferral registry's post-deferral
is going to make a difference relative to where that is
likely to be a risk factor? I understood what you were
saying about markers for other diseases and the paid versus
unpaid donor pool, but just looking at this particular risk,
if it's an older group and they are tracked more closely on
the volunteer side than on the paid side, there is not going
to be much deferral on the interviews that way for this
particular risk factor.
DR. McCURDY: The at-risk behavior that I was
talking about was at risk for either HIV or hepatitis.
There is about to be released another questionnaire which
will ask some questions about possibly at-risk activities
for CJD, that is, eating central nervous system food, and so
forth, but we don't know about that, and actually, we don't
know how much of a risk factor that really is.
DR. CAPLAN: I am going to ask Christopher Lamb if
he would come forward.
MR. LAMB: Good morning, Mr. Chairman. My name is
Christopher Lamb. I am the Vice President of Plasma
Operations for the American Red Cross. I am pleased to be
here with you today to give the Red Cross perspective on the
IGIV shortage.
The first overhead relates to the role of the
American Red Cross in providing IGIV to the American public.
Overall, our goal is to optimize the use of volunteer plasma
recovered from whole blood collections. The American Red
Cross collects about 6 million volunteer donations, whole
blood donations each year, and that translates into about 1
million liters of plasma that is sent for further
manufacturing into plasma derivative products.
Let me just make one comment, a follow-up on Dr.
Gomperts' remark. The average volume per donation for the
American Red Cross is 283 mL per donation, which contrasts
to 800 mL for a source-phoresed donor, and regardless of the
issue of CJD, this has enormous impacts on pool size, which
I will get to in a second, in terms of the ability to reduce
batches from donor pools less than 60,000 is much more
difficult for the recovered side than it is for the
commercial source side.
The American Red Cross is unique in the sense of
what we do is we take our recovered plasma and rather than
sell it outright to commercial companies, we have our own
plasma program whereby we have entered into what is referred
to as "contract fractionation" agreements, where the plasma
is sent for further manufacturing to commercial facilities,
and then those plasma products in general are returned back
to us.
Our primary agreement is with Baxter. Eighty
percent of our plasma goes to the Baxter Highland facility.
All of those plasma products are returned to us for
distribution in the United States. Twenty percent of our
plasma goes to the Swiss Red Cross, again, under a contract
fractionation agreement.
Historically, through 1997, all of the albumin was
returned to the American Red Cross. The IGIV, as you heard
yesterday, because of a long-standing agreement between the
ZLB, the Central Laboratory of the Swiss Red Cross, and
Sandos, now Novartis, the IGIV was distributed under the
trade name Sandoglobulin by Novartis.
We have reached an agreement with the Swiss Red
Cross whereby the IGIV will start coming back directly to
the American Red Cross for distribution in the United
States. We expect the first deliveries of that product to
begin in late June.
In total, approximately 3 million grams of product
are produced from the American Red Cross, either from the
Baxter facility or the Swiss Red Cross, which is
approximately 15 to 20 percent of the U.S. need.
[Slide.]
In terms of the IGIV shortage, our perspective on
this, firstoff, is as we have heard a lot of comments in
terms of increased usage, we have seen about a 10 percent
annual increase in the volume of this product -- and I will
get to this in a second -- and I want to walk through with
you the impact of CJD withdrawals and what they have done to
the supply of our product.
There have been a couple of other impacts on our
supply which I will go to in detail in a second.
[Slide.]
From market research that we have in our
possession, and I don't want -- the market research isn't --
I don't want to be too specific. This is a general overview
of our forecast of what we see in the marketplace and what
it has grown over the years. We extrapolated, in 1997 based
on prior increases, and assumed a 10 percent growth.
Yesterday, people were saying that there may be 8 or 9
percent growth, but it is clear, over the last 10 years,
there have been a substantial increase in the usage of this
product.
Interesting enough, if we look at this forecast as
reasonably accurate, I would guess the total U.S. demand is
between 17 and 18 million grams. If you take a look at the
data that was presented yesterday in terms of industry and
what they are supplying the U.S. market, of maybe 10 to 11
million grams plus the Red Cross, 3 million grams, and other
product that is coming back from the ZLB from non-Red Cross
sources, you probably have a supply of around 17 million
grams, which gives you a estimated shortfall of probably
around 1 million grams.
If this increase continues at a rate of somewhere
between 5 and 10 percent, you can begin to see how probably
the shortfall is not going to be abated over the next 18
months.
[Slide.]
I want to specifically look at how the Red Cross
supply of IGIV has been affected, primarily looking over the
last nine-month period of time when we have seen the
shortage. So, I can go, if the committee would like, and
take a look at 1996 and the full year of 1997 and what we
project for 1998, but looking just at this particular
nine-month period of time from July 1, 1997 through March
31st, 1998, we had a theoretical total supply of our product
of about 1 1/2 million grams of product.
Approximately 10 percent of that volume was
impacted by finished product that was in process and ready
to be released, but was withheld from the market because of
a donor theoretically at risk for CJD.
We had another 6 percent of product that was
either in our finished goods warehouse at the time of a
withdrawal or was returned as a result of a withdrawal. I
did not have the time to break this information out, but
this is product that had been released to the marketplace
and either was in our possession or had been returned, so
about 6 percent of the product was quarantined or returned,
and approximately another 6 percent is other intermediates,
which would be fraction, the fraction paste, whether it is
fraction 1 plus 2 plus 3, or fraction 2, and whatever stage
of intermediates was not able to released to the
marketplace.
Historically, the Red Cross, if we were not able
to fractionate all of the intermediates at the Highland
facility, we would send that to the Swiss Red Cross to
ensure optimal supply of the product, so in one form or the
other, this material is not available to the marketplace.
So, approximately 22 percent of our total supply
has been impacted over this nine-month period of time due to
the CJD issues.
The second issue relates to the 60,000 donor
limit. In late 1996, basically, seeing the recommendation
that was likely to come out of the Blood Products Advisory
Committee of a desire by consumer groups to limit batches
from donors of 60,000 or less, we started to implement this,
and we basically saw a decrease in output of about 3.8
percent.
I want to touch on this briefly. This was raised
earlier. The issue of pool size and batch size is a very
complicated one. Facilities have been designed and
optimized traditionally to maximize output. Interesting
enough, when we first started marketing this product, we
actually promoted the fact that our batches were from a
minimum of 60,000 or more donors to give a broad spectrum of
antibody protection, but facilities, you can't change
facilities overnight.
The tank size, the columns used to purify the
material, the lyophilizers are all very fixed in terms of
the way the production setup goes, and they cannot be
changed overnight, and any changes to them automatically, in
our case will result in a decrease in supply.
The notion of going down to 15,000 donors per
batch would essentially wipe out our supply, would wipe out
any supply from the Swiss Red Cross, and would probably
decrease the available amount of product by close to 5
million grams.
I think the committee ought to seriously consider
this. There was a full day discussion before an expert
panel headed up by Dr. Koop. It's a very complicated
subject, and I think if the committee would like a fuller
briefing on this, we certainly could come back and discuss
it further, but it's a three- to five-year process which
would in essence mean building a new facility to make
smaller batches. It's not a trivial exercise, and one I
have looked at in depth and had engineering studies to look
at this, but just the immediate impact from us, our
standpoint, was about a 3.8 percent decrease in supply.
The third factor has been other manufacturing
problems or issues, for example, which is traditionally
during the course of a year, you have a batch that is
rejected for particulation, a batch that is rejected for
high IGA content, and this impacted about 6 percent of our
supply.
So, during this nine-month period, we saw about a
32 percent decrease in supply or about 500,000 grams of
product.
[Slide.]
The fourth factor impacting our supply relates to
CGD investigations. When we receive a post-donation callback
of a donor, who potentially is theoretically at risk for
CJD, in other words, a donor comes in and donates and says
they received human growth hormone or they may have received
a dura mater transplant.
That product immediately, any product in our
possession immediately goes into quarantine, and we don't
release that material until we resolve the investigation.
Let me give you a couple of examples of how that impacts our
supply.
In late October, early November, we received a
report from a young woman who had donated a few months
earlier. She came back a second time and indicated that she
had received human growth hormone. What happened was she
had come for the first time and donated, she went back,
talked to her mother, and her mother said -- she asked her
mother about the questioning, the questions she had been
asked, and her mother said, you know, you did receive growth
hormone.
So, she comes back a second time. We received
this information. The material immediately gets quarantined
at the manufacturing site. We start an investigation. The
woman allegedly was treated at Georgetown Hospital. We went
to Georgetown Hospital, and determined that it was, in fact,
recombinant growth hormone. However, there was something in
the record that the donor had been treated at Children's
Hospital.
We went to Children's Hospital, searched the
records, and it turned out that the donor had been treated
yet by another physician. We had to track down the
physician, and finally we determined, in this particular
case, that the donor had not received human growth hormone,
but had, in fact, received recombinant growth hormone.
We were able to exonerate the case, and so the
product was, in fact, release in January, but during the
November and December time frame, we did not have this
product.
The same is true with dura mater cases. We
recently, in the last month, had a case where a donor came
back and said that they thought they had received a dura
mater transplant, and, in fact we went back. It was a very
reputable institution, and the dura mater transplant was 30
years ago, 1968, we have a healthy donor, who 30 years ago,
in fact, has received a dura mater transplant.
What we have been able to determine is that, from
the head of the Department of Neurology, is that the dura
mater transplant certainly was a single source, certainly
was from a U.S. source, but we are not sure whether or not
there was an autopsy done on the donor of the dura mater,
which these are the three conditions for releasing material,
and in 1968, autopsies were not common for donors of dura
mater, and so this is an issue that is still under
investigation, but in the interim, the product is in
quarantine.
So, these kind of CJD investigations either lead
to product which is ultimately withheld from the marketplace
or it's delayed in terms of reaching the marketplace.
I would mention that over 80 percent of our
withdrawals relate to the issue of human growth hormone or
dura mater. We have had very few withdrawals from donors
who have died of CJD or donors who have had two or more
relatives with CJD. The major issue relates to growth
hormone and dura mater, and I would urge this committee to
take a look at those two issues alone would substantially
reduce the number of withdrawals in the marketplace.
I would also add that typically, when we are
actually able to get the medical record, it turns out that
in over 80 to 90 percent of the cases, in fact, the blood
donor did not receive growth hormone, they received
testosterone or they received something else, but oftentimes
we can't get to the medical records because we are talking
about 20, 30, 40 years ago, the physician's records are not
available, and we are relying on a lot of anecdotal data,
and that is the situation that we are faced with in terms of
the CJD.
[Slide.]
Let me go to the next overhead, which is the
American Red Cross response to the IVIG shortage. We have
tried to focus every effort on rapid release and
distribution of IVIG. The FDA has done an excellent job in
reducing the amount of time that they take to approve a lot.
It went from several weeks to less than a week, and if any
case, a situation comes up where a lot is held up, I always
can easily make a call to the FDA, Alice Kirkarkijimski, and
she is able to resolve it within a day.
We process probably on a daily basis about 10 to
15 emergency requests. Most emergency orders are filled.
What we do right now, we have two contractual commitments,
guaranteed contract commitments with groups of hospitals.
One is University Hospital Consortium, the other is Premier,
and we guarantee the supply of that, and if we don't fill
that supply, we have got to go out on the open market and
purchase it.
So, we what we try to do -- and that represents
about 70 percent of our supply -- so what we have tried to
do is meet those two guaranteed obligations and reserve the
rest for emergency use.
It is very difficult to target for particular
indications. We were working with IDF. They talked about,
during the December and January time frame, where they were
screening requests. We would get a request and we would say
to a hospital this is for a primary immune-deficient
patient, and they would say, yes, we would have one of
those, yes, we use it for this patient, but when they were
shifting from one group of patients to another, it is very
difficult to know, so it is very difficult from our
perspective to really say that we can target this particular
product for this group of patients with this indication.
But clearly, while we do focus on trying to fill
emergency orders, currently, we have, for example, 126,000
grams of IGIV on back order as of last Friday, and again
back orders are prioritized based on emergency or guaranteed
contract commitments.
[Slide.]
Again, the issue of is there hoarding of product,
I took a look at the last 11 batches that have been released
into our possession, and if you take -- the average time of
batches in our possession is 14 days -- if you take out one
batch, which is Lot No. 6 here, which is actually a 2
1/2-gram-per-vial, which is not a very desirable use, it
takes a lot of reconstitution time, we have offered it to
hospitals. It definitely is not a preferred size, if you
take that out, 10 or our 11 batches are in and out of our
inventory in nine days, and in some cases, it is one day.
So we see rapid turnaround, and at the end of any
month, looking at January through March, at the end of any
month we had basically zero inventory on hand, so each month
we clear out our inventory and rely on releases for the
subsequent month.
So, under no circumstances I think is any product
being hoarded or held back from the marketplace by the
American Red Cross.
[Slide.]
In terms of preventive measures, again, I
mentioned we have a new agreement with the Swiss Red Cross
whereby IGIV from our plasma will be returned to us for
distribution solely in the United States. We do have yield
improvement projects with Baxter, our primary fractionater.
I would tell you that yield is a constant
preoccupation. It has been a constant preoccupation with
the American Red Cross for the past 10 years that we have
had this product. We review this on a quarterly basis. We
look at any opportunities there are to improve yields. We
have made tremendous improvements over the years, and we
continue to make improvements.
I believe Baxter mentioned yesterday next month we
plan to submit an amendment to the PLA, the Product License,
for a new resin which we hope will we hope will further
improve yields. Hopefully, this will be approved by the FDA
in the next six months, and again this will offer some
incremental increase in the supply of product.
We do plan to increase our collections. It was
mentioned earlier that hundreds of thousands of liters are
being tied up with the solvent/detergent-treated plasma
product. This is not the case.
The amount of plasma we fractionate is the same in
1996 as it was in 1997, and is planned to be in 1998, and in
1999, we are hoping that through increased collections and
also with some alliances that we have with other blood
centers, we hope to increase the plasma that we throughput
through our existing contractual arrangements, and I would
offer the ABC, we would be happy to purchase their plasma to
fold into our fractionation program at anytime to ensure
that the products come back to the United States.
Finally, let me just comment on the issue of CJD
research. I would guess that the Red Cross is probably the
most active organization in this area. We have done a
variety of studies.
This committee heard at the last meeting about
work done by Bob Rohrer, Dr. Rohrer at the VA Hospital in
Baltimore, and Dr. Brown, at NIH. One of the experiments
that you heard was a fractionation experiment. This was
done again in collaboration with the American Red Cross, and
where we took 300 mice who had the mouse-adopted CJD strain.
They were sacrificed when they were just about
coming down with the disease. We fractionated that plasma,
and we took a look at is, under these extreme situations, if
TSE or CJD is in blood, is it in plasma, and if it is in
plasma, what fractions are there.
The committee asked that the experiment be redone,
not only redone, but done at an independent laboratory. We
have since worked with Dr. Brown where we redesigned the
study. We went into the FDA. They had some very good
comments.
One change to the experiment was in the original
experiment, we looked at cryoprecipitate, 1 plus 2 plus 3,
fraction 4, fraction 5. What we are doing in the next
experiment is dropping out the fraction 2, which is the
starting material for IGIV, to see if there is infectivity
there, and if it's not, then perhaps we can exonerate the
fraction 2, fraction 4, and fraction 5.
In addition, we have a similar experiment with Dr.
Rohrer. His animal model is hamsters. Scrapie is the
agent. Scrapie is 98 percent homologous with CJD, and that
experiment is about to begin.
So, we are trying to work with the FDA, with the
public organizations, to get more data to better understand
whether or not this is, in fact, a risk and to give more a
fact base to the policy and whether or not we should
continue with the policy or change it.
So, these are experiments. Unfortunately, we are
working with IC inoculation, intracranial inoculation as the
infectivity, so the time to complete the experiment is
generally a year or more. You have to wait until all the
animals die, so it is not something that we can expect a
quick turnaround.
In addition, we are doing other validation
experiments to determine if CJD is in various fractions,
like, for example, cryoprecipitate, would it be removed
during the processing, and we have other experiments also
looking at whether or not we can inactivate it with various
techniques.
So, we have an extremely active program in this
regard, and we hope over the next year or two we are able to
bring more data to the table to address policy issues.
Let me just answer an earlier question that came
up in terms of what is happening in Europe. There is the
CPMP, the Committee on Proprietary Medicinal Products.
Their policy has been not to do -- this is a European-wide
group -- not to do withdrawals for donors who die of CJD,
what we call the common variety of CJD, or for other at-risk
issues like growth hormone or dura mater.
However, the way that is implemented is on a
country-by-country basis. For example, the Swiss Red Cross,
in fact, had a donor who died of CJD, and they did not do a
-- this was a Swiss donor -- they did not do a withdrawal in
Switzerland. In the UK, they do not do withdrawals, they
only do withdrawal with a new variant CJD. In France, they
do do withdrawals. So, you really need to look at it on a
country-by-country basis, while the overall centralized
group has taken a position, it is implemented differently on
a country-by-country basis.
Thank you, Mr. Chairman.
DR. CAPLAN: Thank you. We will open the floor up
for questions from the panel. Keith.
DR. HOOTS: In terms of the cost during the
shortage, since you guy on the spot market, have you
noticed, what has been the purchase price when you do in
order to fulfill your commitments to Premier and UHC, what
has happened over the last year and a half to the price of a
gram of IVIG?
MR. LAMB: Well, because we have those
commitments, we have used our supply to meet those
commitments. We have not actually had to go out and
purchase the product. Seventy percent of our available
volume has been used.
DR. HOOTS: Have you looked at what the impact
would have been had you had to do that, have you gone out to
check?
MR. LAMB: Well, you certainly have heard extreme
examples of product of well over $100 a gram. My guess, it
has probably been between 45 and $55, in some cases, $65, so
probably between 45 and $65 a gram would have been the cost
had we had to go out to the marketplace and purchase the
product.
DR. HOOTS: Secondly, you raise an interesting
question about the fact that even in the face of shortages,
you have longer shelf time for the pediatric size, which
then raises the question, if there is spot shifts and market
demand still very much at work here, and people are still
having preferences, that pediatric size vials might be the
ideal emergency supply to have, so that there would be less
demand for that, and it also would be adaptable to every
source of need or every targeted person.
I mean as a person who treats populations where
convenience is exceedingly important, I don't like to see
that happen, but if there is an incentive for people to get
product, that might be something to keep in mind.
MR. LAMB: I think it is a good point, however, I
would say that because with the smaller batch size, I mean
with the pediatric, the 2 1/2 gram, that batch actually
turns out to be much larger in terms of vials, and so when
we make a batch of that product, actually, the volume is
smaller, so in terms of optimizing output, we are much
better off making a 10-gram size bottle than a 2 1/2-gram,
so actually, we have shifted our production to optimize
output.
DR. HOOTS: Right, and I didn't mean to shift to
production, I meant in terms of what to hold in reserve.
DR. CAPLAN: Let me address two issues to you that
came up in your comments. One is about this matter of pool
size and the conversion of the physical plant, and so forth,
to handle the smaller pool.
When I listen to people talk about this, I think
the major message that I take away is that people would like
to see a smaller pool in part to purchase or acquire safety
and the ability to recall more easily without damage to the
overall supply, and at the same time, there is a concern
that output is going to be adversely affected, so you are
weighing a balance there, but as far as I can tell, what I
think most people are looking for is they want to see the
safety side pushed up, but they would like to have a target,
a firm target, for the conversion.
So, has the Red Cross in your own area been able
to say, well, by the year 2002, we will have done the
redesign or by the year 2004, we will have done the
redesign? I mean what does the long-term strategy look like
for getting us past this continued pool discussion?
MR. LAMB: I think that, firstoff, it is not clear
that there would be any increase in safety going from the
60,000 to a 15. Clearly, there is an article, the Lynch, et
al., article, which has modeled this out, so the benefits of
going from 60 to 15 are really unclear, and in fact, some
might argue that with those small batches, maybe you have,
let's say, the example yesterday where you have 1 in
100,000, and so you would have one batch that is implicated
and four batches that are not.
It is not clear in terms of infectivity about
whether or not the viral load in that smaller batch now
makes it more infectious. So, on both sides of the table,
people have said smaller batch size is good, perhaps
increase the risk, and some people argue it could decrease
the risk, so there is really no consensus that there is any
improvement in safety.
My position would be we have both within the Red
Cross and with our manufacturing partners, very active
programs in viral inactivations and other strategies to
improve the safety of the blood supply, and rather than put
$100 million into building a new plant, which is what a new
plant would cost, we are much better off focusing on getting
additional technologies into our products that would
inactivate non-envelope viruses and potentially other
emerging agents.
I think from a strategy standpoint, I think that
is a much better way to go.
DR. CAPLAN: I think that is very helpful in one
sense because what it tells me is that there still is a
debate about how best to achieve safety, and the issue of
infrastructure changeover is a little bit of a red herring.
If the industry, Red Cross, or anybody else
believed that you would get the safety that I think some of
the patient groups think you will get from a smaller pool
size, the conversion would be being pursued, and so what we
need to do is come clean, I think, about this and say with
respect to pool size and how many units are used, and where
we are going to pool, and so forth, that the debate is over
whether we can stay at the same pool size to maintain output
for whatever economic reasons, and at the same time make a
commitment to get infectious agents out of those pools, or
are we going to go to smaller pools in the name of safety
and all concede that that is the strategy to pursue.
It seems to me what I have heard since I have
chaired this committee about pool size issues, has been a
blurring. If we are convinced that the pool size is the
solution, by going smaller, then, the conversion date should
be set.
If we are convinced that we can handle bigger pool
sizes and make them safer, then, we should, in fact, say we
are not going to do the conversion, but I think what happens
is, to be frank with you, that we are driving a lot of
people crazy about why aren't we, in fact converting.
We go year after year in this debate about pool
size, and no one sees any effort made by Red Cross or
anybody else to go to the smaller pool size. At the same
time, I think it's partly because people on the provisions
don't believe in the smaller pool size.
So, if we could at least be frank about what is
going on, then, I think the public policy debate would move,
we could engage what is the best safety strategy. That is a
little personal angst expressed there.
MR. LAMB: I agree with that.
DR. CAPLAN: The second question. You commented
to us that you were in situations sometimes with these dural
matter look-backs or growth hormone look-backs where the
records are fuzzy and it's not clear what we are chasing or
whether we are going to know exactly what went on, and
personal anecdotal reports, people may not be sure what, in
fact, they ever did have happen to them. They are trying to
recollect events from many years ago, and doctors and
records are also not so good from many years ago.
This committee did take a vote about CJD and
look-back, and tried to argue that there should be an
attempt to work with FDA and others about look-backs, and
these scenarios that you are presenting -- I am just
speaking personally now -- do seem to me to be instances
where some accommodation might be possible about recall of
the supply.
It is one thing to say we have a unit from a known
donor and we are going to try and keep it out there because
we need IVIG. It seems to me -- I am just speaking
personally now, not for the committee -- but I want to flag
it for your attention as you talk to regulatory agencies, if
you have got the look-back, and we are not sure whether it
was really growth hormone or we are holding a unit because
of the dural matter, but we don't know if there was an
autopsy done, that is precisely one area where some facing
the shortage we do right now, there ought to be some room
for some accommodation.
MR. LAMB: I would agree, and we are working with
the FDA on these issues.
DR. CAPLAN: Paul.
DR. HAAS: It is somewhat along the same line.
Did I hear you correct to say that very few of the recalls
were because of actual deaths relating to CJD?
MR. LAMB: That's correct.
DR. HAAS: The source of data that led to that
conclusion, were they birth certificates or --
MR. LAMB: In those cases where -- I am sorry --
what --
DR. HAAS: I am just wondering if birth
certificates were part of the source of making decisions
that people didn't die because of CJD.
MR. LAMB: You mean death certificates?
DR. HAAS: Yes, death -- did I say birth
certificates -- it is wrong. It was a bad day yesterday, I
guess. Death certificates, they are notoriously bad. I
guess I just want that cleared up.
MR. LAMB: We have probably done -- I don't have
the exact number -- we have done more than 25 withdrawals
due to donors at risk for CJD. Only a couple of those have
been for donors who have died of CJD.
In those cases where someone has died of CJD,
actually, the clinical diagnosis is fairly straightforward.
You pretty much can go -- there is usually a neurologist
whose opinion has been sought. In many cases, a second
opinion has been sought.
The clinical course is fairly clear, and in some
cases we have autopsies which have pretty much confirmed the
diagnosis, but in 80 or more percent of the withdrawals that
we do, are not because donors die of CJD, but because a
donor allegedly has taken a human growth hormone or has
received a dura mater transplant.
So, if a policy on those two issues alone were
addressed, this would substantially reduce the number of
withdrawals.
DR. CAPLAN: Ron.
DR. GILCHER: I think Mr. Lamb has made an
important point about pool size, and the point that I want
to make is really one of clarification, and that is, are we
really talking donors per pool or are we talking donations.
What I really hear is talking right now is donations per
pool.
In fact, it would worsen our scenario on the
volunteer sector side if we talked donors per pool because
clearly, I think the number of donors per pool on the
commercial size would be less by virtue of the volume of the
donation and the frequency of the repeat donor by virtue of
being paid.
But I think this is really an important point of
clarification, and to me, what is really important is the
number of donors per pool, and I think that is the real
issue here, because if you are carrying it today, you are
carrying it tomorrow, and you are carrying it essentially
forever, so to speak.
But I think we are getting lost in the shuffle
here when we start talking pool size, because the volunteer
sector plasma is always going to have a much larger number
of donors per pool. There is no way around that. I think
we really have to come to some sort of understanding and
clarification. Perhaps FDA could help us. I would be
interested in the comments from Jay and others.
DR. CAPLAN: Ed.
DR. GOMPERTS: If one focuses on the pool size
issue, but from the efficacy point of view, the efficacy of
the product, and in this situation, IVIG is unique. In
order to document a particular pool size in relationship to
efficacy, clinical research studies would need to be
constructed in all the different indications, Kawasaki, ITP,
primary immune deficiency, and those studies would need to
be done with whatever pool size one is targeting, let's say
100 donors, 1,000 donors, 5,000 donors.
A product needs to be made from that, and patients
need to be treated and then evaluated, so the time and
effort that will be required to determine a particular
efficacious pool size, and almost certainly that will differ
from the primary immune deficiency situation, the acquired
immune deficiency, and the immune modulation situation,
which in itself is heterogeneous.
So, the issue of efficacy, as far as IVIG, one can
hypothesize and talk around it, but to get the data is not
going to be that easy.
MR. ALLEN: A couple of quick questions. You
mentioned that your donations are also volunteer.
MR. LAMB: That is correct.
MR. ALLEN: What is the difference between your
plasma and ABC centers' plasma in terms of getting it
manufactured in this country? Is it because you have
contracts with manufacturers in this country?
MR. LAMB: Yes. We organized the plasma program
so that the plasma is sent to a manufacturing site and the
products are returned, unlike in the ABC situation, they are
selling their plasma outright to a manufacturer, and they
have no control over the distribution of the finished
product.
MR. ALLEN: But they are saying that they can't
get a manufacturer to buy their product here in the States.
MR. LAMB: Well, that's correct. By and large,
the U.S. manufacturers, because of the issues relating to
CJD, had made a decision not to fractionate recovered
volunteer plasma, however, because we are in contract
manufacturing, we in essence buy capacity, and so we have
thrown away $120 million worth of product, the American Red
Cross, of finished product since the policy was implemented
in the August 8th, 1995 memorandum, we take that risk on
ourselves, so we are not passing that risk to a
manufacturer.
So, we bear the risk, we bear the potential
benefits, so that is a much different situation.
MR. ALLEN: Also, in terms of autopsies, maybe you
know something about this, maybe someone from the CDC can
answer this, but I was told that at this point, there is
about four to six medical centers around the country or
maybe around the world that actually do autopsies on known
CJD patients. Do you know anything about that?
MR. LAMB: There are a few select laboratories who
specialize in doing autopsies of patients who are diagnosed
with CJD. In the cases, the donors who, in our case, have
died of CJD, we think have died of CJD, we arrange to have
the autopsy done by the specialized laboratories.
MR. ALLEN: There are only a few, is that correct?
MR. LAMB: There are a few who specialize in it, I
know that. We work with those few. I don't know if there
are -- there may be more, but we certainly try to work with
those who have the greatest degree of specialization, like
Prusner's laboratory is one that does many.
MR. ALLEN: You mentioned projections. How did
you project your needs, the needs of this country in terms
of IVIG? You mentioned that earlier in your statement. Did
you go by last year's numbers or do you guys do a projection
--
MR. LAMB: In terms of forecasting the overall
market?
MR. ALLEN: Yes.
MR. LAMB: We basically, for marketing research,
we got some data, and then given that in the past, demand
has been increasing by a rate of about 10 percent, we just
took the last year and increased that by 10 percent.
MR. ALLEN: Okay. And of the 126,000 grams that
is back-ordered, how many are emergency versus guaranteed
contracts?
MR. LAMB: I don't have a specific breakdown. I
would say very few emergency, because we do fill most
emergency orders, probably the majority of those would be
contract.
MR. ALLEN: Thank you.
DR. HOOTS: Just to put you really on the spot,
and not to ask for an answer, but just in terms of the
response the chairman was talking about, the recommendation
that this committee made in January about recalls, part of
that recommendation was that for the next year, in view of
the shortage, what is implicit in that is that come January
1999, we should be looking at it again or somebody should
be, FDA should be looking at it again.
In all the things we have heard in the last day
and a half so far, that confirms what we all knew --
DR. CAPLAN: Keith, move your mike a little
closer.
DR. HOOTS: I am sorry. It confirms what we have
all known, which is not only are we very effective at
providing for ourselves except in these extraordinary
shortage circumstances, but we are providing a lot of
products to the world.
We don't have, at least we can't recognize whether
we have new variant yet in the United States. The
possibility is certainly there. You alluded to the studies
which we heard and which have been updated, and I think that
is clearly where the answers have to lie.
Over the last six to eight months, one of things I
think that we would want from people like your scientists,
and we have already, the context of how to break out the
exceedingly low risk of sporadic CJD which can be pretty
closely defined -- and we spend a lot of time doing that --
from the totally unknown risk of new variant if it were
transmissible as your experiments have implied, at least to
cryo and fresh frozen.
So, just more as a comment rather than a question,
I know you have thought a lot about this, and you might want
to comment right now, do you think, say, by January, that we
will have more information that will allow us to make that
distinction? The British have made it because they do have
new variant and they can look specifically. We don't know
if it is going to be here, but we have responsibility to
everyone including the whole world, since we are providing
so much of that, to do that.
So, I want to kind of put that out there, because
I think that is one of the leftovers we have from the
recommendation that was made last time.
MR. LAMB: We would like to look at new variant
CJD. We are working with Dr. Brown in this regard. The
issue of bringing in the new variant CJD into the United
States for experimental studies needs to be worked through,
but in an ideal situation, we would like to repeat the
fractionation experiments with the new variant version, but
there are some logistical issues that need to be worked out.
DR. GOMPERTS: Chris, if I could follow up on a
topic that you covered a little earlier on, when I read the
New York Times article, it seemed to me that it identified
essentially three causes for the shortage in the United
States. The one was the increased utilization, secondly,
the CJD withdrawals situation, and thirdly, the compliance
issues.
Now, if we look at the situation in Europe, and
while I do hear of perhaps shortages in Spain, but other
countries there isn't, and ask you the question why is it
that there aren't shortages in Europe. One, obviously, they
are increasing the demand for the product, the patients are
getting it. Certainly, I think in the case of some unusual
diseases, there is a fair amount of utilization there.
The other one that you pointed towards is the
withdrawal issue. As far as the situation of manufacturing
in Europe, could you comment to the committee on that?
MR. LAMB: I can only comment on the CJD issue, as
I mentioned, which is, at least on a country-by-country,
could be less stringent than in the United States. I really
can't comment on overall demand in Europe and overall
capacity and how that is matching up. I don't know.
DR. CAPLAN: Let's do Carolyn and then I will let
Mark Weinstein come forward.
MS. JONES: Just one question. Yesterday, the
plasma, the Baxter and Bayer, and all of those, indicated
that there is an effort to put a hold on the products until
the donor returns. Has the Red Cross considered doing that
with regard to the recovered plasma, holding it for a
period? I know that would present a problem up-front, but
maybe later on, with respect to withdrawals, it may ease
some of that.
MR. LAMB: We have considered it. The issue is a
little bit different with recovered plasma versus source
plasma. With the source plasma, where you can come in as
much as twice a week or multiple times, holding a plasma for
60 days so that you might catch a unit that may have
seroconverted during that 60-day period, there is some
efficacy in that approach.
However, on the volunteer side, donors are only
coming back at most once every 56 days, so having a 60-day
donor hold to catch the seroconversion doesn't give you that
kind of a yield, so I think it is the difference in the type
of collections that doesn't really make it effective on the
recovered side.
MS. JONES: Well, if it's 56 days, why not a
longer hold than what the source plasma hold would be? I
just want to know what the difficulty for Red Cross would be
with respect to that.
MR. LAMB: On the average, a donor comes back
about -- a donor donates about twice a year, so for us we
would be talking about a hold of maybe six months, and at
that point, it really would take out a tremendous amount of
volume out of the system in terms of products for what I
think would be very little return in terms of safety, none
probably.
DR. CAPLAN: Thank you.
MR. LAMB: Thank you.
DR. CAPLAN: Next, we are going to hear from Mark
Weinstein of the FDA. After that, we will have a brief
public comment period, then, we will take a break. Then, we
will resume our deliberations about what, if any,
recommendations we want to make.
Welcome back.
DR. WEINSTEIN: Thank you.
Good morning. I am Mark Weinstein, Director,
Division of Hematology at CBER.
Today, I will give you a brief summary about FDA's
perspective on IGIV shortage, evidence of the shortage, our
assessment of the main reasons for it, some of the actions
that FDA has taken to alleviate the shortage, the current
situation, and finally, some of our considerations for the
future.
First of all, how do we at the FDA know that a
shortage is real? FDA does not have a branch that monitors
the supply of blood products on a routine basis. The number
of lots available for distribution theoretically can be
obtained from lot release data.
However, manufacturers may decide not to
distribute certain lots found acceptable by the FDA for
their own reasons. Thus, the number of FDA-released lots
may overestimate the number of lots actually available for
distribution. Also, lot release data do not include the
amount of product in the lot.
Our primary means of identifying whether a
shortage actually exists is to monitor the number and
persistence of complaints from consumers, manufacturers, and
distributors.
Throughout much of 1997, the FDA received sporadic
reports about shortage of clotting factors, immune
globulins, and albumin. Occasional calls about shortages
are not unusual and may reflect a local transient market
fluctuation. The effect on public health of a transient
shortage may be mitigated by the production of a comparable
product by another company. One manufacturer's shortage may
be another manufacturer's opportunity to sell product.
There may also be a certain degree of skepticism
about reports of apparent shortages because it has been
argued that rumors of a shortage can be used by some to
leverage the release of product that otherwise would not be
released.
During most of 1997, the FDA addressed requests
for information about product availability primarily by
surveying manufacturers as to how much material they had in
inventory, and informing the requester about potential
sources of the product.
In cases involving the theoretical risk of
CJD-contaminate material, there a number of case-by-case
assessments of risk that led to the release of product if
the evaluation concluded that there was no measurable
additional increase in CJD risk.
By November of 1997, however, it became clear that
the IGIV was truly in short supply. FDA received hundreds
of phone calls from many different sources including from
distributors, from major treatment centers, such as Walter
Reed, Johns Hopkins, and Duke University, and from consumer
groups, such as Immune Deficiency Foundation.
Calls from consumers were persistent and came from
all parts of the country. FDA contacted manufacturers,
large distributors, and group purchasing organizations.
They reported that there was little product in inventory or
available on the market nationwide.
Now, we will give you an assessment of the reasons
for the IGIV shortage. The shortage seems to be the result
of many factors including, but not limited to, increased
demand for product, decreased production, and increased
withdrawals and recalls because of compliance and CJD
issues.
Regarding demand, it has been increasing by about
10 percent per year according to the Market Research Bureau,
a private marketing research company specializing in
surveillance of the plasma derivative industry.
The number of approved indications have increased
over the last five years, so that each manufacturer has
increased the approved indications for its particular IGIV.
Among the approved uses, as we have heard yesterday, are for
treatment of primary immune deficiency, immune-mediated
thrombocytopenia, Kawasaki disease, bone marrow
transplantation, and pediatric HIV infection.
There has also been an increase in the off-label
use of IGIV that includes treatment of a large number of
neurological disorders, autoimmune diseases, and
hematological disorders.
Some of these off-label uses are considered as
standard of care at many major medical centers, whereas,
others are not, and are based on limited studies or
anecdotal reports.
Although hard data are not available, off-label
use is estimated by the Immune Deficiency Foundation and
physicians at major centers to represent about 50 to 70
percent of IGIV use. Alternative therapies are available
for many of these diseases.
Concern about CJD is another contributing factor
to the shortage. Multiple IGIV lots have been withdrawn
because of donors who, after donation, were identified as
being at risk of, or having developed, CJD. Many of these
lots were distributed and largely consumed before
withdrawals came into effect. However, substantial amounts
of intermediate materials not yet processed into finished
products were also affected by the withdrawals.
We believe that the failure to process
CJD-implicated intermediates has been the primary effect of
CJD on product availability. Distribution of IGIV in the
United States decreased during 1997 by about 10 percent
compared to 1996. We estimate this from data supplied to
the FDA by manufacturers as part of their reporting
requirement described in 21 CFR 600.81.
Manufacturers are required to report data about
product distribution in the United States every six months.
This regulation was instituted in October of 1994, and thus
gives FDA access to data acquired after that time. While
these data do not give us real time information, they do
provide accurate information about the amount of product
actually distributed in the market.
Recently, FDA has attempted to make a more
quantitative estimate of the relative magnitude of the
possible causes of product shortage by using this
distribution data. This was done by first estimating what
the shortfall was in 1997 compared to 1996. The estimated
10 percent yearly increase in demand plus the decrease in
distribution in 1997 compared to 1996 gives an estimate
total shortfall of about 20 percent compared to actual
distribution in 1997. This is similar to the calculation
that Dr. Penner was making yesterday.
The next chart shows what individual manufacturers
distributed in 1995, 1996, and 1997. You can see that some
manufacturers produced less in 1997 than in 1996. In one
case, this was primarily because of compliance issues. In
other cases, the shortfall could be attributed primarily to
withdrawn CJD-implicated in-process intermediates.
The lack of product from the manufacturer who
produced little product in 1997 because of compliance issues
accounted for about 60 percent of the 20 percent shortfall.
Again, this is a model system, a rough estimate, but it
gives you some sense of the magnitude of these withdrawals
and these activities.
The shortfall of product from other manufacturers
because of CJD issues amounted to about 20 percent of the 20
percent total shortfall. While other manufacturers reached
or surpassed their 1996 distribution levels in 1997, we
assume that they could have produced more had they not been
affected by compliance or CJD issues. These factors account
for part of the remaining 20 percent shortfall in
distribution.
Other factors that may have contributed to the
remaining 20 percent shortfall in distribution include
decisions to retain product for later distribution to cover
periods of planned plant shutdown and potentially not
packaging IGIV for the most efficient use of product.
Regarding the last factor, if IGIV distribution is
considered on the basis of number of vials rather than
kilograms, actual distribution of product was reduced by 19
percent from 1996 to 1997 rather than by 10 percent. On
average, there was 7.7 grams per vial in 1996 versus 8.4
grams per vials in 1997.
The reason for a larger amount of product per vial
is presumably a marketing decision based on assessment of
demand, but might not necessarily lead to the most efficient
use of the product. This is an area that needs further
investigation about product usage and information from
physicians, patients, and manufacturers.
Export of IGIV is another factor that affects the
amount of material available for domestic distribution. FDA
does not monitor or control exports. When we have asked,
manufacturers have told the FDA that exports are not a major
factor responsible for the shortage. Exports account for
zero to roughly 25 percent of distributed product depending
on the manufacturer according to anecdotal information
received by the FDA.
The FDA does not have quantitative information
about the fate of product once it is outside of the direct
control of manufacturers, thus, the amount of product that
might have been released to the market, but was held up in
the distribution chain is not captured by this analysis.
Next, I would like to turn to the actions that FDA
has taken to help alleviate the shortage.
During the third week in December of 1997, Lead
Deputy Commissioner Friedman, Deputy Commissioner
Pendergast, and Dr. Feigal, Deputy Director for Medical
Affairs in CBER, spoke to the CEOs of the leading plasma
derivative manufacturers to convey our concerns, to learn
more about the reasons for the shortage, to stimulate
consideration of bringing in European-approved product for
emergency use in the U.S. under IND, and to set up hot line
numbers and product supplies for emergency use.
The FDA has been working with manufacturers to
facilitate increased production and distribution without
compromising the quality of the products. Obviously, this
involves discussions of industry plans to come into
compliance without disrupting production.
FDA has expedited review of licensed supplements
related to IGIV. The FDA's lot release process has been
shortened from two to three weeks to two to three days.
Two companies have agreed to consider bringing in
European-approved product under IND for emergency use in the
U.S. Also, to address the problem of off-label use, FDA
sent a Dear Doctor letter to physicians on January 28, 1998,
to alert them to the shortage and to provide guidance for
prioritizing the use of IGIV. The letter also listed 1-800
numbers which are now in operation to obtain product for
emergency use.
FDA has increased its efforts to monitor supply.
FDA has repeatedly called manufacturers to assess how much
IGIV is in shippable inventory. In some cases, these
surveys have helped to identify situations where FDA could
help to expedite regulatory review of lots pending release.
On at least one occasion, there was no shippable inventory
available from the major plasma fractionaters. FDA was able
to help relieve the acute shortage by expediting the release
of a few lots of IGIV that were pending.
With regard to CJD concerns, FDA allowed the
release of IGIV made with albumin potentially contaminated
from an at-risk donor for emergency use with appropriate
labeling. FDA is considering further relaxation of the CJD
recommendations of December 1996 in accordance with the
advice of this committee and other advisory committees.
The current situation. Phone calls regarding IGIV
have decreased from November 1997 levels of 10 to 20 a day
to 5 to 6 per week. About 40 percent more lots of IGIV have
been released per month since November 1997 than were
released in 1997 prior to November.
However, this increase is partly due to the
short-term effects of expedited lot release and availability
of material that was under internal review by manufacturers.
The shortage continues and probably will for some time
because many of the causative issues have not been fully
resolved.
In particular, a number of manufacturers are in
the process of coming into compliance with Good
Manufacturing Practices, and are not functioning at full
capability. 800 numbers are in place for emergency
purchase, but in some cases, manufacturers are using them
only for consumers who enter into contractual obligations.
For a period during March, product was not available even
when calling the numbers.
Regarding our future directions. FDA is
considering updating the January 28th, Dear Doctor letter
with more recent information including new hot line
telephone numbers and central distribution points for IGIV
products that are to be used for emergencies.
FDA is considering increasing surveillance of
product distribution to assess the long-range potential of a
product shortage before it actually occurs. This would
involve receiving product distribution reports more
frequently and trending the data.
Modification of current CJD recommendations will
help to alleviate the shortage to some extent. Labeling
products according to CJD risk may be one way of modifying
the current recommendation. Thus, products at minimal
potential risk may warrant a generic label, while those at
higher potential risk may have a lot-specific warning label.
Further modifications in our CJD recommendations
will come about as we learn more about the disease through
research and surveillance.
FDA continues to meet with plasma fractionaters on
an ongoing basis to investigate ways to further improve
product availability. One item of discussion may be
potential violations of the Sherman Antitrust Act involving
vertical ties and exclusionary distribution contracts.
FDA may further investigate why the 800 telephone
numbers are not being used as intended by the FDA. In the
long term, the shortage problem will be reduced most
substantially as manufacturers come into compliance with GMP
and production is increased.
FDA stands ready to assist manufacturers in
meeting all GMP requirements.
Thank you.
DR. CAPLAN: Thanks, Mark.
We are going to again open the floor up for
questions. John.
MR. WALSH: I would just caution the FDA -- and I
know we have talked about this off-line -- to use the number
of phone calls into the agency as a gauge for judging
whether or not, how severe a shortage is.
DR. WEINSTEIN: Right. This is, in fact, I should
say one of the most difficult areas that we have to contend
with, be able to assess where we are at any one time during
this shortage crisis, to obtain some sort of trending
information to know when we are actually getting out of the
crisis or shortage situation.
I think that this is an area that does need to be
explored more fully. We realize that the phone calls that
are coming in to the FDA might be a minority because now
they are being directed out toward some of these 1-800
numbers and directly to manufacturers.
Getting a handle on where we are during the
shortage period is something that is difficult for us.
MR. WALSH: A lot of blood consumers like myself,
blood plasma derivative consumers like myself, you know,
would not necessarily bother the FDA once, twice, three,
four times. We would focus attention elsewhere.
From the alpha-1 community perspective, you
understand there is a shortage and there is going to
continue to be a shortage until there is another
manufacturer being able to produce product. So, no more
phone calls are necessary from our community, we don't want
to bother you with that, but we want that understood and
focused on.
The other thing is you mentioned increasing
monitoring of product shortage. With the distribution side,
the FDA has no regulatory authority over the distributors of
products, that is correct?
DR. WEINSTEIN: That is correct.
MR. WALSH: Is there any way that you could
suggest that this committee would inquire or investigate or
pursue some direct oversight or attempt to understand more
thoroughly some of the inequities in distribution that we
have heard over the last couple days?
DR. WEINSTEIN: I think that this has to do with
the state health boards, I believe who are more involved in
the regulation of distribution of product here. I, frankly,
am not certain where the Federal Government would enter into
this process. Potentially, the Federal Trade Commission may
have a role in this, but it is not clear to me where this
authority would lie.
MR. WALSH: If I may, just one more. With respect
to emergency supplies or emergency inventories, does the FDA
have regulatory authorities as to how the different
manufacturers would use external sources, private or
internal sources, with respect to treatment algorithms or
triage formulations?
DR. WEINSTEIN: We have asked the manufacturers,
as you have heard, to set up the emergency of supply, but we
have not gone further into developing a program specifically
about how each manufacturer would handle the emergency.
DR. CAPLAN: Marian.
DR. SECUNDY: Is it within your purview, can you
do that even if it were just points to consider or
guidelines?
DR. WEINSTEIN: I think that is something we would
have to explore.
DR. SECUNDY: I am speaking about the actual
regulatory authority of FDA, because that is a very deep
concern that I have. You referred to the product
availability and contractual obligations. I imagine that
you were talking about the emergency supply that has been
set aside with your request as one piece of that, and then
there is apparently clearly an absence of guidelines and
standardization or procedures relative to that emergency
lot.
As Art said earlier, that would be of great
concern relative to equity and access issues. So, I would
hope that you would look into the question of what the
authority of the FDA might be in this matter, and we, of
course, will I hope talk about that.
You made a reference, following up on Mr. Walsh's
comment a few minutes earlier, to an antitrust possibility.
Would you expand upon that? I am sure, based upon what you
responded to him, you are not seeing that as an FDA
function, but could you say some more about that?
DR. CAPLAN: Why don't you comment on the
antitrust, second part of that question, and then I see Dr.
Feigal wants to say something about the first part of that
question.
DR. WEINSTEIN: Well, it has just come to our
attention that in some cases, as we heard actually
yesterday, that there is product, that if you buy this
product, then, you have to buy this other product at a
higher price or something of that nature, and these are
issues that --
DR. SECUNDY: What would be the procedure for you
to refer that to FTC or is that something that the committee
ought to do?
DR. WEINSTEIN: FTC is aware of some of these
situations now, and I don't know where they are in their
investigatory process here. I do know that there have been
reports to them about these situations.
DR. CAPLAN: I have to insert before I go to Dr.
Feigal, that I think the American public might be
disappointed to know that it was underwriting 800 numbers
for the private sector to make special deals.
DR. FEIGAL: I think the one example actually was
probably somebody in the middle, a middleman rather than one
of the manufacturers.
I just wanted to comment on what our authority is
for the shortages. None. We have no authority whatsoever.
These are done at our request, and we ask the companies to
voluntarily set up systems to do that. We also tried to
provide some guidance in terms of prioritization with the
Dear Doctor letter where we pointed out the kinds of
conditions that we thought the use of the product was most
effective and the need was the most compelling.
The whole issue of FDA involvement with product
shortages is a difficult one for us, not just with blood,
but in many other types of areas, because we do not have
very direct access to the kinds of information we need, and
it was not a mandate that was given to us by Congress.
Nonetheless, there are some responsibilities that
we do have, and we try and do these with voluntary
cooperation with industry, and, in general, industry I think
makes very good-faith efforts to do this. I think there are
some areas where we have concerns and areas where there is
improvements needed.
DR. CAPLAN: Let me just ask quickly since I am
curious, Mary, do you know from the CDC point of view if
there is any authority here relative to the protection of
the public health about the matters we are pursuing?
DR. CHAMBERLAND: CDC, as an agency, has no
regulatory authority in this area at all.
DR. CAPLAN: Carolyn.
MS. JONES: From the HHS perspective, I think HCFA
has some responsibility here on the reimbursement end, that
some of their regulatory arm could be put to bear on some of
this.
DR. CAPLAN: John.
DR. PENNER: The issues of allowing some of the
important pieces of this to be put together for information,
the hospital pharmacies are really the ones that are
controlling the situation. I presume that these individuals
in the hospital pharmacies are being at least alerted to the
problem and will have the most interaction with you.
I am still getting at least the idea that all of
our pharmacists are ending up calling around to each of the
different manufacturers, and are not calling the 800 number.
Can't they just call the 800 number and from there they
don't have to call the individual manufacturers, is that the
way the hot line is supposed to work?
DR. WEINSTEIN: There are a number of 800 numbers
that manufacturers have set up. There has also been a
proposal by at least some distribution firms, I think that
we heard yesterday, about FFF is being one of the firms that
have volunteered to take on this effort.
DR. PENNER: But I am not so sure it is entirely
voluntary. I suspect there is a profit motive maybe
involved, but at any rate --
DR. WEINSTEIN: This is one of the difficult areas
obviously in this situation.
DR. PENNER: But no attempt to coordinate this
into, say, one phone call at least can get all of the
information at this point.
DR. WEINSTEIN: No, there is not just one phone
call.
DR. CAPLAN: Dana.
DR. KUHN: First of all, I would like to
compliment the FDA on its deliberations in getting some of
the questionable product labeled and released. I think that
that was a very good move until some kind of surety is
established regarding all the questions involved with CJD.
Second of all, Mark, I wanted to ask you, can you
comment upon some of the compliance issues specifically and
how these have slowed production, because I noticed your
chart had a large percentage that had to do with compliance
issues?
DR. WEINSTEIN: I think that we saw that very well
illustrated yesterday. A number of manufacturers came
forward there and showed, let's say, the volume of review
now that is undergone for each lot of material. There is a
great deal more of a review of the batch records. There is
greater assurance of product quality that is going on here.
We heard about the numbers of people that were
being recruited to look, to assure quality, and we heard
about training that was going on to prepare these people do
a proper review. All those elements there have taken a
considerable amount of effort on the part of industry to
achieve, and the effort, the process is time-consuming, it
is difficult, but in the end, we will have a better product.
DR. KUHN: Do you see that being soon resolved?
DR. WEINSTEIN: I think again we heard estimates
from the industry yesterday about their planned scheduling
of improvement here, and that at least one of the
manufacturers felt that they would be in full production by
the end of this year.
There are other manufacturers there who are also
dealing with these same issues, and hopefully, they will
also be able to achieve their compliance duties.
DR. CAPLAN: Let me just follow up on that. We
have talked here about CJD and tried to understand how to
deal with the risks that it poses relative to recall or
trying to understand the probability involved of is this an
endemic problem or is it really a problem at all with
respect to blood transfusion, and so forth.
I don't want a detailed answer here, but just on
the Good Manufacturing Practice, there is always some
judgment involved there, too, about compliance, and so
forth. We have seen reports that there are hundreds of
violations or things that have been tagged in different
manufacturing places.
If the industry is being pushed to produce because
of shortage, and at the same time is being held to the
absolute letter of GMP, is there room for discretion there?
DR. WEINSTEIN: Yes. I think that practically
each one of these situations, there is a case-by-case
analysis if there is thought to be a further analysis that
is needed that will get a result here, you know, there are
questionable situations about whether a person actually
received growth hormone or not. We allow time for an
investigation to occur, as Chris Lamb mentioned.
There is another element I think that we would
like to explore with industry further, that we have
mentioned a number of times here, and this is the idea of
properly labeling according to risk here, that product could
be on the market as it was for the CJD-implicated albumin
and the IGIV with proper labeling here.
We feel that that is one situation that properly,
on a risk assessment basis, could be used to get more
product out there. This involves the cooperation of
industry with this stratification.
DR. CAPLAN: I am going to go to Rick and then
come back over here a second, but before I do, one other
question. Would you comment on whether you think that the
FDA was not as vigorous as it should have been in monitoring
Good Manufacturing Practices over the years, in other words,
what we are seeing is a build-up of problems, because we
weren't watching manufacturing carefully, which is now
taking a long time to clear because it is sort of a logjam
situation?
DR. WEINSTEIN: I think that we have a better
system now than we have ever had before. We have better
training, we have instituted this program whereby inspectors
receive additional training at the center here, and are able
to view things with a more focused view on GMP issues than
ever before.
DR. DAVEY: Mark, I am also encouraged about your
comments about labeling. I would like to follow up on that
a bit. I think, as the committee heard at the last meeting,
I think as Jane pointed out earlier, the CJD withdrawals are
really quite arbitrary and given an illusion of safety for
the non-withdrawn lots and an i |