according to your study, what percent of the total units of blood would
be--are being used today? Of all the
units of blood that are being transfused today, what percent of them would be
from processes that would not meet your--the current criteria? Does that make sense?
In other words, how
big a problem is this?
DR. DUMONT: I think I understand your question. I'm not sure I know the exact answer. More of the red cell products that have been
approved recently have been automated methods, like red cell collection with
different machines. There's been some
red cell collection and leukoreduction with different types of leukoreduction
filters.
But some of the
products that were approved back in the nineties, like the AS-1 and a PBC bag,
I mean those products are the same, and there is not universal leukoreduction,
and it's really hard to put a number on it.
Maybe some of the marketing people would know better than I do.
I think there's a
substantial number of platelets that are--or excuse me--red cells that are made
from whole blood collections, not from machines, and not from apheresis. So I'd say it's probably a big number.
DR. SIEGAL: Okay.
Anyone else for now, before the break?
(No response.)
DR. SIEGAL: Then let's break for ten minutes.
(Whereupon, the
above-entitled matter went off the record at 5:13 p.m. and resumed at 5:22
p.m.)
DR. SIEGAL: All right.
At this time we are scheduled to have an open public hearing. It happens that, at least so far, we don't
have anyone on the list to speak from the public sector.
Is there anyone who
wishes to comment during the open public hearing?
Well, if not--oh,
there is. Okay.
DR. DUMONT: I just wanted to make one more comment,
something that we brought out in our manuscript, that we didn't talk about
today, is if the performance criteria is set so high, that it can be difficult
for people to innovate, then what that means is innovations won't come. And there's a lot of reasons, not only just the
numbers, but also the costs and the time.
So that it might actually drive a stasis in where we are with our
current performance. So that's another
aspect to consider, I think, in your deliberations.
DR. SIEGAL: Okay.
With that in mind, is there any discussion before we specifically address
the questions for the committee, based on what we've heard?
DR. MCCOMAS: Well, I've been thinking about this
innovation, and I'm questioning how does a lower standard spark innovation, and
I'm using an analogy of, for instance, how the U.S. is responding to its fossil
fuel reduction, and how wonderful lower standards have begun to spark
technological innovation compared to other counterparts who have adopted more
stringent standards.
So it seems to me that
the lower standards argument suggests more that we accept the status quo rather
than we spark innovation. So that's all
I would just comment.
DR. ZIMRIN: Can I make a comment. I mean, there are other things besides
red--oh, there's someone else talking?
No. There are other things
besides red cell life span I guess that you'd be interested in, and one is, as
was mentioned earlier in the morning, I guess, was pathogen reduction. So that would be something else that one
would be looking for it. It's not that
innovation might achieve a slightly different goal.
DR. SIEGAL: Okay.
Anybody else?
Dr. Szymanski.
DR. SZYMANSKI: I think it's laudable to have very high and
stringent standards. Another thing is:
Are they possible to achieve, in reality?
I've done a lot of these survival studies in my life, and right now, if
somebody would come to me and say, okay, I need the survival studies because of
this and that, I would not do them, because if I can have only three failures
in 24 cases, I think this is extremely difficult in vivo survival, red
cell survival. Very, very difficult.
And as I said in one
of my comments, that sometimes these might not really be even failures, because
some patients release the red cells later.
They just keep them longer, and this 24 hour survival might not mean,
actually, as bad as it sounds.
So I think for this
reason, I think I might be sort of similar to many other people who are in this
field, that they would not really start going into these studies because it's
so much work, it's a really tremendous effort, and you are faced with a
failure, in the end. That's my only
comment.
DR. SIEGAL: Okay.
DR. TROXEL: I just
want to reiterate a few things that have already been stated, probably, in
various ways this afternoon. But it
seems to me that the purpose of the standard, in this context, is to try to
maintain some reasonable likelihood of achieving some level of quality that's
deemed important.
And I specifically say
that in kind of general terms because I think we can get "hung up"
very easily on 70 percent versus 73 percent and, you know, all of these
particularities, and there is some inherent arbitrariness to them because
they're cutoffs. And so, you know, we
can always argue that you should go from 75 to 74, or 74 to 73, and you can
usually, you know, deal with the slight changes in probability of success and
failure and risk, and so forth, that are attached to those changes because
they're small changes.
But at some point you
have to make a decision, yes, it's approved, or no, it's not approved. And so, you know, that arbitrariness is sort
of built into the system at a certain level.
So one reasonable
rationale for relaxing a standard might be to maintain the same level of
quality and yet still allow more products to be approved.
And I think the
proposal that's been put forth today addresses the approval rate of that, part
of that equation, without really saying anything at all about the maintenance
of the quality standard part of that equation.
And so I think that's something that we really should keep in mind.
Having said that, if
you look at recent history, where "recent" again can be fairly
generously defined, as Tom said earlier, by the last decade, the likelihood of
products getting approved is actually, you know, overwhelmingly--the vast
majority of products have in fact been approved with the current standard.
so there's not a
proposal to increase the stringency of the standard. It's simply a question of maintaining the
current standard until we have such evidence that allows us to say whether or
not we're going to in fact sacrifice any of the safety in terms of the patient
outcomes. That is in fact the bottom
line, ultimately.
So I think it also has
a little bit of a flavor of trying to fix something that isn't really broken at
this point.
DR. SIEGAL: Further discussion?
(No response.)
DR. SIEGAL: All right.
Then let's address the questions.
We have a slide. All right. So question number one.
Does the Committee
agree with FDA's proposal to maintain the current criteria? And we've heard the current criteria stated
about 15 times this afternoon, so I won't read that part.
And if we vote
"yes" on this as a committee, then the further votes aren't
indicated, and if we vote "no," then there are two other questions.
So shall we start
talking, first of all, about this first question. We sort of have done this a little but we
ought to do it some more, because remember that we can't really state our
opinions after the vote. So we want to
come to some kind of conclusion. Yes; we
can't change our vote but we can certainly state our opinions.
DR. MCCOMAS: I have a point of clarification, being new to
this. So when you say does the committee
agree, are you going by--and then if it does, then there's no further votes. Would that be based upon a majority of
people, or a consensus of the people here?
If one more voted yes, than no, then we wouldn't continue on? Okay.
Thanks.
DR. SIEGAL: Okay.
So who wants to talk to this?
Shall we just go around the room?
You want to just call
the question?
All in favor of
calling the question?
(Chorus of ayes.)
DR. SIEGAL: The question has been called. Let's vote.
Do you want to do that, Don.
DR. JEHN: Okay.
And remember, we want to keep--we're going to start with
"yeas" but we want to keep our hands raised until your name is called
off, and I have your vote. Okay.
Who's in favor of this
question? Yea?
(Showing of hands.)
DR. JEHN: Okay.
Dr. Macik. Dr. Fleming. Dr. Kulkarni.
Dr. Manno. Dr. McComas. Dr. Rentas.
Dr. Troxel. Ms. Baker. Dr. Bello.
Dr. Cryer. Dr. Di Bisceglie. Dr. Edwards.
Dr. Finnegan. Dr. Kuehnert. And Dr. Siegal. Okay.
And "nays"?
(Showing of hands.)
DR. JEHN: Dr. Szymanski. Dr. Zimrin.
Okay. So it's one, two, three,
four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen,
fourteen--fifteen years and two nays.
DR. SIEGAL: Do we want to have any further discussion on
how we voted or why?
DR. JEHN: Dr. Katz, do you have an opinion? You can't vote; but do you have an opinion?
DR. KATZ: Of course not.
Yes. I feel very
strongly, both was, and I'm not sure I'm speaking for the industry when I say
this. I think the critical issue here is
it's a bad time for me to go to my heart programs, for example, and say, well,
we've got this bag a buck cheaper but the survival's 3 percent less than the
current standard because we changed the standard. I really don't want to be in a position to do
that. I don't think that's sound
judgment on my part, given all this retrospective data that has got us
concerned about the storage lesion.
So from that
standpoint, I think the current standard's fine, with the caveat that when, as
an example, pathogen reduction is approvable except for one percent too low
survival, or one extra failure in the survival study, that that has to be a
very careful discussion about risk and benefit, so that we don't lose the
opportunity to do pathogen reduction or take certain plasticizers out of the
sets used for neonates. Those sorts of
things can move along and not get "hung up" for a one percent
survival miss, or an extra, a fourth failure in a study of twenty-four.
DR. SIEGAL: All right.
Well, if there's no further discussion--yes, please.
Mark.
DR. BALLOW: I mean, another point of view is, Are we
stringent enough? Should we make the
criteria even more difficult? I mean,
we've heard some clinical studies, and although they have be retrospective, I
think we do need some better-controlled prospective studies to really look at
this issue about, you know, about the age of the product, age of the red cells
and whether they do have an effect on clinical outcomes such as cardiovascular
surgery. So it'd be nice to get some
additional data over the next several years, to be able to come back and
perhaps reexamine the criteria, and make some educated decisions at that time,
based on clinical efficacy and not just mathematics or statistics.
DR. SIEGAL: Somebody else?
Dr. Cryer?
All right.
DR. DI BISCEGLIE: Apparently my microphone doesn't work. So I voted yes, but I would like to express
some dismay. I wrote some notes here
about what I called "a primitive biomarker of questionable relevance." You know, this is a surrogate red cell
survival. The Agency normally doesn't like
surrogates. When a sponsor comes to the
Agency looking for approval of a product, they don't like to hear about
surrogates. So I guess I would challenge
the Agency, and the blood banking community to--I'm not sure it's--somebody
pointed out the difficulties of doing studies based on clinical end points, but
this needs to be examined.
Are there better
surrogates, perhaps, more modern surrogates?
Or maybe some studies that match up the clinical relevance with the
surrogate.
DR. SIEGAL: I actually ought to second that by pointing
out, as I think I sort of did before, that the study that we're debating the
significance of is done on 42-day-old red cells, and it's already been strongly
called into question, that 42-day-old red cells may be really adverse, and
maybe we ought to be really thinking about a major study, possibly funded by an
HLBI.
I just can't help but
wonder whether we couldn't, in fact, get data from a previous prospective study
that was done a long time ago, the transfusion safety study, and perhaps there
are data there that can be mined, that could be looked at retrospectively, but
were collected prospectively, and that could give us some information about
these sorts of things.
Dr. Epstein, is there
any possession of that?
DR. EPSTEIN: GSS is a very old study, and, you know,
products have evolved. On the other
hand, there is now an RFA to look at issues related to red cell preparations
and clinical outcomes. Dr. Glynn had to
leave early and could have addressed, with more precision, what's in the
RFA. I really can't do that. I don't work for the NHLBI.
But I think that
there's a growing awareness that the whole question of the rue safety and
efficacy of not just red cell therapies but transfusion therapies needs a
modern reexamination in the era of prospective randomized controlled trials,
and it's my fond hope that this will be the recommendation that comes out of
the forthcoming meeting of the Secretary's Advisory Committee for Blood Safety
and Availability, which will be taking up specifically the question of
toxicity, or potential toxicity of older red cells at the next meeting, which
is May 29-30. The subject will be on May
30.
So, you know,
certainly I think it'd be a good thing if some of the experts here attended that
meeting, and, you know, I agree fully. I
think that we do need a scientific examination of these issues with modern
tools.
DR. SIEGAL: Thank you, Dr. Epstein. Anyone else want to comment?
All right. Dr. Fleming.
DR. FLEMING: Thanks.
I'd like to actually reinforce what some of my colleagues have been
saying. I think Dr. Dumont, in his
presentation on the slide that I went back to, did hit two key questions,
"hit the nail on the head."
The second of his two
key questions is: What's the availability of current RBC products? Well, given the totality of the data that
we've seen, the capability is very high, to be able to achieve success based on
the current state of the art.
The first of his
questions is what's the clinical evidence, and the best case that was made to
weaken the standard was that the evidence that we have for why percent recovery
is important is not from highly-reliable studies, and then the other argument
that was made is there's a level of arbitrariness.
Well, those two arguments
together don't justify weakening the standard.
The congressional mandate to FDA is you need substantial evidence of
efficacy, and so as I've already mentioned, those arguments are more sounding
like absence of evidence is evidence of absence, as I mentioned earlier. What we really need, or what my colleagues
are saying, we really need more studies that will allow us to improve the
surrogate.
So if it's viewed that
this bar is too high, and in part because there's some arbitrariness to the
surrogate, the answer isn't weaken the surrogate. The answer is let's continue to probe as to
whether or not this surrogate can be improved upon without having to ultimately
go to a clinical end point, which would in fact be something I would love to
see in terms of reliability, but I acknowledge would be very huge trials.
So a bottom line to
this is how do we go about pursuing much more enlightenment about what
biomarker would be reliably screening in effective therapies, and screening out
ineffective therapies, if one wants to move beyond the current standard that
FDA is using.
DR. SIEGAL: We really should have more discussion on
this. However, since there don't seem to
be any takers--okay.
Dr. Szymanski.
DR. SZYMANSKI: Well, I would be very interested in actually
doing a survival study in a patient who receives a unit of two red cells that
are of different age. Then you would
really hit the proper population, to know what happens when you give these
units to patients, how much recovery you have, and this could be done, not so
terribly, in a cumbersome way, because you can measure their red cell volume
with the chromium and you can measure their survival with different techniques,
which gives you actual survival, not the chromium survival.
It would be very
interesting to compare that to the so-called surrogate that we have in normal
volunteers, giving a 10 milliliter, 20 milliliter volume, a blood sample.
And that I think would
open our eyes, to see what really happens with patients when you give them
these cells, young or old. But I doubt
anybody's going to do it.
DR. CRYER: I will comment on that because I think, first
of all, it is the crux of the matter. We
somehow have to be able to figure out whether or not there's something about old
blood cells, or even new blood cells, that's doing something to our patients.
The problem is, is
that, you know, I was a little concerned about the cardiac study where one or
two blood cell transfusions didn't make any difference. It's not until you get a whole bunch.
Well, in cardiac
patients, that's going to be long pump runs, there's going to be other things
that are damaging to the micro circulation of the patient's organs, and so
forth, than just the red cells. and the
same holds in my patient population, the trauma patient, where even--we have a
couple prospective studies that have demonstrated a very nice correlation with
the more blood transfusion you get, that the higher incidence of organ failure,
and then you still are stuck with the problem that the more blood you get, is
directly proportional to the more blood you need, which is directly
proportional to how badly you're hurt.
So you can never
separate out those factors in any clinical study and I don't know how we're
ever going to get around that. I'd love
to do it if any of you have some good ideas, and work with you, but that's the
conundrum.
DR. SIEGAL: I have a question, actually, for people who
know this, because I don't, and that is whether studies have been done that
look at people who are in less catastrophic circumstances than cardiac surgery,
and whether the age of the red cell matters in people who just need routine
blood transfusions, because it might affect how we handle supply.
And the other thing
is, I want to mention, which has been mentioned before by others, that what we
call red cells aren't red cells. They're
an interesting mixture of red blood cells and packets of cytokine-producing
lymphocytes and granulocytes and what have you.
And those cells are there, and unless we do leukocyte depletion studies,
and figure out what their contribution is, it may very well be that they are
the prime offenders in some of the toxicity that we see.
DR. ZIMRIN: The problem with looking at patients that are
not so sick is that you can't look at survival as an end point. Otherwise, you'd need, you know, a tremendous
number of patients. So you would have to
look at much fuzzier end points, which is why I don't think the studies
exist. I certainly don't know of any.
DR. SIEGAL: You know, tat's a good point.
DR. MACIK: I would just kind of make a couple of points,
since I haven't spoken all day, but I would agree, number one, if a person
needs a blood transfusion, they're almost never well. You don't need a blood transfusion if you're
well. There are sicker people.
The other is when we
talk about surrogates--and I am not a blood banker, so I don't know exactly how
these studies are done--but when you look at some of the earlier studies, and
there's a far off-scale outlier, do we know the red cells are normal? If we pick, quote, normal people, how do you
define it's a normal person for your surrogate study? Do we really know they don't have a mild red
cell membrane defect? Therefore, their
recovery isn't as great, even though they are in normal control.
A comment was made
earlier, well, maybe industry wouldn't pick that person again because they know
they didn't have good recovery before. I
would say that wold be a valid point to make, that you wouldn't want to pick somebody
unless you did a full workup of that person and show it wasn't their own red
cells that were bad.
And there are many,
many red cell membrane disorders of varying intensity, they're fairly common,
that, you know, any individual may not be a good model, even though they are
normal as far as more criteria used. To
my knowledge, I don't think with any of these studies, that they go through a
minute workup of the normal controls, red cell membranes and enzyme systems. So you have to be careful with some of these
surrogates from that standpoint also.
DR. SIEGAL: More commentary?
(No response.)
DR. SIEGAL: Well, all right. Then I call this meeting adjourned.
(Whereupon, at 5:47
p.m., the meeting was adjourned.)