So, for example, in
order to supply our hospitals, we have reduced our incubation of the two
bottles from 24 to 12 hours so that we can get product to the hospital with
enough shelf life left on it that they can manage their inventories. Again, there's no regulation or AABB standard
that tells us how to do this. So in the
interregnum between now and whenever we have that sort of regulation, places
are pretty much allowed to do what they want.
Our biggest concern of
some of us, we had, in a sense, funded our plans to mitigate TRALI based on the
decreased outdate rate of 7-day platelets.
So, for example, at my center, we sent from seven to eight percent down
toward one percent. That means that I
had in the range of 1500 apheresis platelets to play with if I'm going to start
screening apheresis platelet donors for HLA antibodies or multi parity, or
those sorts of things, if you look at the pathogenesis of TRALI.
So we wanted to know
what impact the discontinuation of
PASSPORT had on plans for TRALI mitigation.
And, as you can see, 11 of the 15 said that discontinuation was going to
slow it down on average six months, a few for nine months or more. And, again, some of the non-participants as
well were going to have to delay TRALI because of the inability to get enough
platelets to being deferring donors that might present a risk of TRALI.
Okay. So that's the ABC survey. And I want to very quickly go through a risk
assessment that has been put together by an AABB ad hoc subcommittee. And let me just say up front that the heavy
lifting in this has been done by Larry Dumont and Mark Brecher, and the rest of
the people on the subcommittee have provided a lot of input regarding
assumptions and whatnot, but most of the model was done by those two guys.
You know this, that the study was discontinued based on culture
positives, not clinical events. And, in
the best of all possible worlds, we wouldn't have been measuring microbiologic
end points, we would have been measuring clinical end points. We didn't think that was operationally
feasible when the study was originally designed, so we used the Asurrogate@ of culture
positivity.
We have developed a
sensitivity model to explore the risk reduction for clinical sepsis by limiting
bacterially screened SDPs to a 5-day shelf life, and a second model looking at
the potential impact of TRALI mitigation strategies. These models, we all understand, are only as
good as the assumptions upon which they're based and in many areas our
assumptions are not supported by really hard data, so this is an example,
perhaps, of GOBSAT, good old boys sitting around the table.
We've looked at the
literature; we've looked at the abstracts; we've looked at our experience in
the centers who are participating and tried to come up with reasonable
estimates, and this is in my handout so that you can go over these in detail
and we can talk in the hallway if you want, but the basic assumption is the
model is that whole blood platelets are more dangerous than apheresis
platelets.
So to the degree that
you have to replace single donor platelets with whole blood platelets, you may,
in fact, have an increased risk of clinical sepsis and bacterial
contamination. And the reason for that
is a five unit pool of whole blood derived platelets has five skin sticks
involved in it. Okay.
Plus, that with few
exceptions, whole blood derived platelets are not tested with culture. They are tested with surrogate tests that
have a very high false negative rate and that's all in the assumptions. So this is the model.
And this is kind of
complicated, so I'm going to show you on a table later. But, basically, the horizontal axis is the
proportion of day 6 and 7, apheresis platelets, that are replaced by platelets
derived from whole blood. And as that
percentage goes up, the risk goes up, and then the three lines represent
different proportions of whole blood derived tested with surrogate, whole blood
derived tested with culture. And, as you
can see, if you get kind of between 20 and 80, which is where we think reality
will land, the risk of the reversion to platelets derived from whole blood may
actually represent an increased risk of clinical sepsis compared to 6- and
7-day platelets.
So this is the table
and I'll spend a little more time here because this is really where the meat
is. This is just some examples off the
graph, okay. So if you look at 7-day
PASSPORT line, we think that the clinical risk based on the point estimate from
the Red Cross passive surveillance and the upper bound of the 95 percent
confidence interval for clinical sepsis, not microbiologic contamination, okay,
those two risks are 7.4/M and 16/M. That
16/M is the worst case upper 95 percent confidence interval.
In the top line of the
table, if you replace it entirely with cultured 5-day platelets, the risk falls
to about 1/M. So if we were able to
completely revert to 5-day apheresis
platelets, there is a decreased risk and that's the risk associated with
blooming of contaminating organisms later in culture. Okay.
If you go down let's
say to around here, maybe is a reasonable assumption from the ABC survey that
we replaced 25 percent with cultured whole blood platelets, that may be too
high, and 25 percent were surrogate tested, in fact, the risks are about four
and ten and may actually represent an increased risk of clinical sepsis with
reversion from day 6, 7 transfusions to 5-day outdate.
The best estimates
that we have from my center and from Peter Tomasulo Blood Systems is that right
around 20 percent of 7-day labeled platelets get transfused on day 6 and
7. Again, the denominators are not very
robust compared to the entire size of the PASSPORT study, which is about
400,000 distributions per year, but Peter estimated I think 17 percent
transfused on day 6 and 7, and we did a one month survey in our system
hospitals and came up with 23 percent transfused on day 6 and 7.
So the conclusions
regarding septic transfusion risk, this not culture data, this is septic
transfusion risk is replacing 7-day platelets entirely with 5-day will reduce
the current risk avoiding about two septic transfusion reactions per year. The worst case analysis using ARC's
admittedly passive clinical surveillance suggests up to six may be avoided.
If we replace with
surrogate tested 5-day whole blood platelets, it's likely that the septic
transfusion risk will increase, and replacing with cultured will not reduce the
risk. And, again, that's because of the
problem of false negatives and the multiple sticks that are required to produce
whole blood platelet, which increases the risk both of overall bacterial
contamination and probably false negative.
Now, TRALI was a
different issue for the reasons that I told you. We had, perhaps unwisely, essentially many of
the PASSPORT centers had used 7-day platelets as an opportunity to increase
inventories in anticipation of TRALI mitigation efforts, which are required by
AABB November of this year is my recollection.
The risk of TRALI from
platelets is unknown and we looked at a variety of estimates. Mayo, 1/1000 probably, perhaps higher than
that in their ICU population; whereas, many as 1.7 percent of their ICU
patients who are transfused have transfusion related acute lung injury, but
that's not a hard estimate.
Popvosky's original
publication said 1/5000. There's
Canadian passive surveillance, 1/23000.
So we looked at three levels of risk, 1/100 to 1/10000 for the
model. The risk reduction from HLA or
gender-screening of apheresis platelets we don't know.
But if we look at the
UK SHOT data, we thought that 40 to 80 percent probably covered it. So if we take all the alloimmunized donors
out of the apheresis population, we can make a 40 to 80 percent reduction in
the risk of TRALI associated with this high plasma volume component.
The third bullet
point, we can talk about in the hall if we want. The TRALI risk of a 5 unit pool was soon to
be equivalent to that of single donor platelets, and that also is something
that we might want to talk about. It
depends probably on the pathogenesis in the individual reaction.
If it's a human
neutrophil antibody, this may, in fact, be spot on. If it's a relatively weak HLA antibody, maybe
not. And if it's a biologic response
modifier of some point, we really don't know the answer. And then we looked at six to 12 month delays
in optimal TRALI mitigation.
So this is that model
and what you see here is baseline, that is with no TRALI mitigation and 10
percent efficacy at the three risk levels that we used in the estimate, 100/M,
200/M and 1000/M, or 1:10000. And so you
can see here that if you delay for six months, that this fall in cases of TRALI
will not be realized. So it's a little
backwards to look at this.
Let me show it to you
this way, and just pay attention to that which is in yellow. This is the cases not avoided from baseline
with either a 40 percent or 80 percent risk reduction, and at the higher rates,
which I frankly believe are probably more accurate. We're looking at 80 to 160 TRALI cases that
would have been avoided with mitigation that will not be avoided if we have to
delay for some period of time and then stratified by months.
It's pretty
straightforward. I think it's
understandable.
So our conclusions
regarding TRALI is that if discontinuation delays TRALI mitigation measure, 8
to 160 potentially avoidable TRALI cases may be observed with six months and 16
to 320 with 12 months delay. Delay in
TRALI interventions due to PASSPORT discontinuation may result in more TRALI
cases in six months than the anticipated maximum number of septic transfusion
reactions avoided in one year.
This is the
transfusion fatality data reported to FDA and recently made available I think
on the website. And I just want to show
you, we don't know the risk associated with apheresis platelets. We have this passively reported mortality
data.
TRALI is the most
commonly recognized and reported source of transfusion associated mortality,
and that which may be attributable to apheresis platelets, six cases for sure
and nine that received multiple products, and here we can see eight sepsis
deaths attributed to apheresis platelets.
So the balance is interesting.
We may avoid two to
six septic reactions a year while seeing an increased number of TRALI cases,
and I think our real conclusion is that the study's been suspended. We're working on making a proposal. The sponsors are working on making a proposal
to FDA that might allow us to bring 7-day platelets back, but a comprehensive
risk assessment prior to the decision to discontinue PASSPORT would have
allowed for more informed debate about the impact and whether risk exceeded
benefit.
So that's it and I can
take questions if anybody's interested.
Please, don't beat me up for all the assumptions.
CHAIR SIEGAL: Thanks, Louis. There are questions?
DR. KUEHNERT: Thanks.
That was very nice, Dr. Katz. I
just wanted to ask if in the model you mentioned the effect of going from two
bottles back to one bottle by discontinuing PASSPORT. Did you include the decrease in sensitivity
in the model?
DR. KATZ: The assumption in the model was that
everybody would keep doing what they're doing, okay, two bottles. And in our proposal that will -- I think it's
already been sent to FDA, or at least an outline of it, will, in fact, maintain
two bottles and double volume cultured to increase sensitivity. So, no, this model assumes that everybody
does what they did for PASSPORT.
CHAIR SIEGAL: Dr. Epstein?
DR. EPSTEIN: Just a question about the assumption on rate
of TRALI. We know that the vast majority
of cases in the SHOT data, and I think the French hemovigilance data, are
related to FFP and not platelets. And
I'm just wondering whether you adjusted those rates for association with
platelets.
DR. KATZ: No. We
made our best bet about what the rate might be and it's admittedly something
that needs to be --
DR. EPSTEIN: But the amount attributable to platelets
might be no more than 20 or 30 percent of that figure, which would then have a
proportionate impact on the estimated --
DR. KATZ: Yes.
DR. EPSTEIN: -- cases of TRALI.
DR. KATZ: We didn't have hard numbers, so we looked at
this is a bag that has 250 cc of plasma in it, just like a bag of plasma does,
and that the rate would be the same. And
as, Jay, we understand that our assumptions are very important in discussing
this.
CHAIR SIEGAL: Dr. Szymanski?
DR. SZYMANSKI: What about the decreased viability of
platelets between five and seven days?
DR. KATZ: That is not in the model, and when 7-day
platelets were approved by FDA, it was based on data that suggested that these
platelets circulate and do what platelets are supposed to do. Clearly the number of active platelets
declines over time and that's not arguable.
I think 7-day platelets are a balance between availability and efficacy
and that given the efficacy, the availability allowed FDA to approve these
kits.
I don't think there's
anybody in the room that's going to argue for hemostatic efficacy. They'd rather have a 7-day than a 2-day
platelet, but there are no 2-day platelets now because they have to be cultured
for that period of time before released.
So that's a balance.
Thank you.
CHAIR SIEGAL: Thank you, Louis. We're now going to hear from Dr. Haddad.
I'm sorry. There was one other question.
DR. FLEMING: You mentioned that the outdate rates in your
center will go from three percent to approximately seven percent. Could you state that in terms of units and do
you have a number on a national level?
DR. KATZ: Since the largest centers have just in the
last week or two converted back to 5-day platelets, we don't have hard numbers
yet. We distribute about 17,000 doses a
year. So we're going from one percent
would be 170, two percent 300, to above 1,000, well above 1,000. That's based on one month's data. So we're really looking for anything, and
everybody is that had to revert, looking for ways to optimize inventory.
CHAIR SIEGAL: Dr. Haddad from FDA will give us the FDA's
perspective on PASSPORT.
DR. HADDAD: Good morning.
I will be presenting this morning the course of action taken by FDA in
evaluating the preliminary data of the PASSPORT study prior to its suspension.
FDA for a number of
years has been actively engaged in efforts to improve the storage of the
platelets. FDA has previously presented
to this committee for its advisement the topics of pre-storage pooling of whole
blood derived platelets, the extension of the shelf life of platelets from five
to seven days, bacterial contamination of platelets, and most recently the
rapid testing for detection of bacteria in platelet products.
In 2002 FDA sponsored
a workshop on pathogen reduction technologies to be used in cellular blood
products. And as we heard earlier, the
PASSPORT study addressed the issue of bacterial contamination in 7-day
platelets. And prior to the initiation
of the study, FDA had extensive discussions with the blood community both on a
bilateral basis and as a member at that time of the AABB task force on
bacterial contamination.
Very briefly and
perhaps with some overlap with Dr. Dumont's presentation, but just to
substantiate FDA's decision and action, in March of 2005 FDA granted Gambro
clearance to extend the shelf life of its apheresis platelets from five to
seven days when the platelets were tested with the BacT/ALERT bacterial
detection device early in the storage of the platelets.
The users of the
Gambro seven days had to commit to a Phase IV post marketing study, the
PASSPORT study, whose objective was to confirm that 7-day platelets, when
tested early in storage with the BacT/ALERT bacterial detection device,
presented no greater risk for bacterial contamination than untested 5-day
platelets. And later that year Fenwal
joined the study as a co-sponsor under a regulatory pathway identical to
Gambro's.
The study design of the study consisted of sampling the
platelet product between 24 to 36 hours after collection with the BacT/ALERT
device. Units that turned positive were
discarded, and negative units which were not transfused were retested at
outdate after seven days of storage, again with the BacT/ALERT testing.
And the primary
hypothesis was that the upper confidence limit of the residual bacterial
contamination rate for
7-day platelets was no greater than 1/5,000 with 95 percent confidence,
1/5,000 being the estimate of the contamination rate of the untested day 5
platelets. The study sample size was
determined to be 50,000 outdated units, and a successful outcome implied a
detection of less than five positives at day 7.
In January of this
year FDA received a joint letter from Gambro and Fenwal raising safety concerns
about the PASSPORT study based on the initial data. And the data showed that on day 1, out of
about 200,000 collections tested, there were 48 true positives for a true
positive rate at day 1 of about 1/5,000, which is consistent with published
data.
At outdate there were
two true positives out of about 2,500 units tested. And in platelet transfusion recipients, out
of five reported reactions, we estimated that there were three septic reactions
confirmed to be resulting from transfusion of a contaminated platelet product
yielding a septic transfusion rate of about 1/64,000 collections.
This septic
transfusion rate in the PASSPORT study was compared to a surveillance study
being currently conducted by the Red Cross.
It was published last in Transfusion with the most recent update
in two public meetings. And one caveat
is that the protocols of these two studies were not identical.
The main similarities
were that both studies used the BacT/ALERT as the bacterial detection
device. They both sampled the product at
least 24 hours after collection, and the main similarities is that the
BacT/ALERT testing in PASSPORT consisted of using two bottles, one aerobic, one
anaerobic, four amount in each bottle.
Whereas, the Red Cross study used only the aerobic bottle with a sample
in their revised protocol.
Another difference is
that the PASSPORT study was stored for up to seven days and we tested at
outdate. Whereas, the Red Cross studies
were stored only to five days and they were not retested at outdate.
So the comparison was
not ideal, but it was the best comparison available. And what it showed is that the septic
reaction of PASSPORT was almost double that of the Red Cross. However, the two rates were not statistically
different.
The main conclusion
from the PASSPORT interim analysis, at least from our standpoint, was that the
septic transfusion rate comparison while it did not conclusively demonstrate
that the PASSPORT rates were higher than those of the Red Cross, it certainly
raised a safety concern, and that the finding of two positive at outdate
suggested that the probability of a successful outcome was low if the study was
pursued to its completion, meaning 50,000 units.
Many factors went into
the decision-making process regarding the fate of the study. There was divergence of opinion among the
sponsors between insistence on an immediate suspension versus the pursuit of
the study with the introduction of additional safeguards.
There were no stopping
rules established in the protocol, and the reason is that the high
contamination and septic rates observed in the study were not anticipated. And these high rates are related to the
unexpectedly high force negative rate of the Day 1 testing with the BacT/ALERT.
As mentioned earlier,
the transfusion sepsis risk at day 6 and 7 could not be fully assessed because
the study did not include reporting of the proportion of platelets transfused
after day 5. So if there was any incremental
risk between day 7 and day 5 that risk would not be documented and could not be
quantified.
Also, the cessation of
the PASSPORT study meant the suspension of the 7-day platelets and the return
to storage with the potential for platelet shortages.
So taking all those
issues into consideration, FDA balanced the concerns for platelet safety and
availability and opted for a four week phase-out period to allow the
participating centers to adjust to a reversion to 5-day platelets.
In addition to the
potential for platelet shortage, there was also concern over the impact of the
discontinuation on the TRALI mitigation strategy that the blood centers were
instituting to comply with the AABB recommendations.
And, also, there was a
concern on the part of the blood establishment over meeting the good
manufacturing practices if the transition period back to five days was
short. So the concern was over
relabeling, retraining staff, rewriting SOPs.
And then also,
throughout that period, FDA maintained open channels with
And Dr. Katz mentioned
the ABC survey that was done at that time, and one important finding is that it
showed there was a need for a 19 percent increase in platelet production to
compensate for the anticipated platelet shortage. And, again, Dr. Katz elaborated on the AABB
assessment on overall platelet safety in the case of the discontinuation of the
study.
So based on those
concerns, the sponsors requested an extension of the phase-out period from 28
to 90 days, and FDA did not object to the extension in order to allow the users
to go back to five days safely and without too much disruption to the collection
and distribution of the blood system.
The next steps in
terms of the PASSPORT endeavor, FDA, we will continue to monitor and evaluate
the data generated as PASSPORT is phased out, such as the data that Dr. Dumont
presented earlier. And we are committed to
working with the AABB task force and with the sponsors to introduce additional
safeguards to ensure the safety of the day 6 and day 7 platelets and to make
them available once again.
And on that, thank you
for your attention.
CHAIR SIEGAL: Thank you, Dr. Haddad. Are there questions? Dr. Szymanski?
DR. SZYMANSKI: I'm sorry to ask this because this probably
was presented in a previous presentation, but I was unsure as to how severe the
bacterial event was in these two donors.
DR. HADDAD: You're talking about the reactions?
DR. SZYMANSKI: Yes, because you discontinued the study
because of two septic events, but the description of the septic events remains
unclear to me.
DR. HADDAD: I think the two contaminations that you're
mentioning, these occurred at day 7, so these were bacterial contamination
detected at day 7, and according to the protocol, with the 50,000 outdated
units as a sample size, and in order to satisfy the hypothesis, then no more
than five positives are supposed to be detected --
DR. SZYMANSKI: I see.
DR. HADDAD: -- on day 7.
DR. SZYMANSKI: But were these units transfused or not?
DR. HADDAD: No, they were not transfused because the only
units that were tested on day 7 are the ones that were negative on day 1 and that
were not transfused.
DR. SZYMANSKI: Okay.
So that's a question.
CHAIR SIEGAL: Other questions?
DR. KUEHNERT: It seems like there were a number of factors
that conspired to reach these conclusions which were seen as alarming, but I'm
just not sure that safety was compromised.
And, as you pointed out, there were no stopping rules for the study that
caused the study. There were some bad
assumptions about what contamination rates were going to be in part because
most blood centers use one bottle instead of two, and this one with PASSPORT
manufacturer's instructions are being followed.
So that was another factor.
The definitions I
think were suboptimal. I saw one case
that was included where you had an organism that was identified, and then on
confirmation another organism was found and that was called a case.
And, also, the tools
for confirmation don't seem to be present.
I don't see anything on matching staph epi isolets by molecular
typing, which isn't necessary for all organisms, but I think for something
common like staph epi you have to be able to tell whether it's the same
organism.
So I'm just wondering,
you know, we could criticize a lot of things in retrospect, but what I'm
concerned about is in the future, are all these factors going to be considered
to try to ensure that the study can be performed in a way where we can get
useful results?
DR. HADDAD: We agree with you. When we reviewed the revised protocol, these
are some of the items we're going to be addressing. We have learned that we need to improve the
safety of day 7. We have learned that
day 1 testing is not sensitive to pick up all the bacteria on day 7.
And, also, we need to
tighten up the protocol because, for example, the data that Dr. Dumont
presented, we saw a lot of cases that were indeterminate, and, as you
mentioned, there was a discordance between the organisms. And it's unfortunate that you cannot
determine whether there was causality or not.
And so this is an item that we need to address.
And then, also, in
terms of the classification that was used, again, in that instance, we need to
probably tighten up the classification.
DR. KUEHNERT: I just want to add that I mean I think a lot
of effort was put into this and that's why I think it's so important that
something come from it as far as some sort of a continuation because it's very
important. Obviously, it has a real
impact on platelet safety. So it seems
like it would be very important and it's very complicated, too. So it's just very important I think to put as
much thought as possible into it the next time around given what we've learned
from this first attempt at it.
DR. HADDAD: Yes, absolutely. Thank you for your suggestions.
DR. FINNEGAN: I'd like to support what was just said by Matthew. I think that at 2:00 in the morning I'm more
interested in platelets than I am in a fever and I can treat the fever. I can't necessarily treat the problem that I
need the platelets for.
The other thing is
there's good literature in the orthopaedic world on Propiobacter being
attached to everything in the world, and it does not appear to be an actual
pathogen, but it just seems to sit there.
So I think that that sort of data needs to be sorted out from what you
have.
I agree. I think this study is really important. I think we've heard earlier that keeping our
blood supply as maxim as we can is important, and I think the fact that you
can't tell whether these two staph were 5-day, 6-day, or 7-day means
that you don't know that the 5-day protocol actually works. So I think that this study needs to be
encouraged to be rewritten and redone, but to be continued.
DR. HADDAD: Yes, absolutely. We are determined and committed to doing
that.
CHAIR SIEGAL: Okay.
If there are no more questions, we will take a brief break of only 15
minutes because we're running behind. So
please be back here by no later than quarter after.
(Whereupon, the
foregoing matter went off the record at 10:58 a.m. and resumed at 11:12 a.m.)
DR. SIEGAL: Hello, everybody. Let's resume, please. Let's start again.
Now we're going to
have informational reports from CBER safety teams related to blood and
tissue. The first report will be Dr.
Jonathan Goldsmith at FDA.
DR. GOLDSMITH: Thank you for that. Good morning to everyone. I have the opportunity to talk to you about
CBER's Blood Safety Team and I appreciate the BPAC giving us this
opportunity. My talk is really broken
into two parts. One is introductory in
terms of the basis for creating a blood safety team, and then the second part
is to talk about the blood safety team and it's activities over the last couple
of calendar years. I'll talk to you
about the need for a blood safety team, the legal framework for blood regulation,
the layers of blood safety that assure the provision of safe blood products,
and then the blood safety team itself, the goals and objectives, the
organizational structure and the long-term challenges that lie ahead.
In terms of the basis
for the blood safety team, you have to look at the annual
There are appropriately
2.4 million units of recovered plasma from whole blood donation that are sold
for further manufacturing, including fractionation in to plasma protein
products.
There are about 1
million paid apheresis donors who provide an additional 10 million liters of
source plasma for fractionation into plasma derivatives.
Blood is collected
from approximately 1300 blood collection centers in the
There are about 400
device manufacturers who make test kits to test blood from potential blood
donors. Blood grouping reagent
manufacturers, and there are also those who make the bigger equipment, the
apheresis machines that are used to collect blood and blood components, blood
warmers, and other types of paraphernalia.
Drug manufacturers
also make anticoagulants, and there are about thirty of these in the
In addition to the
whole blood collection, there's also the collection of plasma for the
manufacture, there are about 300 plasma pheresis centers in the
Just to review for a
moment the legal framework for FDA blood regulation.
The other broad act is
the Food Drug and Cosmetic Act which addresses drugs and medical devices, and
as you know, the Food Drug and Cosmetic Act was amended from the Congress in
September of 2007, with the FDA amendment act, and this gave additional
authorities to the FDA in the area of pediatric study requirements, public
disclosure of trials, post-marketing commitment by sponsors, amongst other
requirements.
Blood organizations
also keep in mind that they comply with the state laws and with voluntary
standards from their organizations, such as the AABB and the Plasma Protein
Therapeutics Association.
The overlapping layers
of blood safety provide assurance of the safety of blood and blood products,
and it's actually composed of about six layers in this day and age.
The first is donor
eligibility. Potential donors are
provided educational materials to permit self-deferral. Specific questions are asked about their
health, medical history and other risk factors.
Communicable disease
testing is performed for diseases that we require this. HIV-1, 2, HBV, hepatitis C virus, human
T-lymphotropic virus and syphilis, and there's voluntary testing for
communicable disease by those who collect blood for West Nile virus, for
Trypanosoma cruzi, the agent of Chagas disease, and cytomegalo virus.
General donor deferral
registries must be kept current by blood establishments. They have to have a list of individuals who
have been deferred as blood or plasma donors, so that these people are not
accidentally reentered into the blood supply, their donations.
Fourth is quarantining
of unsuitable blood. Blood products are
quarantined until the products have been thoroughly tested and the donation
records have been verified. Investigation
of problems. Blood establishments must
investigate any breaches of these safeguards and correct all system
deficiencies. They must have control of
their manufacturing.
And last, sixth here
is pathogen reduction. Plasma
derivatives undergo viral inactivation procedures and these may be applied to
other types of blood and blood components in the future.
The CBER initiative to
start a blood safety team began in the summer of 2005 when a Blood Safety
Working Group was put in place at the direction of the CBER Center director, to
determine what our current practices were and what some of the problems might
be in terms of how we were trying to do the business of blood safety.
After about a year of
review, we actually had the establishment of a blood safety team in July of
2006 and we have been meeting since that time on an every other week basis.
The goals of the blood
safety team are to formalize the center operating procedures, to make sure that
we do things in a fairly uniform way, so that we do it in a better way, to
establish roles and responsibilities in the management of blood safety issues,
to be certain about whose job it is when something happens, so there are not
errors of omission.
And third is to
enhance internal and external communications that is within CBER, within the
FDA, within government and with those outside government.
The major objectives
of the blood safety team, which were drawn up by the working group and have
been put into effect, are to improve the CBER response to blood safety issues,
and this is done through defined cross-office collaboration, creating increased
sensitivity to safety signals, so that things that occur in one hallway are
quickly picked up and transferred to a central group that can then deal with
these issues.
Second is to improve
the value of safety information and to broaden public and regulated industry
access to the information.
Not to be repetitive
about this, but to make sure that information that we do collect is of use to
the regulated industry as well as to those who regulate.
Third is to improve
the processing of blood safety information through establishment of a forum for
review and evaluation, permitting discussions in a noncrisis mode, and
facilitating anticipation of events.
As we all know,
preparation leads to a better response than what we do at the last minute or
during a crisis.
And fourth is to
enhance external outreach evaluation and risk communication.
This is a staffing
type model of the Center For Biologics, it's highly simplified and just shows
some course areas.
What I've tried to highlight for you is where the membership of
the blood safety team is drawn, which offices contribute members to the blood
safety team.
The Office of the
Director, the Office of Biostatistics and Epidemiology Office of
Communications, Training and Manufacturers Assistance, known as OCTMA. The Office of Blood Research and Review, and
the Office of Compliance and Biologic Quality, all contribute members to the
blood safety team at CBER.
Each office
contributes between probably two to four individuals on an ongoing basis. Individuals serve for about two years.
What are the
activities of the blood safety team? I'm
going to talk about several different areas where the blood safety team has
been actively involved in dealing with safety issues.
The first is
coordination of investigations and potential shortages of blood and blood
products. Shortages can occur due to
manufacturing changes, reports of adverse events, reports of reduced stability
of a product.
For manufacturing
changes, manufacturers sometimes implement changes in their manufacturing
process, and it's up to us sometimes to determine if there's been any impact on
the safety, purity or potency of the product, and whether or not these changes
will have a potential impact on the public health in terms of keeping products
out of the market that have been manufactured in this new method.
Shortages may also be
due to reports of adverse events.
Adverse events can be of a clinical nature, as you're most familiar, or
they can be of a technical nature, and they can lead to the same kinds of
problems in terms of balancing supply with safety.
And third, shortages
that we've dealt with in the last couple of years have been due to reports of
reduced stability and we've had to do investigation of how we could respond to
this.
Part of the job of the
blood safety team is to help explore the regulatory pathways to avert
shortages.
There are things that
can be done. Can a product be given
shorter dating? Can a dose be
redefined? These kind of approaches.
The blood safety team
reviews the required annual fatality reports from whole blood and source plasma
establishments. The sites from the CFR
are shown. The blood safety team provides
oversight for the annual report and reviews communication opportunities about
the annual report on fatalities, and has been noted previously today, this is
published on the CBER Web site and it's open for all to review.
We also seek some
potential etiologies, meaning what puts a donor at risk for dying, if they
donate blood or plasma? And what happens
in terms of trying to increase our understanding about recipients and their
adverse outcomes that end up as fatalities?
We are trying to
develop ways to think about mitigating strategies to reduce the number of
deaths that are associated with transfusion medicine. What could make it safer for a donor to
donate? For instance, are there other
criteria that might need to be incorporated, to exclude people at risk?
The blood safety team
also reviews the biologic product deviation reports, known as BPDRs, and
potential enhancements to reduce reporting burdens. This is a required report also under 21 CFR
606.171. We provide oversight for the
annual report, to try and refine some of the focus, and we also review some of
the potential benefits of continued implementation of some of the post-donation
information requirements that are required of blood establishments and plasma
establishments.
In the last couple of
years, we dealt with issues about tatoos and post-donation information, and
donor history of cancer, and we've made some recommendations for consideration
at the office and center level.
We also evaluate
manufacturing issues and potential safety impacts, including breaches in good
manufacturing practices such as bioburden excursions, starting material that
has more bacteria than are permitted, and what is the impact on the safety,
purity and potency of the product? Can
these stay in the marketplace?
We also investigate
approaches to threats to the blood supply such as emerging infectious
diseases. We review some of the existing
scientific information and try to support and participate in as possible, in
public workshops that deal with these issues.
We investigate the
impact of outbreaks of transfusion-transmissible diseases on potential blood
donors. A recent event, I think we all
know from the media, is the outbreak of endoscopy-associated hepatitis C virus
transmission in the State of Nevada, in which medications that are used for
preparation for these procedures resulted in contamination from one patient to
the next. And we did a fairly extensive
amount of investigative work to learn about what the impact was on the donor
supply in the community, what this adversely impacted.
We also implement
rapid responses to urgent safety events.
One of the most recent ones in terms of adulterated pharmaceutical
ingredients is the hypersulfated chondroitin sulfate, that has ended up in
Heparin products that have been used in the
You don't think of
Heparin, necessarily, as part of biologic products, but it may be used in terms
of manufacture, and some of the plasma derivatives actually contain small
amounts of Heparin in the final container.
We also thought about the issues of Heparin as it's used in our
screening devices for tests for blood donors and those used to diagnose viral
disease.
We've had some very
careful interactions with the regulated industry in terms of procedures they
can take to reduce the risk of having any Heparin with these types of
contaminants in their products.
Our ongoing challenges
are the development and the formalization of best cross-office approaches to
key safety areas.
We're going to focus,
I think in the next year, at further examination of biologic product deviation
reports. We want to seek ways to
increase the value to FDA and to regulate industry. We realize that it is a substantial burden to
file these reports, almost 40,000 a year.
Even though two-thirds are filed electronically, it's still a great
burden, and to make sure that this information is the information that we need
and results in the best possible products at the end of the day.
Also in terms of
emerging infectious disease, we want to explore improvements in informatics as
a way to try and be alert to changes that are occurring around the world.
Some of our members
who have more of a statistical bent are interested in data mining and the use
of advanced algorithms to detect safety signals. There are huge health databases in the
And then we also want
to explore the need for denominators. We
just heard, in the previous study, about the lack of denominators and the
difficulty that poses in terms of interpreting scientific information.
Well, we would like
denominators in terms of the number of units of red cells transfused each
year. That would be helpful for us in
terms of interpreting the safety signals that come to us from around the
country.
One of our goals is to
try and investigate further the role of the hospital-based transfusionist to
improve databases, and are there ways to work together with some of our fellow
governmental agencies to make this happen.
So just in summary,
then, CBER's blood safety team functions as a coordinated, agile, interoffice
team that evaluates processes, investigates and responds to a variety of blood
safety issues, and we believe that we play an important role in external
outreach and risk communication as well.
Thank you for your
attention, and I think I saved a few minutes.
DR. SIEGAL: You certainly did and we thank you for that,
and this is open for questions from the committee.
MS. BAKER: Thank you, Dr. Goldsmith, for that excellent
presentation.
Can you talk a little
bit more about some of the external communications.
DR. GOLDSMITH: Yes. I
think what we try to do is to have a productive interaction with regulated
industry, sometimes in a very formal way but a very confidential way, so things
that are not obvious in the public domain.
We do a lot of work that way, to be honest.
In addition, through
the CBER Web site, I think we try to maintain a way for the public to have
access to the kind of information that we're dealing with, whether it's
something to do with a product withdrawal, which you could read about, or a
product approval, sometimes, that has some safety aspects, and I think those
are the two ways that we're doing this currently.
We also have some
outreach at national scientific meetings in terms of having booths there and
some interaction with the public.
But we'd be open to
further ideas, if the Advisory Committee wants to suggest some.
MS. BAKER: I was thinking about any formal communication,
about your activities with the CDC or NHLBI, about your activities, or some of
the patient advocacy groups.
DR. GOLDSMITH: Oh. I
see. Well, thank you for that
suggestion.
DR. SIEGAL: Is there any more discussion?
DR. KATZ: I have a quick question, Jonathan. In the other governmental agencies that you
interact with, is CMS at the table at this point?
DR. GOLDSMITH: It doesn't--it's not part of the blood safety
team. It's a CBER organization, but by
having a blood safety team, we have a bit of a louder voice, and it will carry
up the chain of command, and then ultimately across to interagency kind of
communications. So I think it's, I think
we serve a useful function that way. It
gives us more of a voice. That's why I talked
about the transfusionist issue, that for that to happen will require many arms
of government to work together, and I think that we can be part of the starting
point for that kind of process.
DR. SIEGAL: Anyone else?
DR. McCOMAS: I was just curious: Do you engage with the
media with your risk communication, or does that go through another office of
FDA?
DR. GOLDSMITH: Well, risk communication, as you know,
because you're an expert, and we've consulted with you in the past about these
issues, this is something that reverberates up through the organization. I mean, the blood safety team may put
together what are the scientific facts about a recall, for instance, but the
communication and the message will come, will be developed, actually, by other
parts of the organization and the actual communication of that may come from
somebody higher in the organization.
DR. BALLOW: Jonathan it seems like you have a very broad,
very comprehensive charge of this committee.
I don't know you can possibly get it all done. So when you identify an issue, do you
actually triage it outside the committee to get some help, or--
DR. GOLDSMITH: Yes.
Sure. Yes.
DR. BALLOW: --or further evaluation, cause I don't see
how a group of five, six, seven individuals, can possibly do all this.
DR. GOLDSMITH: Okay.
Well, it's actually more like 10 or 15 individuals. But it's the same problem that you present. and what we do is we try to work with a
subcommittee structure, that we try to have people who are part of the blood
safety team, when there's an issue that needs more rapid exploration or deeper
exploration as you suggest, to take them and set them aside as a subcommittee,
and then they operate with the authority of the whole team, basically. And they may be able to reach
conclusions. If there's a question about
the safety, purity or potency of a product, you might have to reach some
conclusions within a few hours. So it's
not--a bulky committee doesn't work very well for that but a small subcommittee
can be highly effective if it's drawn from individuals from several of the CBER
offices, so you have expertise in biostatistics or you have expertise on
compliance, expertise on blood. So it
can be effective.
DR. SZYMANSKI: You mentioned about this Heparin catastrophe
and you said you have some involvement, you know, by monitoring that, and I
have a question.
Could it have been
avoided by any means? You know, does
that belong to your, you know, charge, at all?
DR. GOLDSMITH: If I understand your question, in the terms
of the contamination of Heparin products with oversulfated chondroitin sulfate,
was there a way that that could have been blocked in terms of occurring in the
DR. SZYMANSKI: Yes.
DR. GOLDSMITH: And I think it's the question of the day,
right now, in terms of what could be done and how could it be done better, and
I think the agency is making serious efforts to look into ways to avoid these
kind of problems in the future, as well as deal with the ones now, in terms of
making additional--in terms of validating testing that will exclude these kind
of contaminants in the future for Heparin at least.
DR. SZYMANSKI: Thank you.
DR. KULKARNI: That's an excellent presentation,
Jonathan. I was just wondering about
your shortages of blood and blood products.
Would you address in your safety team about emergency preparedness and
shortages resulting--
DR. GOLDSMITH: It's really not our charge. It's only a tangential issue to us. So there would be other parts of CBER that
are specifically dedicated to emergency preparedness. But the person who is responsible for
coordinating some of those efforts at the CBER level is a member of the blood
safety team. So there is some favorable
interaction that way.
We try to choose our
membership in a way that we pick up all these pieces, and so I think it's a
fairly effective strategy.
DR. SIEGAL: If there are no other comments or questions,
let's proceed.
Now we'll hear from
Ruth Solomon about the CBER tissue safety team.
Dr. Solomon.
DR. SOLOMON: Good morning.
This morning, I'm going to be talking about sort of a tangential issue,
the tissue safety team, and I'd like to present to you, since some of you are
new on the committee, a background about what do we consider human cells and tissues,
how are they regulated, how do we define an adverse reaction for them, and
which adverse reactions must be reported to FDA.
Then I'll go on to
talk about the tissue safety team and its challenges, and also to give you some
statistics on what types of reports we've received over the past two years.
Okay. First, what are HCT/Ps? That acronym stands for human cells tissues,
or cellular or tissue-based products, and they are defined--they are articles
containing or consisting of human cells or tissues that are intended for
implantation, transplantation, infusion or transfer into a human recipient.
And some examples
are--well, first, I'd like to say these cells and tissues can come from
cadaveric donors as well as living donors.
So those on the left-hand side are from cadaveric donors,
musculoskeletal tissue such as bone, ligament, tendon, skin, cardiovascular
tissues such as heart valves and blood vessels, and ocular tissues such as
cornea and sclera.
Then from living
donors, we also regulate reproductive tissues such as semen, oocyte and
embryos, hematopoietic stem cells derived from peripheral and cord blood, and
other cellular therapies.
It's important to know
what is not an HCT/P. This is also
written into the definition. First of
all, organs. Many people are under the
conception that FDA regulates organ transplantation and we do not. Organ transplantation is overseen by another
federal agency, HRSA. Also not included
are whole blood or blood components or blood derivative products, secreted or
extracted human products such as milk, collagen, or cell factors, and bone
marrow is another type of cellular product that FDA does not regulate. That also is overseen by HRSA, and
particularly if the bone marrow is what we call minimally manipulated, or for
homologous use, or not combined with another article.
In other words, your
"run of the mill" bone marrow.
Also, it does not
include devices used in the manufacture of the HCT/Ps. We're only focused on human HCT/PS, so cells,
tissues and organs derived from other animals are not included. It doesn't include in vitro diagnostics, and
lastly, we recently added this because this was sort of a "gray
area." But blood vessels recovered
with an organ and intended for use in organ transplantation, and labeled as
such, are not regulated by FDA. HRSA,
since they regulate organs, or oversee organ transplantation, are going to take
on blood vessels recovered with an organ.
Okay. So how are HCT/Ps regulated by FDA? And we began regulating human tissues in
1993, but that was focused on the cadaveric tissue, and was very limited in
scope to having requirements for donor eligibility, donor screening and
testing.
Then, in 1997, we got
the idea to combine cellular products and tissues, and we issued a proposed
approach to the regulation of human cells and tissues, and out of that came
three proposed and then finalized rules.
They're all codified in Part 1271, and the three rules were
establishment, registration and product listing, donor eligibility again, and
also current good tissue practice, which is similar to current good
manufacturing practice, and I'll mention that again.
But these rules,
you've got to realize are fairly new.
They all became effective May 25th, 2005, and the legal authority for
the regulation of cells and tissues comes from Section 361 of the Public Health
Service Act.
That section says that
the Secretary can make rules and regulations to prevent the introduction,
transmission or spread of communicable disease.
So that's what our regulations focus on.
We don't get our legal
authority from Section 351, as Jonathan explained, and also, we do not have the
Food Drug and Cosmetic Act at our disposal.
That is not part of our legal authority.
Okay. So these products under the
umbrella of HCT/Ps can be regulated in different ways.
This approach we put
out was called a tiered risk-based approach, and some of the HCT/Ps which are
lower risk, because they're minimally manipulated, and used for the same use in
the recipient as they had in the donor, so these type of HCT/Ps, which we have
sort a nicknamed 361 HCT/Ps, they don't have premarket review. They can go right on the market, and they do
have to follow the regulations in Part 1271, but that is assessed on
compliance, on inspection. So no
application comes into FDA for these types of products.
But under the umbrella
of HCT/Ps, some of these can be regulated as biologic products for medical
devices, and as biologic products, they'd be like any other biologic product in
that they'd have to follow Part 1271 because they are an HCT/P, but there'd
also be the other applicable regulations like the 600s and the 200s, and those
would need premark review and approval and licensure.
And similarly, medical
devices that contain human cells or tissues are another route for HCT/Ps. They follow Part 1261 and the regulations in
the 800 series, and they have premarket review and either clearance or
approval. Okay.
So the third rule,
called the current good tissue practices rule, contains a section regarding
adverse reactions and their reporting to FDA.
First, we define an
adverse reaction as a noxious and unintended response to any HCT/P for which
there is a reasonable possession that the HCT/P caused the response.
That is somewhat
different from the biologic products definition of an adverse experience, which
means any adverse event associated with the use of a biologic product, whether
or not product-related.
Okay. So first of all, tissue manufacturers, we
call them manufacturers, they're the tissue and eye banks and cord blood banks,
etcetera. These manufacturers, when they
hear about an adverse reaction from the hospital or health care center, they
are required to first investigate it, but notice that only if the adverse reaction
involves a communicable disease.
In other words, that's
where the authority comes from for regulating these 361 HCT/Ps, and so we can't
go beyond that legal authority.
Then they're not
required to investigate other types of adverse reactions but they're encouraged
to do so.
Okay. Then after the investigation what adverse
reactions must manufacturers report?
They must report to FDA any adverse reaction involving a communicable
disease, if it is fatal, so we have fatality reporting, life-threatening
results in permanent impairment or damage or necessitates medical or surgical
intervention, and remember that it's the tissue manufacturer that makes the
decision about whether there's a reasonable possession that the tissue caused
the adverse event and thus reports it to FDA.
So some examples of
adverse reactions that involve communicable diseases would be, for instance, if
the recipient developed a bacterial infection, if there was a failure of the
graft, that the surgeon believed was secondary to infection, any viral
seroconversion in the recipient suspected to be allograft-related.
However, types of
reactions that would not be required to be reported would be something like a
product defect, like, for instance, the package was labeled incorrectly, there
was mechanical failure of the graft. In
other words, our regulations don't say anything about the efficacy of the
graft, just about preventing communicable disease transmission.
If there were an
allergic reaction or a donor-transmitted malignancy, again that's not required
to be reported, or any sort of product damage, but again we recommend that
those are reported also.
So we use the same
mechanism that any other--that CBER uses to report adverse reactions, and
they're reported through what is called the Med Watch system, on a particular
form. There's a form for that
manufacturer, 3500A. They have to report
within 15 days of receipt of the information by fax or mail and that's just the
top part of the 3500A form.
And it's been
modified. Originally, that form just had
boxes for you to fill in. It said
device, suspected device, or suspected drug.
So the tissue people didn't know where to--what they were, what boxes to
fill in. That's now been changed and we
have a section of boxes called suspected product.
Okay. Then any health care worker can also report
an adverse reaction. That's voluntary of
course. They use a slightly different
form, and we recommend that they report to the tissue bank, where the tissue
came from, that there's been an adverse reaction.
Some health care
workers might think that we forward their reports to the tissue manufacturer;
but that's not the case.
So what are some
sources of these adverse reaction reports?
The majority, as I just mentioned, come through these Med Watch forms,
and also voluntary reporting by the consumer or health care professional, or
the tissue establishment is required to report.
But we could also
learn about a case from if CDC learns about it first, or CDRH sends some of the
HCT/Ps, or on regulated medical devices.
And then there's another voluntary program that CDRH runs called MedSun,
and we've tacked on to that.
This is a mechanism by
which individuals--it's a voluntary thing and hospitals agree to participate,
and an individual in the hospital takes responsibility for reporting, making
sure that adverse reactions get reported to FDA.
There's also a
MedWatch Web site, which makes it easy to obtain these forms.
Okay. Now on to the tissue safety team. We have the distinction of being the first
CBER safety team. Next came the blood
safety team as you've just heard about, and we also have a vaccine safety team.
And the idea to form
this team, again, came from the center director in anticipation that the rules
were going to go into effect.
So back in May 2004,
we had our first meeting. The main
purpose of the tissue safety team is to provide a coordinated efficient
approach to the receipt, routing, investigation, evaluation, documentation and
trending of reported adverse reactions involving HCT/Ps across five offices in
CBER, and also beyond CBER.
So it includes
multiple offices, which I'll show in you a minute. A small working group of the team reviews all
MedWatch reports, even if they're not related to the communicable disease. We would still log them into our system but
not do any follow-up on them.
We would conduct
follow-up on infectious adverse reactions, and that involves seeking additional
information from the clinician and from the tissue manufacturer.
These cases are then
presented to the larger group, the tissue safety team, which meets
monthly. We also have an SOP that
describes the responsibilities of each office for handling the adverse
reaction.
So our team, very much
like the blood safety team, consists of five offices within CBER. So we have the Product Office where I'm from,
Office of Cellular Tissue and Gene Therapies, Office of Compliance, the Office
of Biostatistics and Epidemiology. We
also have a representative from the Office of the Director, and we have a
representative from OCTMA for the person
that asked the question about communication, because we feel it's important for
some very serious adverse reactions, where we have to, for instance, in form
the department or inform the public that we have a representative from that
office who's familiar with the case.
Okay. Then we also have points of contact outside
of CBER. For instance, still within FDA,
we have CDRH. We have the Office of
Regulatory Affairs. They manage our
field investigators. The Office of
Crisis Involvement, and we even involve the Office of Criminal Investigation
because you may have heard recently about a recovery establishment where they
were doing criminal activities. Then
outside of FDA, we involve CDC, and there's actually a person from CDC
stationed at DA who helps with the communication there.
We also involve HRSA
because the same donor could be both an organ donor and a tissue donor, and so
HRSA may learn of an infection spread to an organ recipient, that we'd be
concerned that the tissues were also infected.
CMS is also involved
because, as you know, CMS has a contract with the Joint Commission, and we rely
on the Joint Commission, which accredits health care organizations to handle
the tissues once they get into the hospitals and health care facilities. We don't really have jurisdiction over that.
We also have a special
government employee who we consult when we have unusual cases. Okay.
Then the tracking and routing of the reports. They are received by Office of Biostatistics
and Epidemiology, determine if it's a 361 HCT/P, because right now, those are
the only types of HCT/Ps that the tissue safety team is monitoring.
Then we enter into a
database and if it's an infectious adverse reaction, we determine if it's a
high priority, which I'll show you in a minute, and would notify the entire
tissue safety team, the working group and the entire team, and maybe even the
center director's office.
And if it's not a high
priority--oh, and we definitely do follow-up on a high priority case. For other reports, we determine if follow-up
is needed. So we consider high priority
cases, any fatality, any infection with Clostridium species or Group A
strep. You may wonder why we selected
those. Because we've had extremely
severe and even fatal recipient adverse reactions to those particular
organisms. any serious viral disease or
seroconversion. Any possession of a
report that CJD was transmitted through a tissue.
Also if two or more
recipients of tissues or organs from the same donor develop an infection with
the same organism, it's pretty convincing that that originated with the donor,
the infection, and would require follow-up.
Also, if we had the
same unusual organism cultured from the recipient as was found in one of the
cultures done on the donor tissue, or even environmental cultures in the tissue
bank, if those matched, that would be considered a high-priority case.
And so the Office of
Biostatistics and Epidemiology does any clinical follow-up by contacting the
health care person that signed the MedWatch form, and these are some of the
questions that are asked of that person, if they're not already on the MedWatch
form.
Okay. Some surgeons would take cultures of the
tissues or the transport fluid when it arrived in the OR, prior to
implantation, and so that would be important to us, and any cultures of the
wound or explanted graft. I won't go
over the rest, in detail, to save some time.
Often, devices are
implanted along with the tissue, so those would also be suspect, and then the
Center For Devices is brought in.
We also ask the health
care person, What is their general impression? Do they think the adverse
reaction was related to the allograft?
And so if we need more
manufacturing information from the tissue bank, our Office of Compliance would
contact them, and at this point the tissue bank, probably the processor of the
tissue, probably has done an investigation, having heard that there was an
adverse reaction, and so we request the paperwork on that and what conclusion
did they come to.
We would also request
donor medical records, to review them again.
What processing methods did they use?
That would be reviewed. Any deviations,
environmental cultures that were suspicious, pre- and post-processing culture
results, and whether or not there were complaints related to the same
donor. Okay.
So some of the
challenges of the tissue safety team are similar to the ones for the blood
safety team.
First of all, it's a
passive surveillance system where we wait for someone to tell us that there's
been an adverse reaction, and that has its biases and limitations, particularly
underreporting, and then it's common, since these grafts are implanted during a
surgical procedure, some post-op surgeries can develop wound infections.
It's estimated about 2
to 5 percent of people who have surgery develop infection afterwards. So trying to distinguish between whether it's
just your post-op wound infection or attributable to the graft is extremely
difficult, and it's also very labor-intensive to do the follow-up, as I
explained, and often it's not a very satisfying feeling because usually we
would close a case when we think there's no more information to be obtained.
However, that doesn't
mean that we reached a conclusion about whether the tissue caused the
reaction. In most cases, there's no
evidence that we can get, that proves that the tissue caused the reaction.
Okay. This is just some summary data in 2006 and
2007, showing you approximately how many adverse reaction reports we received,
147 in 2006, and then 123, and mostly, as you would expect, they're from
implants of musculoskeletal tissue because that is the most commonly
transplanted graft.
Also, when we people
were first required to report, when the banks were first required, they didn't
realize that they were only required to report the infectious adverse reaction,
so many reported, for instance, corneal graft failure, primary graft failure in
a cornea, which is usually not related to an infection.
However, you'll see in
2007, that that number dropped, and sometimes, as I mentioned, product problems
are reported, and where there's no adverse reaction in the recipient.
Okay. And this is just a summary of where we're
getting the reports. As you would
suspect, most are coming from the manufacturer because they're required to
report, but we do get many reports, they're called direct reports, from the
health care professionals.
Okay. If you would like any further information about
the regulation of tissues, the rules or guidance that we've published, here are
some Web sites, and lastly, this is our small division of seven very dedicated
and committed individuals, that are called the Tissue Program.
So do we have any
questions?
DR. SIEGAL: Are there questions for Dr. Solomon?
DR. BALLOW: I certainly understand that a long time ago,
when this was set up, that the major adverse outcome that people were
interested in was infection because of using cadaver tissues.
But, you know, with
your expanded list of, you know, stem cells and a variety of other tissues, I
am surprised at your, you know, the breadth of the adverse events has not been
broadened just beyond infectious.
I mean, in medicine,
you can never anticipate what's going to happen around the corner, and, you
know, as we get into more use of, you know, stem cells or other cell types like
neuro tissues to, you know, manipulate the host in some way, that you might
come up with some unanticipated adverse events, that wouldn't come under your
program, and perhaps it comes under another program. I don't know.
DR. SOLOMON: Actually, the stem cells, the unrelated
allogeneic stem cells, and the cellular therapies such as neurologic stem
cells, right now there are no licensed products in those areas.
We have many INDs and
there are requirements under an
If we were to expand
our authority for over this, quote, 316 tissues, that would require a rule
change, probably, and that would take quite a while. But we feel we have these other mechanisms,
at least for the more highly complex cells and tissue products, that under IND,
and then once they become licensed, as I showed you, there's requirement
for--they're called adverse experiences and there are requirements for
reporting serious and unanticipated adverse experiences.
DR. MANNO: I'm interested in the establishment of 15
days for reporting adverse events. Can
you talk about that, please.
DR. SOLOMON: That's the standard length of time for not
only these tissues but all products regulated by CBER. We want to give the tissue manufacturer an
opportunity to do an initial investigation, and have some facts under their
belt before they have to report to us.
DR. SIEGAL: Then let's proceed to the open public
meeting.
Don, do you want to
read the rules.
DR. JEHN: Yes.
We have three members of either industry or organizations that requested
to speak. What I request is that they
stay behind the security barrier and they use the microphone behind there, when
they come forward.
The first person will
be Dr. Corash from Cerus.
DR. CORASH: Mr. Chairman, members of the committee, I'm
Laurence Corash, the chief medical officer of Cerus Corporation and professor
of Laboratory Medicine at the University of California, and thank you for the
opportunity to comment on bacterial contamination and pathogen and activation
technology.
May I have the next
slide, please. May we have the next
slide.
The risk of
transfusion-transmitted disease from hepatitis C and HIV and hepatitis B
viruses decrease markedly over the past 40 years due to innovations in donor
screening and testing. But testing is
inherently a reactive technology and would offer little protection against
emerging pathogens, and of course one of the things that you've heard today,
and you see from this publication by Harvey Klein of the NIH, is that the risk
of bacterial contamination and transfusion-transmitted bacteria remains
unacceptably high.
Can I have the next
slide, please. Thank you very much.
In addition to the
passport study that was presented today, there are other studies alluded to by
Dr. Dumont, that have shown the same type of data, that basically with
sensitive release and surveillance culture methods, where sufficient volumes
are cultured and using sufficient technologies, there's a substantial risk of
bacterial contamination of platelet components.
You heard from Dr.
Dumont today that these rates, the prevalence of contamination, if one looks at
these large studies, are about one in a thousand components, particularly if
you culture out to day seven. There are
other studies with similar numbers, and this means that somewhere around 2500
platelet components in the
But if one looks at it
from the patients's perspective, where patients may receive multiple exposures,
for example, an acute leukemic patient during induction therapy may receive six
platelet components, those risks become much higher, and there are some studies
in the literature that show the risk might be as high as one in sixteen
patients receiving a septic event, an actual clinical septic event from a
contaminated component.
The work by Dr.
Yomtovian at the Case Western Reserve shows that surveillance, whether it be
passive surveillance, is particularly poor in terms of identifying clinically
relevant septic events. Their experience
over 14 years showed that 41 percent of contaminated platelet components were
actually only associated with a septic event after the positive culture had
been reported to the clinicians and the medical record had been re-reviewed.
And this has also been
confirmed by the recent work from Murphy and the Irish blood transfusion
service.
Now there is an
alternative to bacterial detection and it has been used for plasma fractions
for some time, Dr. Goldsmith alluded to that, and it is pathogen
inactivation. The system that you see
here is one that we have developed, which is a photochemical system using
synthetic psoralin, amotosalen and ultraviolet light. It's nucleic-acid targeted, and it inhibits
the replication of DNA and RNA, bacteria, viruses, protozoa and leukocytes.
The commercial
embodiment of this is a series of functionally closed plastic containers that
are compatible with whole blood-derived platelets in
The spectrum of
pathogen inactivation is very broad, I won't go through this in detail, but
envelope viruses, a good spectrum of non-envelope viruses, including parvovirus
B19, gram-negative bacteria, gram-positive bacteria, spirochetes, protozoans,
leukocytes, particularly T-cells are well-inactivated, and many emerging
pathogens, and these data are very well-described in a series of publications.
Importantly, I should
point out that picornaviruses and prions are not inactivated by this
technology. Bacteria are particularly
well-inactivated, as I said, both low levels and high levels, gram-negatives
and gram-positives, and the level of inactivation is manyfold greater than
would be present in a newly collected platelet component.
The logistics of this
technology fit very well within blood center operations, and here you see a
comparison of the logistics for testing with bacterial detection plus the
typical viral serologic and nucleic acid tests, compared in the extreme right,
with the use of the pathogen inactivation technology.
With pathogen
inactivation, there is no delay in release of the components, and so one gets
the full benefit of the shelf life as opposed to the obligatory quarantine
process, plus the potential for tracing and recall of the product with
bacterial detection methodology.
This product was
introduced into
The technology is in
use in multiple blood centers in more than 20 countries. To date, more than 120,000 doses have been
transfused, and importantly, an active hemovigilence program has been put into
place, in which 30,000 of these transfusions have been reported.
This is a program that
requires reporting of all transfusions with an electronic Internet-based
system, and analysis of these data, to date, have shown a very favorable safety
profile, and these data are currently published.
So in conclusion,
detection methods are insufficient to prevent transfusion-transmitted
sepsis. There is a technology that
depends upon broad inactivation of pathogens and leukocytes. It's been successfully implemented in routine
use in multiple blood centers.
An active
hemovigilence program has demonstrated no cases of transfusion-transmitted
sepsis, a reduction in acute transfusion reactions other than septic reactions,
and there has been no adverse impact on platelet or red cell component
utilization.
This technology has
replaced bacterial detection, CMV serology, and gamma irradiation in these
centers that are using it, and we are involved in ongoing discussions with FDA
to define a pathway for licensure in the
DR. SIEGAL: Thank you very much.
DR. JEHN: Okay.
Next we have Scott Brubaker from AATB.
DR. BRUBAKER: Hi.
Thank you, and I'd like to thank Mr. Jehn for honoring our request for
ten minutes to speak on this subject.
I'll be talking about
Basically, I'll try to
review some data at the end but I think I'll probably run out of time to go
over that in detail. If you have a
handout, certainly that information is there.
But these four points I will make.
Deceased donation of
HCT/Ps is unique and certain facts must be considered. Pitfalls of infectious disease test kits when
using postmortem specimens, have a profound effect on many. The vast majority of HCT/Ps from deceased
donors are highly processed and safe, and the disease incidence and the disease
donor population is rare.
And then we should
also consider an entire list of expectations of the public that you serve. Next.
And to begin also,
consider this. There have been no reported cases of any transmission of
This discussion
includes possibly introducing a new test to prevent something that has not yet
occurred, and because of the lack of science, we don't know if it would occur
if we did nothing.
But the ramifications
of implementing these new tests are widespread and I'll describe those as we go
on. Next.
I'm scripted to try to
stay within ten minutes. In our donation
world, we cannot tolerate inadequate testing.
Upon death, this is the only chance for a human to donate these tissues,
and the usual tissue donation event includes surgical removal of entire long
bones, of the limbs, as well as soft tissues such as tendons and ligaments.
Pelvic bones are
included. A person's whole heart and
pericardium, the eyes, and sometime veins and arteries. Most often these tissues are surgically
recovered. Then the infectious disease
testing is performed. Next.
Now test kit labeling
approval is obtained, and when testing postmortem specimens, test kits are
flawed. It is true that manufacturers
can receive labeling approvals but these approval methods are not without
problems.
As you can see, true
positive postmortem samples are not required for validation and the variety of
postmortem sample quality issues are not being appropriately addressed.
Total numbers of
samples use din validations that have been reported on the package inserts are
allowed to be very small. I can just
name a few. Twenty, forty-five,
fifty-one, and seventy-one. These test
procedures themselves do not contain steps to identify lab-caused errors.
When a test has
initial reactives, these show a high false-positive rate when using postmortem
samples.
And all those tissues
you saw on the other slide, that were donated, are now deemed ineligible due to
flawed testing and are needlessly wasted.
Next.
So false-positive test
results for postmortem samples. The
ramifications are widespread. First, I
know this has not been thought of, but the donor family can be confused, shocked,
and fearful regarding what the result means to them. They do know that their loved one was
ineligible and not eligible due to infectious disease testing.
Also we found out that
some, and possibly many state departments of health don't follow up on reports
of positive tests on deceased members of the public because they don't have
systems in place to investigate such an odd report.
In a survey the AATB
performed in 2006, another point to be made is that one-third of all organ
donors were tissue donors.
If tissue donors must
be screened for Chagas disease or
One OPO actually
insisted that a tissue processor not test for
When a false-positive
test occurs an the donor's an infant, which did happen with West Nile virus in
that testing, and I'll show you that later, this negates the use of a
life-saving tissue that's also in short supply, and that's namely
cryo-preserved pediatric allograft heart valves. Next.
So public
expectations. This committee must
consider the expectations of the public heavily relying on flawed testing to
protect them, and that discarding useful tissues is harmful. There are many layers of safety employed but
one should not be flawed testing. Only a
few very of the total number of eligible tissue donors actually become a donor,
so discarding tissues needlessly can affect supply of transplantable tissues.
Donors and donor
families expect us, as stewards of their gift, to do the right thing. Is adding these tests the right thing? It will add to the cost of allografts and
costs associated with reporting of positive test results, depending on how
that's investigated or handled. Next.
Now FDA has instituted
a tiered risk-based approach and we have concerns about that because it's not
being applied to HCT/Ps from deceased donors very well.
As I showed this
committee a year ago, a vast majority of tissue distributed in the
Why are processed
blood products, such as source plasma and plasma derivatives allowed an
exemption to
By data to follow, our
profession can expect to identify a few true positive tissue donors and a year
for each disease, but in contrast, there will be a few hundred false-positive
tests. We're also interested in the role
of the advisory committee for blood safety and availability in regard to review
of new tests.
Since their new
charter, it started, I believe it was changed last December, includes not only
transfusion safety and availability, but also transplantation safety and
availability.
Will these tests be on
their agenda soon? And I don't have it
listed there, but what about the advisory committee for organ
transplantation? Are they aware of
what's happening with this committee?
And there's also a
committee that's actually our committee, and I don't think they've discussed
this yet on their agenda, and that's the Advisory Committee for Cells, Tissues
and Gene Therapies. Next.
So what happens when
there is a positive NAT on a deceased donor?
Should that be reported, then, to the local blood center, and that would
then trigger them to start ID NAT testing?
So that's a good question there.
I'll show you on a
later slide, that we have had a positive test on a tissue donor, a deceased
tissue donor in
One of the things you
may not realize is that blood samples for donors of HCT/Ps must be
qualified. In other words, we can't use
a sample that is diluted and might cause
a false-negative test.
Sampling is hard to
find after infusions and transfusions.
Samples of different types are needed for different tests. Different volumes are needed, and that's very
difficult to actually have a qualified sample for a donor-screened acceptable
donor. So we need to keep these in mind
as we add new tests. They may be too
difficult to actually--that we may lose some donors because we cannot test
them. We have no sample.
And also if there's
retesting that needs to be done, that takes up more sample. Next.
So the AATB urges the
CDC to study various human tissues to verify or disprove that either T. cruzi
or
Now this is
irregardless of processing methods, we urge this to be done. Any recommendations being made and future
decisions about testing should be based on science and facts, and I will try to
show you that test kits are not optimized for testing blood collected after
death.
These should be
improved and it should be a priority.
Next.
Now some of the
positives were also organ donors, which was problematic for the OPOs when told
of these results.
This 0.6 percent
positive rate may be acceptable to you, but to us, this is not acceptable. Also note that the
Also look at the two
month old donor in
The other tissue bank
who's been voluntarily testing for
They experienced a .04
percent false-positive rate overall.
Next.
Basically, both tissue
processors now have made decisions to stop this testing due to these high
false-positive rates. Next.
Here's an independent lab's
results. It's for the most recent 12
months. They found three reactives but
only on postmortem samples that they tested.
Next. Hit it again. And again. Okay.
Yes. We're over? Okay.
If you can just review the information, we do have a problem with
testing. It's shown there again. We have a lot of false-positives and we'd
just like the committee to definitely look at al the aspects involved with making
a decision on testing. Thank you.
DR. JEHN: Okay.
Next we have Susan Stramer.
MS. STRAMER: Hello.
I'm Susan Stramer and I'm representing the AABB West Nile Virus Task
Force. The committee should have a copy
of my statement as well as the AABB association bulletin number 0803, which I
will reference.
In 2007, and now
again, in 2008, the AABB provided recommendations to its membership regarding
uniform triggering and detriggering criteria for