1 DEPARTMENT OF HEALTH AND HUMAN SERVICES 

FOOD AND DRUG ADMINISTRATION 
CENTER FOR DRUG EVALUATION AND RESEARCH
BLOOD PRODUCTS ADVISORY COMMITTEE SIXTY-SIXTH MEETING
VOLUME II
				Friday, June 16, 2000 

							9:00 a.m.
	Holiday Inn 8777 Georgia Avenue 

			Silver Spring, Maryland 

	2 P A R T I C I P A N T S
F. Blaine Hollinger, M.D., Chairman 
Linda Smallwood, Ph.D., Executive Secretary 
MEMBERS: 
John M. Boyle, Ph.D. 
Mary E. Chamberland, M.D. 
G. Michael Fitzpatrick, Ph.D. 
Richard J. Kagan. M.D. 

Marion A. Koerper, M.D. Jeanne V. Linden, M.D. B. Gail Macik, M.D. Mark A. Mitchell, M.D. 
Kwaku Ohene-Frempong, M.D. Terry V. Rice 
Paul J. Schmidt, M.D. 
NON-VOTING REPRESENTATIVES: 

Katherine R. Knowles, Consumer Representative Toby L. Simon, M.D., Industry Representative 
TEMPORARY VOTING MEMBERS: 
Paul R. McCurdy, M.D. 

Kenrad E. Nelson, M.D. Carmelita U. Tuazon, M.D. 

		3 C O N T E N T S 

Conflict of Interest Statement, Linda Smallwood, Ph.D.		4 
Committee Updates: 
	Update on Requirement for Syphilis Testing, 
	Martin Ruta, Ph.D., J.D.		5 
	Regulation of HIV Drug Resistance Tests, 
	Martin Ruta, Ph.D., J.D.	21 
	Risk of HCV to Sexual Partners, Robin Biswas, M.D.	24 
	Relative Sensitivity of HBsAG and HBV NAT TESTS, 
	Robin Biswas, M.D.		31 
Open Public Hearing: 
Louis Katz, M.D., American Association of Blood Banks  32 Susan Stramer, Ph.D., American Red Cross	36 
Open Committee Discussion: 
	Proposed FDA Guidance on Leukoreduction: Current	39 
	Thinking Introduction and Background 
		Jong-Hoon Lee, M.D. 
Open Public Hearing: 
	Linda Chambers, M.D., American Red Cross	74 
	Merlyn Sayers, M.D., America's Blood Centers	77 
	Larry Dumont, Gambro BCT	80 
Louis Katz, M.D., American Association of Blood Banks  83 Kay Gregory, Coalition for Blood Safety	86 
	Rich Gammond, South Florida Blood Banks	87 
Open Committee Discussion (resumed)	88 
Open Public Hearing (resumed) 
	Mary Beth Saver, American Hospital Association        123 

			4 1		         P R O C E E D I N G S
	2		MS. SMALLWOOD:  Good morning, and welcome to the 
	3	second day of the 66th meeting of the Blood Products 
	4	Advisory Committee. 
	5		I am Linda Smallwood, the Executive Secretary. 
	6		On yesterday, I read the conflict of interest
	7	statement that pertains to this meeting.  I do have that 
	8	statement available if anyone would like to view it, 
	9	however, those things that were read on yesterday pertain to 
10	today's session with respect to conflict of interest, and if 
11	there are any declarations to be made regarding the topics
12	to be discussed today, please do so at this time. 
13		May I ask that, if you are using a cell phone, 

14	that you would turn it off, preferable, or have it on low 
15	ring so that it will not interfere with the proceedings 
16	here.

17		If there are no declarations, then I will turn the 
18	meeting over to the Chairperson of our Blood Products 
19	Advisory Committee, Dr. Blaine Hollinger.  Thank you. 
20		           Committee Updates 
21		DR. HOLLINGER:  Thank you, Linda.
22		We have some most interesting Committee updates on 
23	some topics that are of real interest to this group, and the 
24	first one is an update on a requirement for syphilis 
25	testing.  And Dr. Ruta is going to give us the background 

			5 1	information.
	2		By the way, after each one of these, there are 

	3	some public hearings--I mean, people who want to speak to 
	4	these issues, so rather than go through the three updates 
	5	and then have the issue discussed, we'll have the 
	6	individuals comments, if they would, afterwards.
	7		Dr. Ruta? 
	8	         Update on Requirement of Syphilis Testing 
	9		DR. RUTA:  Good morning, Dr. Hollinger.  Thank 
10	you.  Good morning, everyone. 
11	10:05	I wanted to give a brief update on where we are

12	with some of the regulations that we published--last year's 
13	committees--where, and the public's aware. 
14		On August 19th of last year the FDA published, in 
15	the Federal Register, two proposed regulations. 
16		If I could have the overhead, it just has the
17	title of the one under discussion now.   It's "Requirements 
18	for Testing Human Blood Donors for Evidence of Infection Due 
19	to Communicable Disease Agents." 
20		Now, this proposed regulation would extend the 
21	current testing requirements for HIV and hepatitis B, which
22	are currently in the regs, to include requirements for 
23	testing for hepatitis C and for HLV 1 and 2.  And it also 
24	proposed to require supplemental testing whenever a donation 
25	tested repeatedly reactive, or for one--by one of the 

			6 1	screening tests for the required infectious disease agent;
	2	and, in addition, a proposed requirement that donors testing 
	3	repeatedly reactive would be deferred as donors. 
	4		Now, we also published a companion rule, is a 
	5	notification rule, that would require that donors who are 
	6	deferred would then be notified that they were deferred and
	7	told why they were deferred. 
	8		And we initially had a 90-day comment period.This 
	9	was extended for another 30 days to allow for oral 
10	presentation of comments at a public meeting.  And, first, I 
11	wanted to thank everyone who sent in comments.  We
12	appreciate that.  We received a total of 23 letters to the 
13	testing regulation, with multiple--you know, with comments 
14	included, and those were submitted to the docket. 
15		Okay--now, specifically, within this reg, we asked 
16	about the continued--or, this rule, we raised the question
17	about the continued utility of testing for syphilis.  And as 
18	the committee's aware, the syphilis test was first 
19	introduced in 1938.  Early on in the AIDS era, it was also 
20	though to have value as a marker of high-risk behavior.  And 
21	the question of continued syphilis testing has come up
22	periodically.  In January--last time was January '95, in 
23	which an NIH Consensus Development Conference concluded--and 
24	I'm quoting here--"Because the contribution of serological 
25	tests for syphilis in preventing transfusions in admitted 

			7 1	syphilis is not understood, the panel concludes that testing
	2	of donors for syphilis should continue." 
	3		So, as part of our rule-making effort, FDA 

	4	solicited comments, along with data, on the value of 
	5	donor-testing for syphilis as a marker of high-risk 

	6	behavior, as a surrogate test for other infectious diseases,
	7	and in preventing the transmission of syphilis through blood 
	8	transfusion. 
	9		We received a total of seven letters containing 
10	comments; five of the comments supported eliminating 
11	syphilis testing, and two of the letters opposed eliminating
12	syphilis testing.  We received some data on the subject, and 
13	the ARC was kind enough to provide some data, which they 

14	also presented at the public meeting in November, and it's 
15	contained in the docket.  And their data was of a 
16	preliminary study which indicated that the DNA for T.

17	pallidum could not be detected in serologic-positive 
18	samples, as with the STS positive as well as 
19	FTA-positive--antibody-positive samples, and the conclusion 
20	is that--their conclusion is that therefore the treponemas 
21	were not likely to be circulating.  And they used PCR
22	methods on a total of about a hundred samples.  But because 
23	the sample size was small the ARC has proposed conducting a 
24	larger study. 
25		In addition, the CDC has been reviewing national 

			8 1	surveillance data to learn more about cases of early
	2	syphilis identified through attempted blood bank donations, 
	3	and the CDC is also conducting laboratory studies to assess 
	4	detection of the T. Pallidum DNA from persons with varying 

	5	stages of infection and reactivity by the traditional RPR 
	6	and microhemoglutination assays.
	7		We are considering bringing the issue syphilis 
	8	testing to the BPAC in September meeting if the data is 

	9	ready for presentation. 
10		That's all I had to say on the subject. 
11		Questions?
12		DR. HOLLINGER:  Any questions of Dr. Ruta? 
13		Yes--Dr. Ohene-Frempong? 
14		DR. OHENE-FREMPONG:  Yes, with regard to high-risk 
15	behavior, what's the current epidemiology of syphilis in the 
16	U.S.?
17		DR. RUTA:  Can I ask--well, I'll answer part of 

18	the question, then I might see if Mary or someone from CDC 
19	wants to address that. 
20		With regard to high-risk behavior, that question 
21	was addressed, in part, in the '95 Consensus Conference, and
22	the issue, more specifically, was raised about the role of 
23	syphilis as a surrogate for HIV, and the panel concluded 

24	that, in the face of the specific HIV test, that there 
25	wasn't a value to syphilis testing. 

			9 1		The ARC also presented--or I guess it's the Rudd

	2	Study also presented a limited amount of data suggesting 
	3	that the syphilis testing also did not have value for 
	4	other--only had value for--let's see--I'll just read what 
	5	they said, so it will be more accurate here--that "the STS 
	6	positive donors have a--"--excuse me--it's their conclusion
	7	that "--the probable risk associated with STS-positive 

	8	donors is largely due to STS-related risk factors. And when 
	9	STS-related risk factors are not considered, STS has no 
10	significant value as a surrogate indicator of behavioral 
11	risk."
12		The actual data is contained within the docket, 
13	which is publicly available. 
14		I don't know if Mary or someone from CDC or NIH 
15	wants to add to that. 
16		DR. CHAMBERLAND:  I think the only think that I'll
17	add is that the Division of STD Elimination is really 
18	putting forward a push to try and eliminate syphilis from 
19	the United States. There has been a concern that has been 
20	brewing for the last year or two of a resurgence of 
21	syphilis--clusters of syphilis cases--that have been seen in
22	places like Los Angeles, and Florida and Seattle-King 
23	County.  And these cases have been occurring in these areas 
24	in--among men who have sex with men.  And I think we heard 
25	yesterday concerns that this may reflect--ahh--sort of a 

			10 1	return to risky behaviors, or new populations of young

	2	adolescents--young men--who have not been part of the 
	3	earlier HIV epidemic.  And so there is concern in that 

	4	arena, and a push to try and move towards prevention.  But 
	5	it would clearly be a challenge. 
	6		If the issue is presented at the September BPAC,
	7	CDC will have representatives from our Division to speak to 
	8	the epidemiology, as well as some of the data that may be 
	9	pertinent to the question about syphilis screening of blood 
10	donations. 
11		DR. HOLLINGER:  Dr. McCurdy?
12		DR. McCURDY:  This is just a comment.  The NHLBI 
13	co-sponsored with OMAR, the Consensus Conference that was 
14	cited a few minutes ago, and one of the major 

15	questions--although it was not specifically stated--was once 
16	you start doing a test on blood donations, can you ever
17	stop?  And the answer thus far has been "no."  So I'm very 
18	curious to see what happens if we go further on this. 
19		DR. HOLLINGER:  We may do that yet. 
20		Any other questions?  Yes, Dr. Epstein? 
21		DR. EPSTEIN:  I just wanted to add a comment.
22		CDC has published an MWUR, in which it is 
23	described that the donor screening for syphilis is one of 
24	the best existing mechanisms for picking up early cases.  
25	And it brings to light the question of to what extent should 

			11 1	we practicing public health in the donor room?
	2		In this country, we don't actually use the 
	3	donation process as a primary instrument of public health 
	4	screening --you know, for example, cholesterol screens, you 
	5	know, ESAs, genetic tests for a variety of inborn metabolic 
	6	disorders, etcetera.  And I think that perhaps one of the
	7	dimensions of the question, when we finally bring it to the 
	8	fore: if we're able to dismiss the issue of syphilis 
	9	screening to protect the blood product with respect either 
10	to syphilis or, you know, co-incident risks, we'll still be 
11	left with the question of are we wiling to drop it,
12	recognizing its public health utility? 
13		And that opens the door to a whole new dialogue 

14	about what are we doing when someone walks into the donor 
15	room?  Again, in this country, we don't see it primarily as 
16	a opportunity to practice public health, but there are many
17	countries where, in fact, they do. 
18		DR. HOLLINGER:  Then it also raises the issue of 
19	who should reimburse that, as well, if that's the issue 
20	going to be dealt with. 

21		Yes--Dr. Simon?
22		DR. SIMON:  I think it's interesting, because I 
23	believe in the plasma donor centers it was instituted 

24	historically as a matter of public health, since plasma 
25	derivatives cannot transmit.  We do the syphilis test every 

			12 1	four--initially, in every four months, and I think that it
	2	was instituted primarily for that reason--as a public health 
	3	screen and donor issue.  So I think that's an interesting 

	4	historical vignette, that there is a precedent, I believe, 
	5	if I'm correct, and it will be interesting to see how that 
	6	plays out.
	7		In other words, we don't do syphilis testing on 
	8	the donated unit.  We do it on the donor every four months. 
	9		DR. HOLLINGER:  Dr. Schmidt? 
10		DR. SCHMIDT:  Just a comment that I don't think 
11	the public health is a function of the FDA, and we get into
12	an awful lot of things if we adopt that attitude. 

13		DR. HOLLINGER:  If there are no other questions, I 
14	do know that there are--there is one group, the AABB,that 
15	has a statement that they would like to present, and I'll 
16	have them do that, and then we can ask further questions at
17	this time. 
18		Yes--Dr. Katz? 
19		DR. KATZ:  Does anybody at the table not know who 
20	AABB is? 
21		[Laughter.]
22		DR. KATZ:  I'll skip the first paragraph. 
23		We thank the committee for this opportunity to 
24	comment. 
25		The serologic  test for syphilis has been retained 

			13 1	in the U.S. for two ends: prevention of transfusion
	2	transmitted syphilis, and as a surrogate for risk behaviors 
	3	associated with HIV infection. 
	4		Transfusion-transmitted syphilis has not be 
	5	recognized in the United States for more than 30 years.  
	6	And, in fact, in 1985 an FDA committee recommended
	7	eliminating STS for blood donors.  This recommendation was 

	8	not implemented when the issue of the STS's value as an HIV 
	9	surrogate was raised. 
10		The reasons for the disappearance of transfusion 
11	syphilis are multiple, including the declining incidence of
12	infectious syphilis in this country and donor deferral 

13	policies' reducing the presentation of those at risk for 
14	infectious syphilis.  Storage of red blood cells at 

15	refrigerator temperature is probably an important 
16	contributing factor as well.  Still, there is transfusion of
17	fresh red cell components--albeit rare--and platelets are 
18	stored at room temperature. 
19		Receipt of antimicrobial therapy by those ill 
20	enough to require transfusion support may also be important 
21	in preventing either infection or recognition of transfusion
22	syphilis. From a biological standpoint, it must be 
23	emphasized the spirochetemia associated with transfusion 
24	transmissibility to T. pallidum generally occurs before the 
25	STS is reactive. 

			14 1		At the NIH Consensus Conference in January '95
	2	that's been referred to a couple of times, it was 
	3	concluded--and I quote--:current blood storage conditions 
	4	would not appear to provide an adequate margin of safety 
	5	against transfusion-transmitted syphilis.  Should the donor 
	6	screening test be eliminated.  Further information
	7	concerning T. pallidum survival under blood and platelet 
	8	storage conditions, and the application of molecular 
	9	techniques to assess the presence of T. pallidum DNA in 
10	serologically positive units, would allow better assessment 
11	of this question."
12		Data presented at the AABB Annual Meeting in the 
13	fall of 1999 addressed this recommendation.  Orton, et al., 
14	tested platelets from 82 PK-TP positive, FTA-ABS confirmed 
15	donors using two PCR methods, and found none with detectable 
16	DNA.
17		Regarding the value of the STS as a surrogate for 
18	other transfusion-transmissible diseases, even prior to the 
19	implementation of sensitive NAT assays for HIV and HCV, the 
20	Consensus Development Conference concluded--and I 
21	quote--"Cross-sectional studies and examination of prior
22	donations from donors undergoing HIV seroconversion indicate 
23	that serologic tests for syphilis have very little value as 
24	a surrogate marker for HIV infection in recently infected 

25	persons who have not yet developed detectable antibodies to 

			15 1	HIV.  Syphilis testing is likely to identify less than one
	2	such donor annually within the United States.  This low 
	3	efficacy of syphilis testing as a surrogate marker of HIV is 
	4	not sufficient by itself to warrant its application to all 

	5	blood donors.  Low positive predictive values for HBV, HCV, 
	6	or HTLV infections similarly do not support retention of

	7	syphilis testing as a surrogate for these infections." 
	8		Ramsey and Sherman reviewed FDA-reported blood 
	9	component recalls in the United States from 1990 through 
10	'97.  Of an estimated 241,800 components recalled, 57 
11	percent--or 137,000, were for incorrect syphilis testing. 

12	These were primarily in a single large recall of units where 
13	weakly reactive STS results might have been called negative.  
14	This recall was classified by FDA as a class III 

15	recall--quote--"not likely to cause adverse health 
16	consequences."
17		With these points in mind, AABB supports the 
18	elimination by FDA of the requirement for performing an STS 
19	on each whole blood donation. 
20		DR. HOLLINGER:  Louie, before you leave--and I 

21	also want to ask Dr. Simon about this--could you tell us
22	what the--give us some numbers of donors that are eliminated 
23	each year?  First-time donors and repeat donors that have 
24	positive tests, that are removed from the donor 
25	screening--in the blood banking industry and then the plasma 

			16 1	industry, as well?
	2		DR. KATZ:  In my center, we turn up between 100 

	3	and 120 reactive RPRs a year, less than 5 percent of which 
	4	confirm with FTA.  Those--the components from those 
	5	donations are generally lost, because of the time-frame 
	6	involved in completing confirmatory testing.  The donors are
	7	not deferred if their FTA is negative.  But, as I said, of 
	8	100 to 120, less than five a year at my center, out of 
	9	55,000 donations confirm. 
10		And I can't give you accurate first-time versus 
11	repeat, but most of ours are repeat donors.  As a matter of
12	fact, we have probably 25 or 30 donors, I believe, who have 
13	repeatedly reactive STS on repeated donations, and we're 

14	able to salvage their red cells, but not their platelets. 
15		DR. HOLLINGER:  Is Dr. Stramer here?  Can she tell 
16	me--from the American Red Cross standpoint?  And then I'd
17	like to ask Toby? 
18		DR. STRAMER:  For Red Cross donations, I just have 
19	percentages, and we collect 6.2 million.  So one just needs 
20	a calculator to convert. 
21		Our reactive rate for FTA is .18 percent.  And of
22	those--of the total, then, .08 percent--or about half of the 
23	FTA positives--are also RPR-reactive.  So our algorithm 
24	includes a total treponemal confirmatory test by 
25	florescent-antibody test, and that was the reactive rate of 

				17 1	.18 percent, and then we take the FTA reactives and test
	2	them by RPR. 
	3		And, again, of those--of the total donations, .08 
	4	percent are RPR-reactive. 
	5		Sharon Orton from the Holland Laboratory is also 
	6	here, and can add a little bit more about the
	7	characteristics of donors who are FTA and RPR-positive.  So 
	8	I would suggest that we let her make a comment as well. 
	9		DR. HOLLINGER:  If I look at these numbers, from 
10	what you just said, that's about, then, 62,000--correct me 
11	if somebody has also done this--but it looks like about
12	62,000 that are then reactive with the RPR.  And these were 
13	deferred, is that correct? 
14		DR. STRAMER:  Correct. 
15		DR. HOLLINGER:  Okay.  And they haven't been 

16	tested for DNA or anything like this at the present time.
17		DR. STRAMER:  Well, just the subset that was 
18	described by Dr. Ruta and Dr. Katz. 
19		DR. HOLLINGER:  Okay. 
20		Yes? 

21		DR. RUTA:  So, I'm a little--I have a question, if
22	you don't mind.  I'm a little confused, because I'm looking 
23	at the data, and the data that you guys gave us said there 
24	were 1.8 million donations between May '93 and September 

25	'95.  Of those, 2,151 were STS reactive, and 1,274--0.7 

			18 1	percent--were confirmed by FTA.  And then you go on to say
	2	that you have 6 million donations annual, 7,200 lost 
	3	components, and 4,200 temporarily deferred donors. 
	4		I was wondering how you get a number of 60,000? 

	5		DR. STRAMER:  Well, I believe the percentages on 
	6	the data--okay, well then they do--
	7		[Pause.] 
	8		DR. HOLLINGER:  It looks like, from mine, it's 
	9	12,400 and 6,200, then--approximately.  Yes. 
10		Dr. Nelson: 
11		DR. NELSON:  The public health benefit was

12	mentioned, given that despite the loss of donors the 
13	screening might detect some infected cases or people who 
14	don't otherwise know they're infected. 
15		Are there any data on how many of these .1 percent 
16	or so already know that they're--are already aware, and how
17	many are really--have public health significance; are new 

18	cases, unknown cases? 
19		DR. ORTON:  Yes, I'm Sharon Orton, from the Red 
20	Cross, that has done the work the infectivity.  I've also 
21	done a case-control study of blood donors who are

22	PK-TP-positive, and both FTA-positive and FTA-negative.  And 
23	in that case-control, 50 percent of individuals who do have 
24	a confirmed positive FTA do report a previous history of 
25	syphilis, and knew that they had a previous history. 

				19 1		And, interestingly, there was also about 40
	2	percent of individuals who have a negative FTA who report 
	3	having a previous history with positive screening tests in 
	4	the past.  So even the serology is not consistent over time. 
	5		DR. HOLLINGER:  Thank you. 
	6		This is really just an update here, but it gives
	7	us some idea of what we're going to be discussing, probably, 
	8	in the future. 
	9		Louie, do you have another question--comment? 
10		DR. KATZ:  Well, the numbers from Red Cross and my 
11	center sound a little difference, which is because they
12	screen with a confirmatory test--PK-TP--and we screen with 
13	the RPR, which is substantially less specific, I think, than 
14	the PK-TP. 
15		DR. HOLLINGER:  Thank you. 
16		Colonel Fitzpatrick?
17		COL. FITZPATRICK:  The DOD rate for RPR is about 
18	.03 percent--0.3 percent--for the screening.  And I don't 

19	have the confirmatory.  And those are mostly first-time 
20	donors. 
21		But our confirmatories are very low.  I'll see if
22	I can--I think I have those. 
23		DR. HOLLINGER:  Okay.  Thanks. 
24		Yes--Gail? 
25		DR. MACIK:  I wanted to get--with these positive 

				20 1	tests, but there has not been a documented transmission?  Is
	2	that what I heard when you started off--in 30 years? 
	3		DR. HOLLINGER:  Well, documented transmission but, 
	4	of course, it's tested--I mean, one would argue it's tested 
	5	for syphilis.  So-- 
	6		Louie, do you want to comment on that?  You made
	7	the statement. 
	8		DR. KATZ:  I actually didn't say "documented."  I 
	9	said "recognized"--number one.  And I think that's a legit 
10	issue, and gave some reasons. 
11		In the 15 years I've been doing STS, 50,000 times
12	a year, and I also happen to run the STD clinic in our local 
13	health department, and we've not picked up an early syphilis 
14	through that testing in 15 years.  And it's only early 
15	syphilis.  Often, prior to seroconversion, in fact, where 

16	spirochetemia that would be transmissible by transfusion
17	occurs. 
18		DR. HOLLINGER:  Dr. Schmidt? 
19		DR. SCHMIDT:  I reported that last case in the 
20	United States, and I can bring the picture next time.  It 
21	was a florid, secondary syphilis, with multiple skin
22	problems.  So it became very obvious, very soon. 
23		DR. HOLLINGER:  Thank you. 
24		Thank you, Dr. Ruta.  I think--oh-- 
25		DR. RUTA:  If you don't mind, I had one more 

			21 1	update.
	2		DR. HOLLINGER:  Yes.  Yes. 
	3		Regulation of HIV Drug Resistance Tests 
	4		DR. RUTA:  Thanks.  It looks like there's a lot of 
	5	interest in the syphilis question, and thank you for your 
	6	comments.
	7		There's one more update that I wanted to give, and 
	8	that is on regulation of HIV drug-resistance tests, and the 
	9	committee remembers that we brought this for discussion in 
10	September, and we've been getting a number of letters on the 
11	subject, and so I just wanted to make a statement, both for
12	the Committee and for any interested public, as to what our 
13	current thoughts are on the subject. 
14		As of now, we have not yet approved any tests, but 
15	as the Committee knows, drug resistance--HIV drug resistance 
16	tests are tests that detect mutations in the HIV virus and
17	may be useful in monitoring infected patients and in their 
18	treatment.  And such tests may be provided in several 
19	different formats, and those would included as an intact 
20	finished tests manufactured by a company that's then shipped 
21	to a laboratory for use; two, it can be presented as an

22	anilide-specific reagent--that is, a company would make 
23	primers or probes, and that they would be shipped to a 

24	laboratory for use at the clinical laboratory; or, three, it 
25	can be provided as an in-house test by the clinical 

			22 1	laboratory, using only in-house developed reagents, and the
	2	primers and probes.  And as the Committee is aware, if a 
	3	manufacturer makes a--or produces a finished HIV drug 
	4	resistance test that's shipped to a laboratory for use, they 
	5	are required to obtain FDA approval.  And last September we 
	6	brought the issue of approval of drug resistance tests to
	7	the BPAC for discussion, and the Committee voted that they 

	8	thought such tests could be re-classified from Class III to 
	9	Class II. 
10		I wanted to talk a little bit about the other two 
11	categories, because we've been getting some questions about
12	it. 
13		So, as I mentioned, the HIV drug resistance tests 
14	can be performed using in-house developed tests.  And FDA 
15	believes that ASRs--anilide-specific reagents, or primers 
16	and probes, using tests intended for post-diagnosis
17	monitoring and treatment of patients infected with HIV, 

18	including ASRs using HIV drug resistance assays, fall within 
19	the definition of a Class III device that's described in the 
20	ASR regulation in our regulation.  And just for purposes of 
21	anyone who wants to know, the cite of the regulation is 21
22	C.F.R.	864.4020.  And manufacturers of ASRs would be 
23	required to obtain FDA approval. 
24		A clinical laboratory that develops an in-house 
25	test using an anilide-specific reagent that is in commercial 

		23 1	distribution is required to append the following statement

	2	to their test result--and I'm going to quote now.  This is 
	3	also in the regulations--but I'm quoting: "This test was 

	4	developed and its performance characteristics determined 
	5	by--"--and you fill in the laboratory name--"It has not been 
	6	cleared or approved by the U.S. Food and Drug
	7	Administration." 
	8	          And moving on to the third category in which we're 
	9	talking about in-house tests using in-house developed 
10	reagents:  "The FDA also believes that clinical that develop 
11	in-house tests are acting as manufacturers of medical

12	devices and are subject to FDA jurisdiction under the 
13	Federal Food, Drug and Cosmetic Act.  Currently CBER is 
14	exercising its enforcement discretion in electing not to 

15	require pre-market approval for in-house tests developed by 
16	a clinical laboratory for its exclusive use in the
17	monitoring of HIV, provided that claims made by the clinical 
18	laboratory are only for the analytical capability of the 
19	test.  Clinical laboratories are advised to provide only the 
20	actual results of analytical sensitivity testing conducted 
21	on samples, and no clinical or medical claims about the
22	benefit of making treatment decisions on the basis of these 
23	tests should be promoted, suggested or claimed. 
24	          "The FDA encourages clinical laboratories that 

25	have developed the reagents for in-house use to append the 

			24 1	statement--"--and, again, it's the same statement that I
	2	read before, I'll just read it again--and I'm quoting--"This 
	3	test was developed and its performance characteristics 
	4	determined by--"--fill in the laboratory name--"It has not 
	5	been cleared or approved by the U.S. Food and Drug 
	6	Administration." --end quote--"--to the test results."
	7		I also wanted to let people know that while we are 
	8	not, at this point, requiring submission of applications 
	9	from clinical laboratories that develop their in-house tests 
10	for HIV drug resistance, we are--will accept submissions on 
11	a voluntary--if they're submitted on a voluntary basis for

12	such HIV drug resistance tests. 
13		Thank you. 
14		DR. HOLLINGER:  Any questions in regards to this 
15	issue? 
16		I know there's a lot of interest in both genotypic
17	and phenotypic testing for drug use and so on, and so I 

18	think this is going to be an important issue to do--to 
19	regulate in some regard, down the line anyway. 

20		No other?  Okay, thank you, Dr. Ruta. 
21		The next update is on the risk of HCV to sexual
22	partners, and--Dr. Biswas. 
23		     Risk of HCV to Sexual Partners 
24		DR. BISWAS:  At the December 1997 Blood Products 
25	Advisory Committee, the issue of whether or not sexual 

			25 1	partners of persons who test positive for antibody to
	2	hepatitis C virus--anti-HCV--should be deferred was 
	3	addressed.  At that meeting, scientists from NIH, CDC and 
	4	the Harvard School of Public Health presented data from 
	5	studies of anti-HCV-negative spouses or sexual partners of 
	6	individuals with anti-HCV.  The data indicated that
	7	transmission of hepatitis C virus between spouses and sexual 
	8	partners appears not to be a problem. 
	9		Under current procedures, at the discretion of 

10	blood establishments' medical directors, prospective donors 
11	who are sexual partners of anti-HCV-positive individuals may
12	donate blood, provided that their partner does not have a 
13	history of clinically apparent viral hepatitis during the 
14	year prior to donation. 
15		A somewhat different approach has been taken with 
16	regard to donors of tissues for transplantation.  The July
17	29, 1997, FDA Guidance for Industry document entitled 
18	"Screening and Testing of Donors of Human Tissue Intended 

19	for Transplantation" states that persons who have had sex in 
20	the preceding 12 months with any person suspected of having 
21	hepatitis C infection should not be accepted as a tissue

22	donor.  FDA will be reconsidering the policy of tissue 
23	transplantation. 
24		FDA is maintaining an awareness of results of 
25	further studies that are designed to evaluate sexual 

			26 1	transmission of HCV.  While sexual transmission of HCV, such
	2	events appear to be rare.  For this reason, history of 
	3	HCV-positive sexual partner is not a strong correlate of HCV 
	4	risk in a donor. 
	5		DR. HOLLINGER:  Thanks, Robin. 
	6		I think I'll have the--I think, again, Dr. Katz
	7	has a comment.  Where did Louie go? 
	8		Any comments?  Oh. 
	9		Yes, Dr. Simon. 
10		DR. SIMON:  I think it's worth making the panel 
11	and the representative of the agency aware that in the
12	plasma industry, the comment practice is defer sexual 
13	partners because of the global harmonization issues.  And 
14	most of the fractionators insist that we defer these 
15	individuals.  Scientifically and medically, I agree with the 
16	agency and find this a troublesome practice.  It also, I
17	think, gets into issues of privacy and so forth, when we 
18	start intruding into people's sexual histories. 
19		So it is a very hot issue, and if it were possible 
20	to come to conclusive scientific conclusions here and to 
21	seek harmonization internationally on this issue it would be
22	very beneficial to the plasma industry. 
23		DR. HOLLINGER:  Thank you. 
24		Yes--now, Dr. Katz. 
25		DR. KATZ:  Thank you for your patience while I 

		27 1	practice medicine.
	2	          The AABB opposes addition of deferral of 
	3	whole-blood donors as a consequence of sexual contact with 
	4	HCV-infected partners.  Data from CDC and multiple other 
	5	published sources suggest that the prevalence of infection 

	6	in the steady sexual partners of HCV-infected people is at
	7	approximately the population background.  Although persons 
	8	with multiple sexual partners may be at increased risk, it 
	9	remains controversial whether this represents sexual 

10	transmission or un admitted and unrecognized parenteral 
11	exposures.  Because the infection is uncommon, if not
12	absent, among the steady sexual partners of HCV-positive 
13	persons, the CDC does not recommend that HCV-positive 
14	persons with a steady sexual partner need to change their 
15	sexual practices; nor is it recommended that such partners 
16	be routinely tested.
17	          If the risk is low enough that neither barrier 
18	precautions nor routine testing is the standard of care, it 
19	would seem illogical to recommend that such partners be 
20	excluded as donors.  As a result of the above 
21	considerations, the FDA to date has not required donor

22	deferral for sexual contact with HCV-infected persons. There 
23	is even less reason to consider such deferral at this time 
24	because the implementation of NAT testing has reduced an 
25	already low risk of HCV transmission by blood transfusion to 

			28 1	virtual zero.
	2		Thus, the AABB feels that donor deferral based on 
	3	contact--sexual contact--with an HCV-positive individual is 
	4	inappropriate and a wasteful use of limited donor resources. 
	5		Thank you. 
	6		DR. HOLLINGER:  Thank you.
	7		Any other comments from the public on this issue?  
	8	And how about comments from the committee?  Or questions? 

	9		I'll just share with you, if I could, the little 
10	bit of data that we've done, because we've had an interest 
11	in this issue about sexual transmission.  We've looked at
12	about 400--over 450 couples that--in which the index case 
13	had hepatitis C.  And of those, all but four--all but 
14	four--admitted to a potential parenteral risk factor.  So 

15	only four didn't admit to one potential risk factor that was 
16	parenteral.
17	5:00	In this group there were 30 couples--approximately 
18	30 couples that were both positive; in which both partners 
19	were positive.  We've looked at 18 of these--or 19 of these, 
20	so far--for--by single-stranded confirmation polymorphism 
21	evaluations to see how close they were to each of the
22	individuals.  Nine of these, or 10 of these had different 

23	genotypes. So, clearly, they didn't get it from each other. 
24		OF the remainder, only one was sufficiently close 
25	to each other to suggest that they might have acquired it 

		29 1	from that individual.  And when discussing that with that
	2	individual--they'd been married 20 years, I think since 
	3	1982, and this was about 1998--they'd been married about 18 
	4	or 20 years, and the woman had shared needles only with her 
	5	husband during that period of time.  So it's been our 
	6	contention most of the time--I think Dr. Nelson and their
	7	group has had lots of experience with the issue also--that 
	8	it's very unlikely, or very uncommon for sexual transmission 
	9	to occur from one partner to the other.  You can never 

10	really exclude it.  If you assume that they're getting it 
11	from the parenteral source, then you never can really say,
12	well, they might have also gotten it from a sexual 
13	transmission.  So, I mean, that's--you have to sort of take 
14	that into account.  But it must be very uncommon. 
15	          Now, I believe--I think there probably is a 

16	difference in acute disease, where there is very high
17	concentrations of RS in the window period, with very little 
18	antibodies and other things, and I think that may be part of 
19	the difference that we've seen with the comments that have 
20	come from the CDC initially, where they were looking at 
21	acute transmission, and felt that there was some
22	transmission going on at that time.  But outside of that 
23	source, I think it's very uncommon, at least in our 
24	experience. 
25	          Yes--Dr. Nelson? 

			30 1		DR. NELSON:  I think, you know one issue that--the
	2	biology of HIV is pretty well known, in terms of receptors, 
	3	and where the receptors are.  And receptors for hepatitis C, 
	4	actually a couple, have just been identified.  And it's not 
	5	clear--I mean, it doesn't make logical sense as to why 
	6	hepatitis B and HIV should be readily sexually transmitted. 
	7	And this debate was--you know, early on, the feeling was 
	8	that HIV was only transmitted by male-to-male sex, and it's 
	9	obvious now that that's not the primary transmission 
10	worldwide. 
11		But I think that, you know, a lot more needs to

12	been done on the biology of infection with hepatitis C.  
13	It's conceivable that its related to receptors in the 
14	genital tract or something like that, and I think that, you 
15	know, more needs to be done on this. 
16		But I think that, really, all studies have shown
17	it's rare.  The real question is, you know, is it absent?  
18	And I don't think it's absent. Because, you know, if it 
19	requires a blood-to-blood transmission, that can occur with 
20	sexual transmission, as well.  So there's a lot we don't 
21	know about the biology of hepatitis C transmission.
22		DR. HOLLINGER:  I would agree with that.  It's 

23	probably not zero, and that's what we tell our patients. 
24		Any other comments? 
25		Okay.  Thank you, Robin. 

			31 1		Colonel Fitzpatrick?
	2		COL. FITZPATRICK:  I just need to go back and 
	3	correct those figures, since it went into the record. 
	4		For 1996, the deferral rate in DOD for FTA 
	5	positive donors was .039 percent, which equates to about 429 
	6	donors.  In '97, it was .037 percent, which is about 407
	7	donors, and in '98 it dropped to .023 percent--about 250 
	8	donors. 
	9		DR. HOLLINGER:  Thank you for that correction.  
10	It's on the issue of syphilis. 
11		Okay.  Thank you, Robin.
12		The final update is on the relative sensitivity of 
13	HBsAG and HBV NAT tests.  And, again Dr. Biswas. 
14	      Relative Sensitivity of HBsAG and HBV NAT Tests 
15		DR. BISWAS:  Data presented at the March 16, 2000 
16	Blood Products Advisory Committee meeting indicated that
17	hepatitis B virus nucleic acid testing--HBV NAT--of source 
18	plasma donations using the format of testing mini-pools 
19	containing 512 donations currently being performed under 
20	IND, might offer little improvement in sensitivity compared 
21	to hepatitis B surface antigen--HBsAG testing--of individual
22	donations, using some of the more sensitive HBsAG tests.  In 
23	regard to this, FDA is organizing studies in collaboration 
24	with NIH, NHLBI, that directly compare: one, HBsAG testing 
25	of individual samples using various HB-AG screening assays 

			32 1	to, two, HBV NAT testing using the 512 sample mini-pool
	2	format for testing source plasma. 
	3		At the present time, whole blood and components 
	4	for transfusion in the United States are not tested by HBV 
	5	NAT assays.  HBV NAT testing of all blood donations has been 
	6	implemented in Japan and is being discussed in Europe.  FDA
	7	is also reviewing the lower limits of detection of all 
	8	currently licensed HBsAG tests and their various incubation 
	9	times, tests that are used to screen the blood supply.  
10	After completion of this review, FDA will decide whether to 
11	change the lot-release requirements of licensed HBsAG tests
12	in regard to lower limits of detection. 
13		We welcome the submission of any existing data on 
14	high-sensitivity tests for HBsAG.  The data should contain 
15	sufficient details so that meaningful head-to-head 
16	comparisons between tests can be made.  And, in fact, we're
17	beginning to receive such data. 
18		DR. HOLLINGER:  Thank you, Robin. 
19		There are two people who have asked to speak to 
20	this issue.  Again, the AABB, Dr. Louie Katz, and then 
21	followed by the American Red Cross.
22		          Open Public Hearing 
23		DR. KATZ:  The review of the relative sensitivity 
24	of approved and pending hepatitis B surface antigen assays 
25	versus HBV NAT by FDA is timely, as U.S. blood collection 

		33 1	facilities are being asked to instituted mini-pool NAT
	2	screening for HBV by European plasma fractionators within 

	3	the next year.  Major U.S. blood banking organizations are 
	4	resisting this request, based on a combination of 
	5	cost-benefit considerations and the general, but not 
	6	universal, benignity of HBV infections acquired by
	7	transfusion. 
	8	          The  European fractionators are being asked to 
	9	consider the use, instead of NAT testing in mini-pools, of 
10	more sensitive HBsAG assays, detecting less than .1 

11	nanograms per mil of antigen, that are pending FDA
12	consideration and approval.  In addition, some U.S. 

13	suppliers of recovered plasma to the  European market have 
14	proposed the exclusive use, when a donor is found to be 
15	antechoir-positive of anti S-reactive units, and perhaps HBV 
16	NAT when acceptable assays are available.  The use of
17	choir-positive donors positive for anti-S would minimize the 
18	fractionation of HBV-DNA position units in the interval, and 
19	preserve levels of anti-HBS in plasma derivatives. 
20	          Preliminary data from the Red Cross and Blood 

21	Systems, Incorporated, indicate that new highly sensitive
22	surface antigen tests will detect antigen at levels 

23	equivalent to approximately genome equivalents per 
24	milliliter or higher per donation.  This is equivalent to 
25	the sensitivity, NAT HBV testing in pools of 100 to more 

			34 1	than a thousand that are currently proposed.
	2		We would consider supporting HBV NAT assays in 

	3	mini-pools if an ultra sensitive assay were developed and 
	4	validated in a multiplex format to be combined with the 
	5	current HIV and HCV assays.  NAT HBV mini-pool sizes of 16 
	6	to 24 samples as currently performed in the U.S. on whole

	7	blood donations for volunteer donors for HIV and HCV may 
	8	improve HBV detection to 500 to 1000 genome equivalents per 
	9	mil--per donation, using current technology.  This would 
10	result in about a five to ten day closure of the HBV window 
11	period based on the observed HBV doubling time of 2.5 to 4
12	days in the pre-surfacing antigen ramp up phase. 
13		The estimated cost for this additional benefit is 

14	roughly $36 to $48 million annually in the volunteer sector.  
15	Given the current incidence of HBV among U.S. volunteer 
16	blood donors--9.5 per 100,000 person years of
17	observation--and this estimated window period reduction by 

18	mini-pool NAT relative to highly sensitive B surface antigen 
19	assays of five to ten days, we project that the yield of HBV 
20	NAT, compared to the unlicensed but more sensitive surface 
21	antigen assays will be between 1.3 and 2.6 HBV detections
22	per million volunteer donations per year; that is 
23	NAT-positive B surface antigen on an ultra sensitive assay. 
24		From data presented at recent meetings, it appears 
25	that the majority of HBV DNA positive, surface antigen 

			35 1	negative units detected in Europe and Japan are found to be
	2	positive in tests for antechoir.  All volunteer blood 
	3	collected in the U.S. is screened for antechoir, so 
	4	detection with HBV NAT will be substantially less than in 
	5	those countries where such screening is not routine, 
	6	especially the countries of the European Union.
	7		Most recipient exposed to such units will have 
	8	sub-clinical, transient HBV infections, with no long-term 
	9	sequelae.  Additionally, as all blood derivatives are 
10	subject to one or more highly effective viral inactivation 
11	procedures, the goal of testing plasma for further
12	manufacturers to ensure as small as possible a viral load in 
13	the starting material.  Thus, the practical benefit of 
14	mini-pool NAT for HBV is exceedingly poor. 
15		We recognize that the blood community's commercial 
16	relationship with plasma fractionators is not of regulatory
17	interest to the FDA.  Still, we encourage FDA to give 
18	expedited considerations to applications for more sensitive 
19	hepatitis B surface antigen testing, both for enhanced 
20	safety of the U.S. blood supply, and to help the membership 
21	of AABB answer the concerns of fractionators on both sides

22	of the Atlantic. 
23		Thank you. 
24		DR. HOLLINGER:  Thank you, Dr. Katz. 
25		And then let's follow this with the comment from 

			36 1	the American Red Cross--Dr. Stramer?
	2		DR. STRAMER:  Okay.  Thank you.  I'll make the 
	3	comment from here. 
	4		I will skip the first two paragraphs.  You know 
	5	who I am, and you know who the Red Cross is. 
	6		THe American Red Cross supports the continuing
	7	efforts to increase the safety of whole blood components and 
	8	plasma derivatives, and therefore supports the effort to 
	9	examine methods to reduce the small residual risk of 
10	hepatitis B virus transmission through blood, blood 
11	components and plasma derivatives.
12		Currently the risk of hepatitis B through 
13	transfusion from whole blood donations is estimated to be 

14	one in 63,000, based on an incidence of 9.5 per 100,000.  
15	Those are the figures that Dr. Katz just presented.  More 
16	recent data from the American Red Cross for 1997 to 1999

17	demonstrate incidence of 4.5 per 100,000, which reduces the 
18	risk to one in 135,000. 
19		Studies performed by the American Red Cross and 
20	presented at the last Blood Products Advisory Committee 

21	meeting highlighted the low concentration of HBV DNA in
22	seroconverting HBsAG-negative individuals early in 
23	infection.  The median concentration of virus was reported 
24	to be 600 copies per mil, in 13 individuals studied.  Of 
25	those 13 individuals, five would have been detected by 

			37 1	pooled HBV NAT if one assumes comparable test sensitivity
	2	with current HIV and HCV-NAT tests used today in mini-pools.  
	3	This translates to a window-period reduction of four days of 
	4	a 25 total--25-day total. 
	5		Data were also shown at the BPAC documenting that 

	6	HBsAG assays having sensitivities of .1 nanogram per mil or
	7	less are able to detect samples having DNA copy 
	8	concentrations in the range of 100 to 8,000 copies per mil, 
	9	with a median detection of 3,440 copies per mil.  This 
10	sensitivity is comparable with the sensitivity of NAT 
11	testing currently performed in the source plasma industry,
12	using relatively large pools.  Therefore, it would seem 

13	logical to follow a step-wise pathway to decrease an already 
14	small risk from hepatitis B virus as follows. 
15		One--implement sensitive HBsAG assays with a yield 
16	comparable to HBV NAT that is performed in large pools of
17	100 to 1,200 donations; two, develop ultra-sensitive HBV NAT 
18	methods, having 20 to 50 copies per mil sensitivity that can 
19	be multiplexed with the current HIV and HCV nucleic acid 
20	tests in the mini-pool environment. 
21		It is worth noting that due to the low incidence

22	of hepatitis B in whole blood donors, long inter-donation 
23	intervals, and therefore the possibility of only one 

24	window-period donation from any positive donor, and 
25	antechoir screening of all whole-blood donations, that even 

			38 1	upon the implementation of HBV NAT testing the yield will be
	2	very low--approximately 1.2 per million, using the Red Cross 
	3	1997 to 1999 incidence data. 
	4		The American Red Cross's proposed current strategy 
	5	for the management of hepatitis B virus in the context of 
	6	manufactured plasma products is designed to assure the
	7	absence of detectable HBV DNA in the final products.  As I 
	8	discussed yesterday for hepatitis A virus, hepatitis B virus 
	9	PCR will be performed on pools of plasma prior to 
10	fractionation.  In the event of a positive result, the 
11	manufacturing pool would not be used and would be destroyed.
12		Red Cross has performed a qualification run to 
13	determine the logistics and feasibility of this strategy.  A 
14	pilot study involved the equivalent of 540,000 donations 
15	that were pooled into 45 manufacturing pools of 3,200 
16	liters.  Each pool was tested for HBV DNA by PCR at National
17	Genetics Institute.  It is no surprise that all pools tested 
18	negative for HBV.  Although this strategy allows the 
19	detection of only high titre units, there is no evidence 

20	that high titre units are not being detected currently. 
21		As part of the strategy, consideration is also
22	being given to HBV DNA screening of antechoir reactive 
23	donations, and use of only those units that test HBV DNA 

24	negative.  We believe that this strategy for HBV screening 
25	for recovered plasma from volunteer whole-blood donors is 

			39 1	the most reasonable approach until sensitive pooled HBV NAT
	2	methods are available. 
	3		Thank you. 
	4		DR. HOLLINGER:  Thank you, Susan. 
	5		Questions?  Anybody else from the public wish to 
	6	make a comment?
	7		Committee members--comments? 
	8		Okay.  Thank you, Robin. 
	9		We're going to move on, then to the next item, 
10	which is proposed FDA Guidance on Leukoreduction: the 
11	Current Thinking, and Dr. Lee will give us an introduction
12	and background to the issues. 
13		       Open Committee Discussion 
14	 Proposed FDA Guidance ON Leukoreduction: Current Thinking 
15		DR. LEE:  Thank you, Mr. Chairman, and good 
16	morning.
17		I believe you're on the home stretch now.  This is 
18	the last topic before we adjourn, so hang in there. 
19		This is a topic that we've visited several times 
20	before, and we will do so once again this morning, with the 
21	aim of shaping a future FDA guidance on this topic:
22	leukoreduction. 
23		Let me give you a brief introductory background 

24	about leukoreduction; the regulatory milestones associated 
25	with that topic--although much of this is probably familiar 

		40 1	to most of you.
	2	          I guess I'll start with the March 1995 FDA 
	3	workshop on leukoreduction, where the topic of 
	4	leukoreduction as a process to generate a special class of 
	5	products was discussed.  All of the blood 
	6	components--cellular blood components, more specifically,

	7	red cells and platelets--could be leukocyte reduced for 
	8	increased product purity, which had certain clinical 
	9	benefits in--at least at that point--selected, 
10	well-recognized clinical cases.  And as a result of this 
11	workshop, in May 1996 an FDA memorandum was written on the

12	topic of leukocyte reduction, and that memorandum focused on 
13	manufacturing issues, and left the use of this class of 
14	products to medical discretion for those patients that were 
15	recognized to potentially benefit from that product.  And 

16	that memorandum basically stated that--recommended the
17	specific term "leukocyte reduction" or "leukocytes reduced" 
18	as the proper term to use for these class of products; 
19	recommended that the residual white blood cell threshold to 
20	be no greater than 5.0 x 106 residual white blood cells per 
21	unit, that 85 percent of the original therapeutic blood be
22	retained in the leukocyte reduction process, and the whole 

23	process be conducted in a GMP setting to assure a quality of 
24	the product that are subjected to this process. 
25	          The indications for use of those products were 

			41 1	left to medical discretion,  and clearly recognized
	2	indications were few: febrile nonhemolytic transfusion 
	3	reactions were one, and that claim made its way into the 
	4	circular of information which is blood product labeling; a 
	5	product insert for blood and blood components.  And the 

	6	indications were beginning to be broadened, and the first
	7	effort at that was in September of 1997, when the topic was 
	8	discussed by this committee for the specific indication of 
	9	whether or not leukocyte reduced blood products are 
10	effective in reducing the potential for CMV transmission by 
11	blood.  And the committee, by overwhelming majority, voted
12	in favor that leukocyte reduction is effective in reducing 
13	the transfusion-transmitted CMV, and also noted that the 
14	different methods for reducing leukocytes--I'll use the fly 
15	as my pointer-- 
16		[Laughter.]
17		--I guess I don't have my pointer any more.  
18	That's all right--that the different methods for leukocyte 
19	reduction were not equivalent, however all methods were 

20	effective, probably to different levels that were too 
21	difficult to demonstrate clinically.
22		Now, one would anticipate that additional 
23	discussion about indications for use would be brought to 
24	this committee, such as the effectiveness in reducing the 
25	potential HLA allonization which complicates patient 

		42 1	management.  And, most importantly, the potential for

	2	leukocyte reduction to reduce the transfusion-related 
	3	immunosuppression that has a very significant clinical 
	4	effect yet--although it is a very difficult effect to 
	5	demonstrate clinically. 

	6	          The fact that leukocyte reduction might--the fact
	7	that blood transfusion might suppress the immunity of the 
	8	recipient such that tumor progression or post-operative 

	9	bacterial infections--things of this sort--can--that effect 
10	of transfusion, if demonstrated, can also be diminished by 
11	leukocyte reduction if demonstrated--those are very
12	important clinical indications that are currently being 
13	discussed, but the magnitude of the clinical trials that are 
14	necessary to demonstrate these effects is such that it is 
15	probably not possible to demonstrate that effect in a 

16	reasonable--in reasonable recent future, other than by
17	consensus of accruing experience over time. 
18	          Nonetheless, that's an important indication, and 
19	along with many others, those indications could have been 

20	discussed.  However, that topic was sort of short circuited. 
21	In September of 1998 this committee was charged with the
22	question of whether or not leukocyte reduction is effective 
23	in--whether or not universal leukocyte reduction--that is, 
24	the use of leukocyte reduction for all red cells and 
25	platelets at least--would be a scientifically sound thing to 

			43 1	do, in view of the fact that it has several clear-cut,
	2	demonstrated clinical benefits and a whole multitude of 

	3	other controversial, yet nonetheless important, clinical 
	4	indications. 
	5		And this committee supported, by overwhelming 
	6	majority, that on a clinical, scientific basis, that
	7	leukocyte reduction is to be recommended for all cellular 
	8	blood products; more specifically, red cells and platelets. 
	9		Based on that outcome, in December of 1999, FDA 
10	sponsored a public workshop on the implementation of 

11	universal leukocyte reduction as to how this transition
12	might be best accomplished.  Of course, the scientific 

13	issues are not the only ones affecting leukocyte reduction, 
14	and in April of 2000 the PHS Advisory Committee discussed 
15	the issue of reimbursement; that is, although it is clear 
16	that scientifically this is desirable, on a broader public
17	health level is it also desirable, given that cost is an 

18	important concern, more specifically reimbursement is an 
19	important concern which might have detrimental indirect 

20	effects if universal leukocyte reduction were to be hastily 
21	implemented.
22		And, to close the loop, in June of 2000 this topic 
23	was brought before the Transmissible Spongeform 
24	Encephalopathy Advisory Committee with respect to the 

25	effectiveness of leukocyte reduction in reducing the 

			44 1	potential infectivity of variant CJD.  The charge to BPAC in
	2	September of 1998 was to consider all clinical indications 

	3	except CJD, and that last topic of CJD was brought before 
	4	the TSE Advisory Committee in June of 2000, and that 
	5	committee found that the current existing evidence was 
	6	insufficient to conclude that leukocyte reduction is
	7	effective in reducing the potential infectivity of variant 
	8	CJD by blood transfusion.  That was no surprise.  We 
	9	anticipated that, but at least we visited the topic 
10	thoroughly, and we know exactly where we are, given the 
11	amount of information available.
12		And here we are today, in trying to shape an FDA 
13	recommendation--FDA guidance to industry about leukocyte 
14	reduction, as to how we might now proceed forward, given 
15	this amount of discussion, and this amount of information 
16	that is currently available.
17		Next slide. 

18		Just to pick up where we left off in September of 
19	1998, this committee voted 13 votes "yes," "no" votes zero, 
20	with three abstentions to the following question: is the 
21	benefit-risk ratio associated with leukocyte reduction

22	sufficiently great to justify the universal leukocyte 
23	reduction of all non-leukocyte transfusion blood components, 
24	irrespective of the theoretical consideration for 
25	transfusion-transmitted CJD.  And both the consumer and 

			45 1	industry representatives voted--were in agreement with the
	2	"yes" vote; and just to remind you, the cost and 
	3	reimbursement concerns were not considered by this 
	4	committee. 
	5		Next slide. 
	6		And this scientific decision was then further
	7	developed at the FDA workshop--as I briefly alluded to just 
	8	awhile ago, and three predominant themes were discussed at 

	9	that FDA workshop in December 1999 on implementation of the 
10	universal leukocyte reduction.  We talked about the 
11	transition period, as to how we might--given that this is to
12	be desirable--how we might best go about making the 
13	transition period, and generally the workshop participants 
14	favored a transition period of something like two years, 

15	where people are getting ready for a ramp up, making changes 
16	to their operating procedures, their personnel, adjustments
17	to their scope of manufacturing to accommodate increased use 
18	of leukocyte reduction. 
19		At that workshop, another theme that emerged was 
20	that the current method of monitoring the quality of 
21	leukocyte reduced blood was insufficient; that the current
22	recommendation, which is really meant to be a minimum FDA 
23	recommendation, but nonetheless taken as the recommendation 
24	of testing only 1 percent, or four units per month, per 
25	process variation of leukocyte reduction, that was felt that 

			46 1	that method is grossly insufficient to assure the quality of
	2	leukocyte reduced blood. 
	3		The third theme that emerged was that of 
	4	streamlining licensing.  The workshop participants agreed 

	5	that the current mechanism of licensing blood centers for 
	6	leukocyte reduced blood could be streamlined so that

	7	reporting burden is diminished, without necessarily 
	8	jeopardizing public health. 
	9		So, having said that, I have identified three 
10	issues--three fundamental issues; there are whole slew 
11	of--at least several dozen specific issues that can be

12	discussed, but we only have this morning, and I think these 
13	three fundamental issues are plenty for discussion, and it 
14	will actually be very helpful if you can actually derive 

15	some kind of a direction based on this morning's discussion. 
16		The first--and I take this in the order of
17	increasing complexity, and reserve the most complicated 
18	question for last.  Starting out with a manufacturing issue, 
19	and that is an issue of quality monitoring.  How can we 
20	better assure the quality of the leukocyte reduced blood, in 
21	accordance with the previous discussions; the current
22	recommendations that are meant to be minimum are adhered to 
23	as the recommendation are clearly insufficient. 
24		The next issue is that of licensing, and how we 
25	might streamline the licensing of leukocyte reduction. 

			47 1		And, thirdly, we can again revisit the dilemma of
	2	leukocyte reduction as a clinical choice or as a 
	3	manufacturing requirement, and we'll see how much--what kind 
	4	of a resolution we can bring to that current dilemma. 
	5		Okay--so this is the first major topic--major 
	6	sub-topic of leukocyte reduction for this morning.  And in

	7	order to discuss this thoroughly, I think we might start 
	8	with a definition. 
	9		We talk about pre-storage leukocyte reduction.  I 
10	think we might begin with a definition so that we're all on 
11	the same page.  And this is a working definition, which can
12	certainly be modified.  And I'll read this definition: the 
13	reduction in the content of contaminant leukocytes in a 

14	blood unit to 1.0 x 106 cells or fewer while retaining at 
15	least 85 percent of the therapeutic product within 24 hours, 
16	using a method which assures, at 95 percent confidence
17	level, that more than 95 percent of the units meet these 
18	product specifications. 
19		That's a long definition, however it has some key 
20	words in it which are highlighted in orange.  First of all, 
21	the word "contaminant."  I put that word in there to
22	indicate that we mean blood components that are meant to be 
23	non-leukocyte blood components; certainly, granulocyte is a 
24	blood component and is excluded from this definition.  So 

25	we're talking about red cells, platelets and, potentially, 

			48 1	plasma, because they are blood components and leukocyte
	2	contaminants are present--to very low levels, but 
	3	nonetheless still present in units of plasma.  So, first of 
	4	all the word "contaminant" appears in this definition. 

	5		Secondly the threshold of residual white cell 
	6	content per unit currently reads, in this definition "
	7	1.0 x 106," whereas before, per the 1996 memorandum, which 
	8	is still in effect today it's 5.0 x 10 to the sixthXXXX.  
	9	And this is an adjustment that can easily be made, because 
10	we know that we can get there with the current filtration 
11	technology.  This is the standard that's being used by
12	Europe.  And really, from an operational standpoint, it is 
13	not much different from 5.0 x 106, but this is a slight 
14	change towards increasing the stringency as the technology 
15	permits.  So therefore 1.0 x 106 was chosen. 
16		Retention of product--85 percent.  This is a

17	carryover from the previous memorandum.  There is really no 
18	reason to increase--although I suspect that we could.  But, 
19	for the moment, I decided to retain this 85 percent.  
20	Certainly this can be discussed further by this committee 
21	today.
22		So the 1.0 x 106 and 85 percent, those are numbers 
23	that are geared at increasing product purity and product 
24	safety, while retaining product efficacy. 
25		Now the word--the time frame of this process 

		49 1	"within 24 hours of blood collection." A variety of
	2	different time frames can be chosen for this.  The committee 
	3	might be well reminded that the current leukocyte filtration 
	4	equipment, or more specifically, blood filters and 
	5	cytapheresis instruments--well, I guess more specifically, 
	6	blood filters--they had been approved under 510(k) for
	7	pre-storage leukocyte reduction for periods that extend up 
	8	to five days.  So--we don't want to say five days, however, 
	9	because clearly five days would be a fairly long period, and 
10	it's not really pre-storage anymore if a product has been 

11	sitting around for five days, then leukocyte reduced.  Yet,
12	operationally, any time period more stringent than 24 hours 
13	would be nearly impossible, and even 24 hours might be too 
14	burdensome operationally.  But for right now, we might go 
15	with the 24 hour as a working definition so that we can 

16	minimize cell degradation and cytakine release which
17	contributes to adverse transfusion effects. 
18	          And lastly, but most importantly, to process a 
19	unit of blood for leukocyte reduction in a way that assures, 
20	with a certain level of confidence--and what is that level 
21	of confidence?  Typically what's been used in clinical
22	trials is 95 percent, so we have consistent with that 95 
23	percent confidence level was chosen.  And what is the 
24	process specification?  With the product specifications--if 
25	product specifications are defined as 1.0 x 106 residual 

			50 1	cells, with 85 percent of product recovery, then what are
	2	the process specifications?  You might say that the process 
	3	specifications is assuring that 95 percent--greater than 95 
	4	percent of the products subjected to this method are 
	5	actually acceptable units, and you know that to be the case 
	6	with 95 percent confidence.  And those two numbers are meant
	7	to be--meant to define the process specifications. 
	8		Next slide. 
	9		Okay.  So we have--that definition does not 
10	necessarily mean that--i's not necessarily recommended as 
11	the one--as the final definition, but certainly recommended
12	just as a starting point for discussion. 
13		Okay.  Now, let's move to a case example.  Just to 
14	illustrate why current methods of QC testing, or quality 

15	monitoring, is insufficient to assure product quality of 
16	leukocyte reduced blood.
17		Let's go through this case example. 
18		A blood center manufactures and leukocyte reduces 
19	400 red blood cells units per month.  Let's say that an 

20	error in filter priming procedures used by a new staff 
21	member results in achieving acceptable final product
22	standards in only 80 percent of leukocyte reduced units.  
23	Per current FDA recommendations, the blood center performs 
24	QC testing on four units, and the units are found to be 

25	satisfactory.  That's entirely possible; with a process 

		51 1	specification of only 80 percent it's entirely possible that
	2	when you test four units, you might come across four units 
	3	that are quite acceptable. 
	4	          So what is our sensitivity in detecting that a 
	5	procedural error has crept in and is jeopardizing many units 
	6	as unacceptable units?  Well you might calculate that by
	7	taking 80 percent--.8--and raising that to the fourth power 
	8	for the chance of occurring an acceptable unit four times in 
	9	a row, and that overall chance of seeing four units that are 
10	acceptable, consecutively, is 41 percent. 
11	          Now if that's 41 percent, then 1 minus 41 percent,
12	or 59 percent, is your chance of detecting at least one unit 
13	that is unacceptable.  Now, notice I used .8 raised to the 
14	fourth power than .2 raised to the fourth power because .2 
15	raised to the fourth power would mean detecting an 
16	unacceptable unit four times in a row, and we're not
17	interested in that statistic.  We're interested in detecting 
18	at least one unit, so we have to go with 1 minus .8 raised 
19	to the fourth power for a 59 percent figure--which is really 
20	the test sensitivity if you consider the entire quality 
21	control and monitoring process as a test, then you might say
22	that the sensitivity of this test or this quality monitoring 
23	program is 59 percent, which is really not sufficient at 
24	all.  And in this case I've defined that sensitivity as your 
25	confidence level in assuring the quality of leukocyte 

			52 1	reduction process.
	2		Next slide. 
	3		So as you can see that the current methods are 

	4	grossly insufficient, grossly insensitive, and does not 
	5	assure, with any level of confidence, that when you see 
	6	acceptable units only in your QC testing that the entire
	7	process is working properly.  That assurance cannot be 
	8	obtained. 

	9		Then we have to define some process specifications 
10	in addition to product.  I said before that the product 

11	specifications are 1.0 x 106 residual cells per unit, and
12	the recovery of 85 percent of the product.  And then, once 
13	again, the process specifications are that the percent of 
14	units that are acceptable be greater than 95 percent, and 
15	that we know this to be the case with 95 percent confidence 
16	that greater than 95 percent of the units are acceptable. 
17	So those are process specifications on top of the more 
18	familiar product specifications. 
19		To achieve these specifications, we have to 
20	increase our sample size.  And we have to do so in a way 

21	that's not overly burdensome for blood centers.  And sample
22	size is closely related to the concept of a manufacturing 
23	period.  Obviously a large blood center has a large sample 

24	size, and a small blood center will have only a small sample 
25	size.  However, if given enough time, a small blood center 

			53 1	will make lots of products, too.  So we can't just think

	2	about sample size as a number, we have to think of it in 
	3	terms of the time period, therefore the concept of 
	4	manufacturing period becomes important.  And in order to 
	5	detect a procedural error as early as possible, whatever 
	6	sample size is chosen, that sample size be divided in

	7	multiple alloquots, and that testing be performed as 
	8	frequently as possible within practical limits so that any 
	9	error in procedure can be detected at the earliest possible 
10	time. 
11		Okay.  Now, this chart is meant to be a chart full
12	of numbers of confidence levels, or sensitivities of the 

13	quality monitoring program.  Across the top are numbers 
14	which represent the percent of units that are acceptable.  
15	So 50 percent, 60 percent, on up to 99.9 percent, that are 
16	the percent of units that meet product specifications of	1.0
17	x 106 cells per unit or less, and 85 percent product 
18	recovery.  And along the left-hand column are the number of 
19	QC units that might be chosen. 
20		The case example that I went through just awhile 
21	ago--if you read across to 80, and then drop down to "4" for
22	QC units, you see the number "59," and that's the 59 percent 
23	confidence level, or sensitivity, which I just explained. 
24	12:35	And, recognizing that that is grossly 
25	insufficient, what would we like?  Well, we just defined, at 

		54 1	least for the purposes of discussion, 95 percent confidence
	2	level, with 95 percent--more than 95 of the products meeting 
	3	product specifications.  So if you move across the top 

	4	column to 95 percent, and then drop down  to 95 percent 
	5	confidence level, and then read of the left-hand column of 
	6	the number of QC units, we arrive at 60 unites.  So it
	7	appears if you quality control 60 units and do not find any 
	8	unacceptable unit in your 60--pool of 60 samples, then you 
	9	can be assured that more than 90 percent of the products 
10	that you claim as leukocyte reduced are indeed leukocyte 
11	reduced, and you can make that claim with a 95 percent
12	confidence level.  So this is a way to put a handle on the 
13	amount of uncertainty that necessarily accompanies the fact 
14	that you're not testing every unit.  If you're not testing 
15	every unit, there's always room for some uncertainty, but 
16	this way at least your know what the level of uncertainty

17	is. 
18	          Now, that chart that I just went through is really 
19	for conceptual purposes, and it's not rigorously accurate.  
20	In fact, as you decrease the number of sample--as you 

21	decrease the total number of samples, or total number of
22	units that a particular blood center manufactures, the 

23	number of units becomes a little bit smaller than 60.  So if 
24	you make 250 units or more, I think if you test 60 units the 
25	process specifications hold.  However, as you drop down, the 

			55 1	number of units that you actually need to test is slightly
	2	smaller.  Now, you might argue that this is not 
	3	significantly different from 60, and that's a point that can 
	4	be discussed further, but there is some small reduction in 
	5	the actual number of units that you have to test if you are 
	6	making less than 250 units.
	7		Next slide. 
	8		Now, of course, as I said earlier, the sample size 
	9	has to be considered in terms of the manufacturing period or 
10	some kind of time interval.  Now if you define your time 

11	period or more frequent, then the QC burden becomes quite
12	high.  Now, if you define your time period as ten years, 
13	then the QC burden is very, very low, but then you won't 
14	know where you're at for a ten-year period.  Only after a 
15	ten-year period has elapsed you'll know that whatever you 
16	did is whatever the process specifications you're aiming

17	for.  So we have to strike some sort of a balance.  And for 
18	purposes of discussion, we chose three months.  Anything 
19	more frequent than three months would be fine, but 
20	recognizing that this may be a significant QC burden, chose 
21	three months as the upper limit.
22		And as I alluded to earlier, there are advantages 
23	of a long manufacturing period; the longer it is, the 

24	smaller the QC burden, obviously.  The 60 units can be 
25	spread out over three months is less burdensome than 60 

		56 1	units spread out over one month.  There is a price to pay
	2	for that, however, and that is the duration of uncertainty.  
	3	If you choose a short time period, such as one month or 
	4	shorter, with each passing of that time period you know for 
	5	sure that you've closed the loop; everything you've done, 
	6	provided that you haven't encountered an unacceptable QC
	7	unit is per process specifications and all product 
	8	specifications are met.  You know that at the end of that 
	9	manufacturing period.  If you choose a long period, that 
10	uncertainty continues until you close the loop by completing 
11	QC testing for that period.  And, of course, if you were to
12	uncover--discover an unacceptable unit, then you'll have to 
13	perform some kind of investigation, not only to correct the 
14	process, but to initiate action for all the products that 

15	had been released under that process, in terms of product 
16	retrieval and notifications.  So the chances of that becomes
17	higher with lengthening the manufacturing period.  So this 
18	is a trade-off. 
19	          And whether you choose a short period or a long 
20	period depends on your manufacturing scope.  If you're a 

21	large blood center QC burden is relatively small with
22	respect to your entire manufacturing production capacity, 
23	and you might go with a reasonably short manufacturing 
24	period; whereas if you're a large blood 
25	center--sorry--whereas if you're a small blood center, you 

			57 1	might choose a longer period just so that the QC burden does
	2	not overwhelm your operation. 
	3		Whatever the sample size is, and whatever the 
	4	manufacturing period is chosen, the number of total units 
	5	that are subjected to QC testing should be divided so that 
	6	testing can be performed at weekly intervals or more
	7	frequently, towards the aim of detecting an unstable process 
	8	as early as possible.  So although finding a portion of the 
	9	units acceptable does not assure that you're okay with your 
10	process, finding something certainly tells you that 
11	something is not okay.  And to increase that possibility of
12	detecting as early as possible, you might divide that into 
13	multiple alloquots and test them periodically. 
14		Next slide. 
15		In terms of process validation, right now the 
16	Agency looks at the quality monitoring program as a
17	two-phase effort, and this is a concept that carries over 

18	from the previous 1996 memorandum that's still currently in 
19	effect.  You might initially validate your process by 
20	testing a certain number of units up front, consecutively 
21	and, as per previous discussion, that number may be 60

22	consecutive units per process variation, and when you 
23	discover no unacceptable units, having directly QC tested 60 
24	units consecutively, then you can be assured that, at least 
25	for the time being, your process is robust. 

			58 1		How do you ensure that your process remains robust
	2	for the next ten years, or as long as you manufacture 

	3	leukocyte reduced products?  That's where you have to 
	4	perform continuing quality monitoring through quality 

	5	control testing, and this depends on the--as I stated just 
	6	awhile ago--predefined sample size, and predefined
	7	manufacturing period.  And these are criteria that are 
	8	facility-specific, and you may choose your own, depending on 
	9	your manufacturing scope. 
10		If every unit that you initially test as part of 
11	process validation, and then you subsequently test as part

12	of continuing quality monitoring, if all the units turn out 
13	to be acceptable per QC testing, then everything is fine.  
14	But, of course, you will not.  You will encounter an 
15	unacceptable process every now and then.  And that point, 
16	revalidation of process will be necessarily.
17		But even without encountering an unacceptable 
18	unit, you might just change your process, just because new 
19	technology became available, you are now able to hire an 
20	increase level of staffing.  Whatever the change is, if you 
21	introduce a change, you should revalidate the process

22	anyway.  Even if you don't change your process, if you 
23	encounter an unacceptable unit, then you should also 
24	revalidate your process. 
25		Next slide. 

			59 1		So--either a change in the process or discovery of
	2	an unacceptable unit triggers revalidation.  If the 
	3	revalidation is being performed as part of having detected 
	4	an unacceptable unit, then, of course, that has to be 
	5	preceded by process investigation; you have to look to see 

	6	where you--if your process went wrong somewhere.  And if you
	7	find it, of course, you will correct it and revalidate. 
	8		Even if you don't find anything, you'll have to 

	9	revalidate before you can determine that the unit that you 
10	detected as unacceptable is sheerly by chance; everything is 
11	fine; your process is fine, however, since your process
12	specification to begin with is only greater than 95 percent, 
13	not 100 percent, then you might encounter a product that's 
14	still within your process specification, it's just on a 

15	statistical chance basis.  Before you can arrive at that 
16	conclusion, you should revalidate another 60 consecutive
17	units. 
18		So the need for revalidation--you might think 
19	that, based on chance, you might stumble onto an 

20	unacceptable unit so frequently that you're revalidating all 
21	the time.  That is not necessarily true.  The need for
22	revalidation is unlikely if your process is stable, and that 
23	your process standard--whatever it is--exceeds the minimum 
24	standard significantly.  The minimum standard that we just 
25	talked about is 95--more than 95 percent of the product 

			60 1	being acceptable.  If you operate very close to that
	2	standard, then, yes indeed, the chances are high that you 
	3	might, by chance, encounter an unacceptable unit and subject 
	4	yourself to a process revalidation requirement.  However 
	5	current filtration technology allows operating at a standard 
	6	much higher than that.  I suspect that it's easily 99.9
	7	percent.  And under that scenario where you are exceeding 
	8	the minimum standard by at least 50-fold, and provided that 
	9	your process is stable, your need for revalidation is highly 
10	unlikely. 
11		So, I just kind of, step by step, went through
12	what might be a reasonable alternative, in terms of quality 
13	monitoring--alternative to the ones that are in place today. 
14		So let's consider other alternatives.  Well, the 
15	first alternative is to simply retain what we have--four 

16	units or 1 percent, whichever is greater, per month.  The
17	problem with this, of course, is that it does not assure 
18	product quality.  But it is simple, and it's already in 
19	place, and it's a reasonably low QC burden. 

20		An alternative to this might be to simply increase 
21	this number.  While this is also simple, an the transition
22	for that  would be easy, and it would likewise be a 
23	relatively low QC burden, however it's only a marginal 
24	improvement in assuring product quality, and you won't know 
25	how much you've improved. 

			61 1		You can make a drastic change.  You could switch
	2	to device QC testing.  Yesterday we talked about 510(k) 
	3	notification not being subject to product-release 
	4	requirements, whereas PMA is.  Currently, blood filters are 
	5	clearly under 510(k).  There is--typically, there has not 
	6	been a clinical trial requirement, and once cleared,
	7	typically there is no continuing requirement from the filter 
	8	manufacturer to demonstrate continuously that all filters 
	9	are manufactured according to product specifications. 
10		If we were to increase the burden, or shift the 
11	burden to the device side, that might potentially relieve
12	the blood centers of having to perform any QC testing, since 
13	QC testing is being done up front by the device 
14	manufacturers.  That's a drastic change, and I point that 

15	out only for discussion, not necessarily as the Agency's 
16	current thinking.  The problem of that approach, of course,
17	is that everything that happens after the filter--all the 
18	variables that are operational, that are associated with 
19	training of the people that are actually performing 
20	leukocyte reduction at the blood center, those are all 

21	variables, and none of that would be captured under that
22	kind of paradigm. 
23		In addition to these three alternatives, the 
24	fourth is the one that I just went through in great detail.  
25	The problem with that is that QC burden is high, especially 

			62 1	for small centers.  But, actually it can be quite low for
	2	large centers, not requiring 1 percent anymore, but 
	3	requiring simply 60, provided that you make enough products 
	4	within a reasonably short time period, that 60 may turn out 
	5	to be below 1 percent.  The advantage of this is that it 
	6	gives you statistical confidence, and it tells you exactly
	7	where you are in assuring minimum standards. 
	8		Next slide. 
	9		So, I think this sub-topic deserves an interim 
10	summary.  So, in terms of quality monitoring, we're shooting 
11	for statistical confidence of an acceptable process.  The

12	process performance might be defined as better than 95 
13	percent of acceptable units.  The confidence level might be 
14	defined as 95 percent, and this is to be implemented with 

15	respect to initial process validation and continuing quality 
16	monitoring.  Important concepts to incorporate in
17	implementing such a plan would be the sample size and the 
18	definition of the manufacturing period.  An the process 
19	investigation is necessary whenever you discover one--even 
20	just one--unacceptable unit, and revalidation will be 
21	needed.
22		Alternative to this process are either retain the 
23	current approach, or shift the QC burden to the device side 
24	and accept the operational variables that exist at the blood 
25	centers. 

			63 1		Next slide.
	2		Okay.  So I thought that was the most 
	3	straightforward and least controversial and least complex of 
	4	the three questions that we want to discuss.  The second is 
	5	the licensing paradigm.  And although this is more complex, 
	6	I have less to say about it.
	7		Per 1996 memorandum, currently require up front 

	8	submission and review of the following elements: quality 
	9	control data, labelling, standard operating procedures, 
10	manufacturing records, and all of those are elements--and 
11	those are the major elements; there are others that are

12	minor--those major elements are to be submitted up front as 
13	prior approval supplement--or PAS--for all submissions 
14	requesting licensure of leukocyte reduction. 
15		The proposed revision is as follows: retain the 
16	requirement for submission of quality control data and
17	product labelling, however drop the remaining, and simply 
18	require evidence of quality assurance oversight, and the 

19	reporting can also be expanded.  Not all submissions need to 
20	come in as prior approval supplement, but may be submitted 
21	in one of three ways, depending upon what it is--what
22	situation fits you best. 
23		One might be CBE, or "Changes Being Effected."  If 
24	a blood center implements leukocyte reduction per FDA 
25	recommendations, FDA recommendation can be regarded as a 

		64 1	protocol of leukocyte reduction implementation, and if
	2	you're following that protocol then you may simply implement 
	3	at the same time that you report under licensure.  So that 
	4	would be a CBE licensing.  So you'll be submitting less, and 
	5	you will be able to implement your change quicker. 

	6	          However, if you were to deviate from these
	7	recommendations and propose an equivalent or better 
	8	manufacturing recommendations, those submissions are 

	9	certainly welcome.  But in order for FDA to agree with you, 
10	we would have to see that submission up front, an we would 
11	review them in detail.  Under that scenario, we would fall
12	back to all of the previous submission elements to be 

13	submitted, and require and up front review as a prior 
14	approval supplement. 
15	          For blood, there are often multiple sites that are 
16	under control of a single applicant, but typically, multiple
17	sites under the control of a single applicant uses the same 
18	SOP, uses virtually the same everything except for the fact 
19	that they're at a different center.  And for those centers, 
20	you might simply report under CBE, if you do not deviate 

21	from the current protocol--from the FDA protocol.  But if
22	you do deviate from the FDA protocol, then your protocol 

23	needs to be submitted as a prior approval supplement for up 
24	front review.  But once reviewed and accepted, the addition 
25	of multiple sites under that protocol can be reported as 

			65 1	CBE.  And this would be the "Comparability Protocol
	2	Mechanism." 
	3		Next slide. 
	4		Let me go over two pieces of regulation that we 
	5	think will allow us to do this.  Under 21 CFR 61.112(c), the 
	6	changes being effected in 30 days is first described--and
	7	I'll get to CBE in just a minute, but this is a broader rule 
	8	that subsumes CBE; CBE 30 subsumes CBE. 
	9		And CBE-30 reads as follows: "A supplement shall 
10	be submitted for any change in the product, production 
11	process, quality controls, equipment, facilities or
12	responsible personnel that has a moderate potential to have 
13	an adverse affect." So if you have a significant affect, 
14	that's a PIS, if it's a minor affect, it's something even 
15	less than CBE 30.  If it's a moderate potential to have an 
16	adverse affect on the identify, strength, quality, purity or
17	potency of the product as they may relate to the safety or 
18	effectiveness of the product, that's a CBE 30. 
19		Now, under this rule, CBE is explained further. 
20	"FDA may determine that, based on experience with a 
21	particular type of change, the supplement for such a change
22	is usually complete and provides the proper information, and 
23	particular assurances that the proposed change has been 
24	appropriately submitted, the product made using the change 
25	may be distributed upon receipt of the supplement by FDA."  

			66 1		So, under the case of CBE 30, when experience has
	2	shown that submission requirements are typically met, the 
	3	FDA has the option of designating that as CBE. 
	4		This rule goes on further to say, "These 
	5	circumstances may include substantial similarity with a type 
	6	of change regularly involving a CBE supplement of a
	7	situation in which the applicant presents evidence that the 
	8	proposed changed has been validated in accordance with an 
	9	approved protocol."  So this allows the comparability 

10	protocol provision for multiple facilities, while at the 
11	same time this may serve as the basis for viewing FDA's

12	guidance to industry as leukocyte reduction as a protocol 
13	which allows CBE submission to be made under that protocol, 
14	if you follow that protocol. 
15		And I tried to summarize this in a chart.  On the 
16	left-hand column are the submission elements, and across the
17	top are the different mechanisms of submission.  For PAS 
18	column--now this is referring to PAS submitted as an 
19	alternate to FDA's guidance.  If you deviate from FDA's 
20	guidance--you're certainly welcome to do so, but it has to 
21	be a PAS submission for up front review and approval.  And
22	under that submission you would include all the elements 

23	that are x-ed for FDA's close review. 
24		Second two columns is for comparability protocol.  
25	If you have multiple facilities and you want to deviate from 

			67 1	FDA's guidance, you're certainly welcome to do so, but you
	2	should first provide a protocol.  And in that protocol, you 
	3	should include the elements that are x-ed for FDA's up front 
	4	review and approval.  Once reviewed and accepted by the FDA, 
	5	then you may report much less for multiple facilities under 
	6	that protocol, as CBE.  And that includes the product
	7	labeling, quality control data, and manufacturing records. 
	8		If you do not deviate--if you simply follow FDA's 
	9	guidance to the letter--then that can abe viewed upon as a 
10	protocol itself which allows the applicants to submit simply 
11	product labelling, quality control data, and manufacturing
12	records in support of a CBE submission; you're implementing 
13	the change at the time you're requesting licensure. 
14		Next slide. 
15		I think that's straightforward enough that I did 
16	not do a summary for that, and I'll move to the most
17	complicated question, but I have the least to say about 
18	that. 
19		And this is the issue of product use. Is it a 
20	clinical choice, or is it manufacturing? 
21		In the 1996 memo, per outcome of the '95 workshop,
22	leukocyte reduction was left as a clinical choice, a medical 
23	decision to be made.  Physicians may choose from available 
24	products, both leukocyte reduced and leukocyte not-reduced.  
25	The proposed revision is as follows--once again, the 

		68 1	decision to use leukocyte reduced product remains a medical
	2	decision.  Once again, both leukocyte reduced and 
	3	non-leukocyte reduced products will be available.  "If a 
	4	physician chooses to use a non-leukocyte reduced product for 
	5	a particular patient he may do so, and the product should be 
	6	available.  However, the clinical benefits of leukocyte
	7	reduction have been clearly recognized and the indications 

	8	for using them are continuing to expand.  In recognition of 
	9	that, FDA encourages the use of leukocyte reduced product 
10	whenever feasible." 
11	          Let's talk about that just a bit further. 
12	Pre-storage leukocyte reduction, as we defined about  20 

13	minutes ago, and let's consider the clinical benefits of 
14	increasing product purity through leukocyte reduction.  

15	These--the four indications that are listed up at the top, 
16	that much we already know.  Pre-storage leukocyte reduction
17	is superior to bedside filtration, and there is no 

18	controversy about that.  It eliminates much of the 
19	inconsistency that accompanies a bedside procedure, and also 
20	it eliminates the often--the clinically very significant, 

21	although relatively infrequent, consequence of precipitous
22	hypotension that has been associated with bedside 
23	filtration. 
24	          In addition to that, the potential to virtually 
25	eliminate febrile reaction is well recognized through 

			69 1	pre-storage leukocyte reduction, but no necessarily by
	2	bedside filtration.  The potential to reduce CMV 
	3	transmission, perhaps comparable to the level of CMV 
	4	seronegative units is clearly recognized.  The potential to 
	5	reduce HLA alloimmunization is clearly recognized. 
	6		And let me skip down to the bottom, with the
	7	orange print, to further argue in favor of using leukocyte 
	8	reduced products whenever possible. 
	9		Although arguments against leukocyte reduction as 
10	a routine use has pointed out that not every patient 

11	benefits from leukocyte reduced blood, and on a cost
12	consideration, this should be reserved for only those 
13	patients that are recognized to be beneficiaries, the 

14	following arguments can still be made.  Why should patients 
15	suffer through several transfusion reactions before being 
16	recognized as a candidate?  Second question:  HLA
17	alloimmunization may not necessarily be important for 
18	current patient management, however you never know what's 
19	going to happen to that patient in the future.  He may 
20	receive a transplant in the future.  So we should probably 
21	try to minimize that for all patients.
22		Also, even if everything works out perfectly, in 

23	terms of recognition, there are medical and clerical errors. 
24	A physician may order leukocyte reduced blood, yet a 
25	leukocyte un-reduced blood may be sent to the floor.  A 

		70 1	patient may not recognize the need for leukocyte reduced
	2	blood when it's clearly indicated, and not prescribe it.  So 
	3	there are errors that can be eliminated by routine use. 
	4	          And, lastly, there are a whole slew of indications 
	5	that argue in favor of routine use, and although they remain 
	6	controversial at present, we might consider those as a
	7	precautionary measure, even for these controversial 
	8	indications.  And let's just quickly go through that in the 
	9	middle part of the slide.  And those are: transfusion 

10	associated immunosuppression--a very important effect, 
11	almost impossible to demonstrate through clinical trial, but
12	a very important effect; red blood cell and storage 

13	lesion--a very important effect in terms of product 
14	manufacturing and product shelf life; bacterial growth 
15	during product storage--although not clearly the sole answer 
16	to the problem of bacterial contamination, perhaps a partial
17	answer; leukocyte-induced viral reactivation--another 
18	important consideration; as is transfusion-related acute 
19	lung injury--re-perfusion injury after cardio-pulmonary 
20	by-pass procedures; and even the theoretical transmission of 
21	CJD and variant CJD.  TSE advisory committee found the data
22	is insufficient.  The advisory committee did not conclude 

23	that it is ineffective.  It simply found that data was 
24	insufficient to recognize effectiveness at this point. 
25	          Next slide. 

			71 1		Are there any drawbacks, other than cost, of
	2	leukocyte reduction?  There are, but those are 
	3	filter-specific--device specific.  These are reactions that 
	4	are caused by filter failures, and provided that there is 
	5	enough scrutiny at the device manufacturing level, these can 
	6	be avoided. So far, two reactions have been reported, and
	7	this is the red-eye reaction, I think most everyone in the 
	8	audience is familiar with.  There's been more recent reports 
	9	of severe back pain associated with the use of certain 

10	filters, and the circumstances around that is even less 
11	clear than the red-eye, but nonetheless recognized as a
12	potential complication of filter failure. 
13		But even with these failures, the numbers are 
14	small, and the problems were readily controlled by 
15	withdrawing particular lots of filters. 

16		So, in terms of FDA's current thinking on the use
17	of leukocyte reduced blood components, they recognize the 
18	advances in scientific understanding with respect to 
19	leukocytes in transfusion medicine.   The indications for 
20	leukocyte reduced blood products are growing all the time.  
21	And whether or not it's effective in reducing variant CJD
22	really remains unresolved at this point. 
23		With respect to reimbursement, we recognize this 
24	as the only, but very significant concern, and this problem 
25	is being addressed at the Department level, with the PHS 

			72 1	advisory committee as the focal point.  Of course the key
	2	player is our sister agency of Health Care Financing 
	3	Administration.  But these efforts are aimed at minimizing 
	4	the potential adverse impact on transfusion safety, if 
	5	routine use were to be implemented without thorough 
	6	investigation.
	7		So the Agency continues to recognize both 
	8	leukocyte and non-leukocyte reduced products, however the 
	9	agency supports the use of leukocyte reduced products 
10	whenever feasible. 
11		You might ask when will leukocyte reduction become
12	a manufacturing requirement?  Well, I guess there's two ways 
13	that this can become a manufacturing requirement.  The first 
14	is the most obvious, straightforward one, and that is if the 
15	agency moves towards changing the Code of Federal 
16	Regulations to recognize leukocyte reduction as a
17	manufacturing step--as an integral manufacturing step in the 
18	collection of blood; much like testing for HIV.  If that 
19	happens, then it is a regulatory requirement and is directly 
20	enforcement all GMP. 
21		There's an alternate pathway.  The industry might
22	beat FDA to the punch; might decided that there is enough to 
23	go with leukocyte reduced product, and adopt, as a voluntary 
24	industry standard, the use of leukocyte reduction for all 

25	patients.  In that case, it is not a regulatory requirement 

			73 1	per se, however, once it is clearly recognized as the
	2	industry standard, it will influence the agency's review 
	3	decision, in terms of licensing--licensure submissions and 
	4	review. 
	5		You might think, "Why not move directly to 
	6	rule-making?"  Well, of course, there's the cost concern,
	7	and there's the potential for indirect adverse impact on a 

	8	large scale of reducing transfusion safety.  And, much as a 
	9	physician is taught not to do harm before that physician 
10	intervenes in the management of a patient, I think the same 
11	might be true for regulatory actions: do not over-regulate
12	when you don't have to, unless you're clear that the 
13	regulatory action will be beneficial. 
14		So that's sort of where things are.  And I guess 
15	at this point I will try to entertain some questions. 
16		DR. HOLLINGER:  Thank you, Dr. Lee, for this--what

17	I think is a well thought out and presented--the issues that 
18	are available.  Appreciate that. 
19		Yes, there are some questions.  There are some 
20	groups that want to speak to this issue from the public, but 
21	let's--what I'd like to do, maybe have them just talk just a
22	minute, and then we'll come back to that. 

23		          OPEN PUBLIC HEARING 
24		DR. HOLLINGER:  There are two groups that have 
25	asked, again, to speak.  One, again, is the American Red 

			74 1	Cross--Dr. Stramer, and is Susan--I'm sorry, Dr.
	2	Chambers--Dr. Linda Chambers from the American Red Cross. 
	3		DR. CHAMBERS:  Since I'm relatively new to these 
	4	meetings, I will read my first paragraph, but beg your 
	5	indulgence. 
	6		Thanks for the opportunity to speak regarding
	7	leukoreduction of red cells.  I'm Dr. Linda Chambers, the 
	8	Senior Medical Officer for the American Red Cross Biomedical 
	9	Headquarters.  Red Cross, as you know, collects over 6 

10	million units of blood from volunteers each year in the 
11	United States, and is responsible for almost half of the
12	nation's blood supply. 
13		In September '98, when BPAC voted in favor of 

14	leukoreduction of all cellular transfusion components, the 
15	Red Cross received a powerful message and took this as a 
16	unanimous recommendation to convert our manufacturing

17	processes to universal pre-storage leukoreduction.  We began 
18	this process as soon as it was feasible for two specific 
19	reasons.  First, Red Cross is a very large organization; we 
20	had to convert 36 regions, with physically different 
21	manufacturing sites.  In some instances, facilities had to
22	be remodeled and extensive new equipment designed and 
23	purchased.  We also needed to develop new procedures and 
24	conduct training for thousands of staff involved. 
25		More importantly, we regarded it as an ethical 

			75 1	responsibility to the patients we serve to help move

	2	transfusion practice as quickly as possible to  this 
	3	emerging standard of care.  In November of 1998, during our 
	4	initial assessment of the implications of the BPAC vote, 

	5	about 13 percent of red cells Red Cross distributed were 
	6	leukocyte reduced at the request of the ordering hospital. 
	7	Six months later, and before Red Cross leukoreduction 
	8	initiatives had been implement, that number had risen to 25 
	9	percent; in other words, the requests for leukocyte reduced 
10	products were increasing, even before our conversion efforts 
11	were fully underway.  At the end of April 2000,
12	approximately 56 percent of red cells distributed were 
13	leukoreduced. 
14		Red Cross supports BPAC's 1998 decision and 
15	believes we've taken the right steps to increase  the use of 
16	leukoreduced products.  We support FDA's intentions to issue
17	guidance and regulations on this matter for several reasons. 
18		First, a specific statement describing 
19	leukoreduction as a requirement would enhance the public's 
20	confidence in FDA.  A document and related regulations would 
21	provide strong reassurance that the agency is maintaining
22	their vigilance over the safety of the blood supply and the 
23	purity of these products. 
24		Second, a guidance is needed to help ensure that 
25	the product being manufactured meets quality expectations.  

			76 1	An FDA directive will help guide standardization across all
	2	manufacturing process sites in the quality control 
	3	procedures, and establish appropriate expectations for FDA 

	4	inspections.  All blood programs will have a more uniform 
	5	understanding of the measures that must accompany 
	6	appropriate manufacturing practices and can plan
	7	accordingly. 
	8		It would be helpful to Red Cross to have 
	9	clarification of FDA's intentions and expectations.  As you 
10	can imagine, implementing universal leukoreduction in our 
11	manufacturing practice is a resource intensive effort.  The
12	longer FDA takes to issue its proposal, the more resources 

13	we expend in a direction we believe is appropriate, but that 
14	may not be exactly as expected by FDA. 
15		And finally, an FDA guidance document and related 
16	regulations will serve to clarify for customers the
17	deadlines and other specifications around which 
18	leukoreduction is being performed. 
19		Thus, we ask that the Committee affirm its 
20	recommendation for leukoreduction of all cellular components 
21	for all patients, and we encourage FDA to take specific
22	regulatory action by issuing related guidances and rules as 
23	expeditiously as possible. 
24		Thank you for the opportunity to speak, and I'll 
25	be happy to answer any questions. 

			77 1		DR. HOLLINGER:  Thank you.
	2		Yes--Dr. Schmidt? 
	3		DR. SCHMIDT:  Question--is this--in monitoring the 
	4	quality of the units, the Red Cross sacrifice whole units to 
	5	do the testing, or does it get alloquots from the units to 
	6	do their testing?
	7		DR. CHAMBERS:  I don't know.  Is there someone 
	8	here from Red Cross who can answer that question? 
	9		I believe it's alloquots. 
10		DR. LEE:  Yes, I'm not Red Cross, but I know that 
11	it's simply alloquots.  There are sterile tubings that are

12	already attached to the blood units, and you simply express 
13	to the blood in the tubing into the unit, mix the unit up, 
14	and let it fill the tubing back up.  Then you take the 
15	tubing off--all sterilely.  So the product integrity is not 
16	breached when you take a sample off of it.
17		DR. HOLLINGER:  Thank you. 
18		The next person who would like to speak in the 

19	public portion of this is Dr. Merlyn Sayers, for America's 
20	Blood Centers. 
21		DR. SAYERS:  Thanks, William.
22		America's Blood Centers' position on universal 
23	leukoreduction is simple: if implementation is required, 
24	then ABC is going to participate and comply. 
25		ABC members provide something like one-half of 

		78 1	this nation's blood supply, and the membership agrees that
	2	many patients might benefit from leukocyte reduced products.  
	3	And it's even possible that patient outcomes from universal 

	4	leukoreduction, and those that--we've heard of them from Dr. 
	5	Lee--those outcomes might even offset some of the costs of 

	6	universal leukoreduction, and those costs are estimated at
	7	somewhere upwards of $500 million.  Obviously that offset 
	8	would take some period of time to achieve. 

	9	          Nonetheless, the data showing offsetting benefits 
10	are inconclusive, and for that reason there's no consensus 
11	regarding the value of universal leukoreduction among the

12	membership of ABC.  Many members still consider the 
13	selection of components for specific indications to 

14	constitute the practice of medicine, and thus outside the 
15	purview of the FDA. 
16	          If the FDA does go forward with a recommendation
17	for universal leukoreduction, ABC has several implementation 
18	concerns.  Firstly, the issue of reimbursement.  The major 
19	impediment to implementation of universal leukoreduction is 
20	the delay in reimbursement adjustments for Medicare and 
21	Medicaid, and they pay for over half of all blood
22	transfusions.  Hospitals tell us loudly and clearly that 

23	they cannot wait two or more years for reimbursements to 
24	catch up with practice, and the time between an FDA 
25	recommendation and adjustment of reimbursement has to be 

			79 1	shortened.  The Health Care Financing Administration has the
	2	authority to do this.  Unless a public health emergency 
	3	exists, FDA must coordinate the timing of its 
	4	recommendations with increased reimbursement from HCFA. 
	5		New recommendations for blood safety should, then, 
	6	have two components: an FDA recommendation for
	7	implementation, at the same time as a HCFA approach for 
	8	reimbursement, and ABC believes that a recommendation for 

	9	universal leukoreduction should be the subject of a joint 
10	message from the Health Care Financing Administration and 
11	the FDA.
12		Then there's the concern about the implementation 
13	period.  While universal leukoreduction does have some 
14	patient benefits, it is not a compelling public health 
15	concern.  And in addition to the reimbursement 
16	considerations, ABC is concerned that an FDA recommendation
17	concerning universal leukoreduction does have some 
18	impediments.  For example, there already are spot shortages 
19	of filters, and a short implementation period is going to 

20	aggravate those shortages.  Also, the logistics of providing 
21	filtered platelets from whole blood units have not yet
22	worked out, and a short implementation period may create 

23	serious platelet shortages because random donor platelets 
24	would not be available. 
25		Taking all this into consideration, ABC believes 

			80 1	that any recommendation for universal leukoreduction should

	2	allow sufficient time for these issues to be addressed both 
	3	nationally and locally. 
	4		And then, from a logistical point of view, any 

	5	recommendation from the FDA should allow blood centers to 
	6	design the implementation criteria that best serve the needs
	7	of patients in their community, and allow emerging knowledge 
	8	to be quickly incorporated into current practice.  In simple 
	9	terms, ABC membership asks that any recommendation from FDA 
10	specify the goals and standards, but leaves implementation 
11	criteria to be worked out between filter vendors, blood
12	centers and  hospitals. 
13		And, finally, FDA's recommendation must be 
14	published as formal guidance or as a regulation.  Anything 
15	less sends ambiguous statements to the public, to the blood 
16	industry, to hospitals and to the health care community; and
17	anything less than formal guidance or regulation will make 
18	it far more difficult for hospitals to obtain proper and 

19	timely reimbursement from third-party payers. 
20		Thanks. 
21		DR. HOLLINGER:  Thank you, Merlyn.
22		Is there anyone else from the public that wishes 
23	to make a statement? 
24		Yes--please.  And state your organization, name. 
25		DR. DUMONT:  I'm Larry Dumont.  I'm with Gambro 

			81 1	BCT, and also a member of the Biomedical Excellence for
	2	Safer Transfusion Committee of the ISBT. 
	3		These comments are not on behalf of either of 
	4	those organizations. 
	5		First, I'd like to congratulate Dr. Lee for his, I 
	6	think, excellent handling of a very complex, difficult
	7	subject.  And I've been working in this area for several 
	8	years, and I believe that his proposal is definitely a step 
	9	in the right direction, and brings some rigor and clarity to 
10	these difficult issues. 
11		A couple comments that I would like the Agency to
12	consider in their final document, whatever that might 
13	be--first of all, in the definition of "pre-storage," where 
14	you mention--"pre-storage leukoreduction should happen 

15	within 24 hours," I think in many cases, that might be 
16	logistically very difficult for some blood centers. And I

17	would suggest that the data available does not support that.  
18	In fact, 48 hours or some number like that might be better. 
19		First of all, there's--certainly in red cells, 
20	there's no significant increase in cytakine production, and 
21	even the studies that have been published in platelets that

22	are held at 22 degrees, there's no significant rise in 
23	cytakine production until after 48 hours. As far as 
24	degranulation or apoptosis in granulocytes, I think there's 
25	very little data on that at all.  So that I would suggest 

			82 1	that time frame be reconsidered.
	2		Secondly, the data presented, as far as quality 
	3	monitoring with respect to sample sizing--actually I've seen 
	4	a lot of those tables before, so they look pretty familiar.  
	5	But I think--I wanted to remind the Committee that this is 
	6	a--what could be termed a "non-parametric" approach, that's
	7	strictly a pass-fail.  And it definitely does have 
	8	application in this arena, but that's driven by one's own 
	9	definition, I think, locally of what a failure is, or their 
10	approach--also driven by the measurement method that a 
11	particular blood center may choose to implement to look at
12	number of white cells.  And while this is definitely a 
13	viable way to go, there are also alternatives that should be 
14	allowed in guidelines, where one would have adequate 

15	measurement method, and they could apply parametric 
16	statistics to the population and still be able to make

17	adequate and viable inferences regarding the distribution of 
18	the product.  And, in fact, if that's the case, then the 

19	numbers that were presented to the Committee this morning 
20	would actually be smaller, and the blood center could then 
21	have a lower burden as far as sampling and ongoing process
22	monitoring. 
23		So, I think those are all the comments I have. 
24		Thank you very much. 
25		DR. HOLLINGER:  Thank you. 

			83 1		Dr. Katz?
	2		DR. KATZ:  Probably this is one I should read the 
	3	boiler plate in the AABB statements, only to point out that 
	4	of the blood banking organizations, AABB is certainly the 
	5	most diverse, and I think that that should be understood 
	6	from the comments I'm going to make.
	7		The AABB appreciates this opportunity to provide 
	8	comments to BPAC.  Universal leukoreduction of blood 
	9	components is a very controversial issue for our membership, 
10	a diverse group, representing not only blood collection 
11	facilities, but hospital transfusion services and
12	individuals and clinicians involved in transfusion medicine. 
13		The Committee should be aware that there is 
14	substantial divergence of very well informed opinion on the 
15	propriety of FDA mandating universal leukoreduction.   This 
16	is based on the perception, after extensive review of the
17	scientific evidence, that there is inadequate scientific 
18	proof that the benefit will be worth the cost; a cost to the 
19	entire population of transfusion recipients.  Viewed in this 
20	light, there are many in AABB who consider the choice of 
21	components to be the practice of medicine and, in some sense
22	then, beyond the purview of FDA. 
23		Others agree that a preponderance of evidence 

24	supports the benefit of universal leukoreduction, even if 
25	that evidence represents diverse studies, often with 

			84 1	conflicting results.
	2		In the end, we believe that opposition to 
	3	universal leukoreduction is rooted in economic concerns.  If 
	4	additional costs, in times of contracting reimbursement were 
	5	not involved, opposition would likely be much more muted.  
	6	We are aware that FDA and its advisory committees are
	7	charged to evaluate safety, efficacy and purity, and that 
	8	strictly economic arguments are beyond their charge. 
	9		Against this background--if, as we perceive--FDA 
10	is not planning to reconsider the medical merits of 
11	universal leukoreduction, we would ask for two things:
12	first, that formal guidance and regulation for 
13	implementation be expedited, so that blood collection 
14	facilities and hospital transfusion services they serve will 
15	have time lines allowing proper planning and budgeting; and 
16	second, that FDA, in cooperation with Blood Safety and
17	Availability Committee and HCFA be explicit about the 
18	medical benefits of universal leukoreduction, so that the 
19	adjustments in reimbursement required to support this effort 
20	are in place before implementation is mandated. 
21		Thank you.
22		DR. HOLLINGER:  Thank you. 
23		Is there anyone--yes, please.  Dr. Sayers? 
24		DR. SAYERS:  Blaine, thanks. 
25		I've come back here and I've taken off my ABC hat 

			85 1	and just speaking as a blood banker.
	2		We've heard of all the potential benefits for 
	3	transfusion recipients, in terms of universal 
	4	leukoreduction, but I would like a word of caution to be 
	5	added to the record concerning what happens at the donor end 
	6	when universal leukoreduction becomes mandated.
	7		This is going to be an intervention which might 

	8	well be in place well before we understand all the various 
	9	circumstances which influence whether universal 
10	leukoreduction is consistently effective or not.  And, in 
11	particular, I'm referring to how universal leukoreduction is
12	going to be managed by those blood programs which have a 
13	significant percentage of their donor population that are 
14	African American.  Something like 6 to 8 percent of African 
15	Americans are sickle trait-positive, and we know there is 
16	overwhelming evidence that these units either do not filter,
17	they filter inconsistently, or they appear to filter but on 
18	quality control analysis, do not, apparently, have their 
19	leukocytes removed. 

20		This is an important donor issue.  It superimposes 
21	an obligatory deferral of another group of donors against
22	the background of an already compromised national inventory.  
23	For those blood programs that have a significant of African 
24	American donors--and, for some of them, it is upwards of 50 
25	percent--the local blood supply is going to be dramatically 

			86 1	compromised.
	2		And also, universal leukoreduction, at least as 
	3	far as the African American population is concerned, will be 
	4	a deterrent to identifying exactly those rare donors that 
	5	are required for the maintenance of patients who are in 
	6	sickle cell transfusion programs, and also those individuals
	7	who are needing marrow transplants against a background of 
	8	difficulties in identifying individuals of similar ethnicity 
	9	who might have compatible marrows. 
10		So these comments aren't in any way meant to 
11	detract from the value of universal leukoreduction for
12	certain patients, but just a caution that the effect on the 
13	donor population has also to be taken into account. 
14		DR. HOLLINGER:  Thank you, Merlyn. 
15		Yes--Kay Gregory? 
16		DR. GREGORY:  Thank you, Blaine.
17		I'd like to say just a few words on behalf of a 
18	group that you have not heard from before in this particular 
19	committee, and that's a group that is known as the Coalition 
20	for Blood Safety.  This is a group that is comprised of the 
21	American Association, including the American Red Cross and
22	the Department of Defense, ABC--America's Blood Centers--and 
23	the American Blood Resource Association--or ABRA. 
24		This group was formed explicitly at the request of 
25	the FDA to work originally on what was known as regulatory 

			87 1	reform, and we decided perhaps it would be better to change
	2	our name and be a little broader. 
	3		I'd like to comment specifically on the licensing 
	4	provisions that Dr. Lee spoke about, primarily because I 
	5	believe this may be the first time that we've heard them say 
	6	that whatever they're going to do will not necessarily be a
	7	prior approval supplement.  And we think that's definitely a 
	8	step forward. 
	9		Since we hadn't heard the proposal before, we 
10	can't comment any more specifically, but it does appear that 
11	this is a step in the right direction, and we will be

12	looking at the proposal carefully when it comes out. 
13		DR. HOLLINGER:  Thank you. 
14		Yes, please.  State your name and association. 
15		DR. GAMMOND:  Rich Gammond, South Florida Blood 
16	Banks.  I just have a couple brief comments here.
17		One, at our blood bank we feel that leukocyte 

18	reduced products are medically superior products and should 
19	be considered a standard of care.  In that regard, we would 
20	be in support of an FDA document requiring universal 

21	leukocyte reduction, and we also want to emphasize that
22	reimbursement issues do need to be addressed. 
23		Thank you. 
24		DR. HOLLINGER:  Anyone else? 
25		So we're going to close the public hearing for 

			88 1	right now, and we'll open it up to Committee members for
	2	discussion. 
	3		       OPEN COMMITTEE DISCUSSION 

	4		DR. HOLLINGER:  Yes--Dr. Simon? 
	5		DR. SIMON:  I think--I'd just like to make sure I 
	6	understand correctly--from Dr. Lee's presentation, it would
	7	appear that as of this point, FDA is saying that they are 

	8	not--I don't know what the right term is--they have not 
	9	determined that they are going to do any rulemaking to 

10	require universal leukoreduction, but rather, I would use 
11	the term "let it happen"--all the medical community to move
12	in that direction, and in the interim, sort of tighten up 

13	the quality control issues, and maybe loosen up, or at least 
14	facilitate the licensing issues. 
15		Is that a correct interpretation? 
16		DR. EPSTEIN:  Not exactly.  What Dr. Lee has said
17	is that the proposed guidance document would not contain an 
18	explicit recommendation for universal or routine 
19	leukoreduction.  However, it remains FDA's current thinking 
20	that we would move forward with appropriate rulemaking.  The 
21	only scenario in which that might be unnecessary, is if

22	universal or routine leukoreduction becomes a voluntary 
23	industry standard; FDA could make a determination on that 
24	basis, that it's now current good manufacturing practice, 

25	and regard it as enforceable under existing GMP regulations. 

			89 1		But if it remains the case that only a part of the
	2	industry adopts it, and not the predominance of the 
	3	industry, then we would not be able to make that 
	4	determination, as GMP. 
	5		So, what you're hearing is that we still think 
	6	that it is an advancement in the safety and the purity of
	7	the products.  We are seeking  to facilitate centers' 
	8	ability to implement now voluntarily, both by clarifying the 
	9	quality control standard expected by the FDA For products 

10	bearing those labels as leukoreduced, and by facilitating 
11	the approvals mechanism.  We will be encouraging voluntary

12	implementation by recommending that it be performed whenever 
13	feasible, recognizing that there are implementation 
14	concerns. 
15		So, over time, one of two things will happen, and 
16	I don't know which will be first.  Either there will be a
17	continued industry voluntary implementation, and we may 
18	determine that it's enforceable as a product standard under 
19	GMP, or we will, in the end create a regulatory requirement 
20	through rulemaking.  But that's not a rapid process. 
21		So the bottom line in what I'm saying is, that for
22	legal reasons we do not believe that we can simply create a 
23	mandate through guidance.  As you know, guidance, in its own 
24	right, is not binding on the industry or the Agency.  

25	Guidance is guidance; it expresses current thinking and 

			90 1	interpretations and expectations of the Agency with regard
	2	to existing regulation. 
	3		So, we think we can continue to make progress in 
	4	guidance.  We certainly are expressing the view that we 
	5	consider leukoreduced products to be superior from the 
	6	standpoints of purity and safety.  We're seeking to
	7	facilitate continued expanded use of routine leukoreduction, 
	8	but that process, in and of itself will not create a 
	9	requirement.  But we remain committed to developing such a 
10	requirement. 
11		Is that clear enough?
12		DR. HOLLINGER:  Dr. Schmidt? 
13		DR. SCHMIDT:  A couple of comments, and then sort 
14	of a question. 
15		The disadvantages of leukoreduction listed did not 
16	include the reduction in potency.  If up to 85 percent of
17	the red cells can be lost, that means that-- 
18		DR. HOLLINGER:  Not up to 85 percent can be lost. 
19		DR. SCHMIDT:  I'm sorry--if only up to 15 percent 
20	can be lost, that means that 15 percent of the blood, 
21	potentially down the drain, and the patient who would
22	ordinarily have six exposures in transfusion to red cells 
23	would have seven exposures. 
24		Another comment on Dr. Lee's excellent analysis is 
25	that there is something--quite a few things built on the 

			91 1	blood center that collects 400 units a month, and I think

	2	that's totally unrealistic.  I would guess there are not 
	3	very many blood centers that only collect 5,000 a year at 
	4	the present time. 

	5		But a larger comment is this:  When we're talking 
	6	about the industry, I'm not quite sure if that needs a
	7	definition, but there are the people who collect blood, and 
	8	the people who transfuse blood, and since the FDA has 
	9	requirements for the transfusers, I presume they're part of 
10	the industry. 
11		Now, the statements by the Red Cross and American
12	Blood Centers, who are the blood collectors, always sort of 
13	remind me of architects.  Architects win prizes, but they 
14	win them at the expense of their clients.  It doesn't cost 
15	the architect anything to do this wonderful building and 

16	design it, because somebody else pays for it.  And when we
17	get into the other part of what I think you consider the 
18	industry, for which Dr. Katz has mentioned, doesn't the 

19	regulation--doesn't the attitude of the FDA have something 
20	to do with that medical transfusion end, which is not just 
21	concerned with the manufacturing, but the usage.
22		DR. HOLLINGER:  Yes--one of the architects are 
23	going to-- 
24		[Laughter.] 
25		DR. EPSTEIN:  Well, yes, you're right, Paul, but, 

		92 1	you know, you're talking about who pays the cost, and, as
	2	you know, the FDA makes product decisions related to safety 
	3	and efficacy independent of cost.  That's why we separated 
	4	the cost issue from the deliberations in September '98.  We 
	5	feel that, you know, given a nearly unanimous recommendation 
	6	of the Committee--13 in favor, three abstentions--that the
	7	benefits outweighed the risks of universal leukoreduction; 
	8	that independent of cost there was a fairly clear consensus. 
	9	          Now, recognized, however, that cost was a daunting 
10	implementation issue, and that's the real reason that we've 
11	not moved forward more quickly.  You know, everyone is
12	asking us: "Please consider the reimbursement issue before 
13	you create any requirements."  Well, that's what we've been 
14	doing.  It's just that we can't do it directly as FDA.  We 
15	have partners in the Public Health Service.  We brought the 
16	issue to the attention of the Department has been working
17	with Health Care Financing Administration.  Progress was 
18	made in creating a new fee structure for the unit 
19	administered in the out-patient setting.  The problem is 
20	that Health Care Financing Administration is fearful that if 
21	they start making DRG exceptions for in-patient
22	reimbursement, that there will just be, you know, a 
23	watershed of requests for exemption. 
24	          And it's the current view of HCFA--and, I guess, 
25	shared by the Department--that if that part of it is to be 

			93 1	fixed directly, through regulation, that there should be
	2	some sentiment expressed by the Congress about creating that 
	3	exemption. 
	4		So that's kind of where the issue is. 
	5		Now, what we see is that now that there has been a 
	6	fee schedule established for the out-patient unit, it is at

	7	least possible for blood centers to argue to hospitals--and 
	8	I would hope successfully--that the real cost of providing 
	9	an in-patient unit is no less.  Because the argument that 
10	HCFA has made repeatedly is that the problem is not lack of 
11	funds; it's that the hospitals, which HCFA believes receive

12	adequate funds, simply are not electing to spend them on the 
13	blood unit.  In other words, they're not accepting that 
14	that's the cost of what a filtered unit, or a NAT-screened 
15	unit really is. 
16		So we think that not all these problems belong to
17	the FDA to be solved; that there is more advocacy needed 
18	directly with HCFA, and potentially even with Congress. 
19		Where FDA stands is, that we understand that the 
20	cost issue needs to be resolved before you could comply with 
21	a mandate.  We also have the problem that our attorneys tell
22	us, that even if we were to make a recommendation, but put 
23	some future date of implementation, that that would also 

24	have the force of rulemaking through guidance, and we 
25	shouldn't do that. 

			94 1		This is different than other issues, because the

	2	current products are defined in the regulations, and the 
	3	notion is that if we somehow make obsolete the products 
	4	defined in the regulations, aren't we doing rulemaking 

	5	through guidance?  And, of course, under the Administrative 
	6	Procedures Act, we can't do rulemaking solely through
	7	guidance. 
	8		So we simply have the convergence of the legal 

	9	constrains on how far FDA can go in guidance; the problem 
10	that, you know, reimbursement won't be solved by FDA, but 
11	needs to be solved; and then the issue of time-frame for
12	creating a  regulatory requirement.  And so we're simply 
13	moving, you know--lurching forward at an uneven pace on 
14	these three fronts. 

15		But we are moving on all three fronts, and I think 
16	that that's the major take-home message; that FDA remains
17	convinced at a scientific level, independent of cost, that 
18	universal leukoreduction is a general improvement in product 
19	purity and safety for the non-leukocyte-dependent products.  
20	We remain committed to facilitating the expanded use of 

21	leukoreduction on a voluntary level, and have taken the
22	actions that Dr. Lee--or the pending actions that Dr. Lee 
23	has described, and we are cooperating with the Department 
24	and other health care agencies to see if the reimbursement 
25	problem can't be solved within a reasonable implementation 

			95 1	time-frame.
	2		And I would suggest that progress is being made on 
	3	all three fronts.  It's just that everybody is trying to 
	4	envision the end-point, and everybody recognizes we're not 
	5	there yet.  And that's true.  But it's not for lack of 

	6	awareness that these things play off against each other.
	7		And I have to say that I think one of the 
	8	difficulties has been that a large number of very highly 
	9	respected experts in the field of transfusion medicine have 
10	either written to the FDA or published articles, or made 
11	public statements, in opposition to universal leukoreduction
12	on scientific grounds.  And yet there's the nagging concern 
13	that many of the same people are the ones who are in the 
14	economic bind.  And the thing that's unclear is: what would 
15	they be saying if there weren't the same economic issue? 

16		And so I think it's quite significant, what we
17	heard from Dr. Katz, that it's at least the view of the 

18	AABB, as an umbrella organization, that if the cost issues 
19	could be put aside, many of the arguments that we are 
20	hearing would be greatly muted.  And, you know, again this 
21	is one of the numerous factors that we have to deal with. 

22	We understand that people can't ignore the cost problem, but 
23	the extent to which it's coloring the scientific 
24	arguments--or purported scientific arguments--is confusing. 
25		Again, when we brought the question, independent 

			96 1	of cost to, you know, a dispassionate, non-conflicted
	2	committee, we got a very clear answer.  And I'm not sure 

	3	that it was a wrong answer.  I don't believe that it was. 
	4		And I can tell you that in private conversation, 
	5	even some of the signatories of the published letters 

	6	decrying requirements for universal leukoreduction have
	7	stated to me that if the reimbursement problem were solved, 
	8	you know, that wouldn't be their position; they'd do it in a 
	9	flash. 
10		So, you know, I mean, I guess that that's anecdote 
11	and it's, you know, sort of not evidence, but it does tend
12	to convince me that we have at least muddied the debate.  
13	But the bottom line is that the FDA is not seeking to impose 
14	this in any way that could not be implemented at a practical 
15	level. 
16		DR. HOLLINGER:  Yes, Dr. Linden, and then I'll
17	come back to the military. 
18		DR. LINDEN:  I'm concerned about the quality 
19	control procedures that you're talking about, and I'm hoping 
20	someone from the Agency can comment further, as they would 
21	apply to small facilities.
22		Dr. Lee talked about "small centers," and Dr. 
23	Schmidt, you know, mentioned "blood centers," but, in fact, 
24	a significant amount of blood is collected by 
25	hospitals--it's over 10 percent in New York State. 

			97 1		And it seems that if there is a burden, that
	2	hospitals collecting only a few thousand, perhaps even a few 
	3	hundred, units had to quality control a significant portion, 
	4	or perhaps even all of their units, versus a large blood 
	5	center that might do a tiny, tiny fraction, there is really 
	6	going to be a burden that would be a tremendous disincentive
	7	for those hospitals to collect their own blood. 
	8		So I'm--I guess I'm concerned about this approach 
	9	to the quality control.  And we did hear from one of the 

10	public commenters that there might be other approaches, so 
11	I'm just wondering about the Agency's thoughts on this
12	issue. 
13		DR. LEE:  Yes, that's quite true.  And we have 
14	thought carefully about how we might impose only an 
15	equivalent burden on small centers--hospitals--and still 
16	come away with the same level of assurance that your process
17	is in control.  And we haven't really been able to come up 
18	with a solution any better than what I just presented this 
19	morning. 
20		One approach might be to reduce the QC burden 
21	based on track record.  Even though initially you might go
22	with a fairly high burden of QC testing if, over time--say, 
23	a period of two years or so--that it's clear that your 

24	process remains under control, perhaps that level can be 
25	diminished.  And from a statistical rigorous standpoint, I'm 

					98 1	not sure exactly how that can be justified, but that's to be
	2	further debated.  But I think there is room for using track 
	3	record as evidence for perhaps diminishing the burden. 
	4		DR. HOLLINGER:  John? 
	5		DR. BOYLE:  Just a question on the same issue, and 
	6	that is: I was sort of surprised by your sample sizes for
	7	the small facilities.  It didn't look like you were using a 
	8	finite-population correction factor in the selection of 
	9	those sample sizes. 
10		DR. LEE:  Actually, I have. 
11		DR. BOYLE:  You have?
12		DR. LEE:  Yes--the initial chart, where I pointed 
13	out the confidence level and the sensitivity, that did not, 
14	and that was just to illustrate a point.  But the subsequent 
15	chart of 60 units as the upper limit for large centers 

16	making 250 units or more, and then the numbers that are
17	smaller, for centers that are making a smaller amount of 
18	units, those numbers have been adjusted for that. 

19		DR. BOYLE:  Well, what I don't understand is, with 
20	the smallest unit you're basically requiring the full 
21	population.
22		DR. LEE:  Right. 
23		DR. BOYLE:  The question is: why?  Because a 
24	sample is a sample.  You don't need the full population to 
25	be able to detect the level that you're talking about, 

				99 1	unless I didn't read this stuff correctly--which is

	2	possible.   But it seems like you should be looking 
	3	at--there seems to be ways around those smaller 
	4	centers--there's no reason why you have to do 100 percent 
	5	quality control to be able to identify a process failure. 
	6		DR. LEE:  That goes with the number of signals
	7	that you're going to get.  I mean, if you're making only, 
	8	say--let's say you're making 20 units.  That's all you're 

	9	making.  That means if you operate very close to the process 
10	requirement of more than 95 percent units being acceptable, 
11	then that means you're going to only have one unit.  The
12	chances of you picking up that one unit alone, it's pretty 
13	slim, unless you test every one of them.  That remains a 

14	problem. 
15		DR. HOLLINGER:  Yes, Dr. Linden. 
16		DR. LINDEN:  Yes, if I could just ask a follow-up
17	question: you're talking about lowering the acceptable 

18	limit--right?--to 1 x	1.0 x 106 instead of 5x1.0 x 106? 
19		So--and I think that's largely because it's 

20	achievable, more so than the scientific data have shown that 
21	that's absolutely necessary--at least we haven't seen those
22	data today, at least-- 
23		DR. LEE:  Yes, it's-- 
24		DR. LINDEN:  --to know where that figure came 
25	from. 

				100 1		So, couldn't there be some flexibility? I mean
	2	5x1.0 x 106 has been okay all this time. 
	3		DR. HOLLINGER:  The Europeans use one--less that 
	4	1x1.0 x 106. 
	5		DR. LEE:  That's true.  I mean, I don't know, from 
	6	a medical standpoint, what 1 versus 5 means, in terms of the
	7	benefits that you derive from increased product purity. 
	8		We can remain at 5x1.0 x 106, but the Europeans 

	9	have gone forward with 1.0, and there is no reason for not 
10	doing that, because that's readily achievable. 
11		DR. LINDEN:  Right--yes, I mean, I'm not saying
12	that I don't think 1x1.0 x 106 is appropriate, I'm just 

13	suggesting that there may be, I guess, a gradation of ones 
14	that are close that--I mean, clearly you need to detect ones 
15	that are unsatisfactory and that there's a real problem in 
16	your system.  But if you have only minor deviations, so
17	that, well, maybe one comes out to be 2x1.0 x 106, that may 
18	not be quite such a concern.  And this has, again, to do 

19	with sample size, and what type of deviations you're going 
20	to be picking up. 
21		DR. LEE:  So you're referring back to the quality
22	control burden. 
23		DR. LINDEN:  Yes, yes. 
24		DR. LEE:  For instance, if you picked up an 
25	unacceptable unit, but that's between 1 and 5-- 

					101 1		DR. LINDEN:  Exactly.
	2		DR. LEE:  --then you might kind of--I see.  That's 
	3	another approach to perhaps diminishing the quality control 
	4	burden. 
	5		DR. LINDEN:  Yes, I may not have been clear 
	6	with--yes, that's what I meant.
	7		DR. LEE:  I see. 
	8		DR. HOLLINGER:  Yes--Marion.  Dr. Koerper? 
	9		DR. KOERPER:  Just a point of clarification with 
10	all of your calculations. 
11		If you're talking about a center producing 400
12	units, are you talking about 400 units a month, or 400 units 
13	a year? 
14		DR. LEE:  That ties in with the concept of 
15	manufacturing period. 
16		DR. KOERPER:  Exactly.
17		DR. LEE:  The current recommendations--the 1996 
18	memorandum--that are currently in effect today, that goes on 
19	a monthly basis; number of units per month.  So four units 
20	per month, or 1 percent of the units produced in that month. 
21		DR. KOERPER:  No, what I'm going by is--you were

22	saying if a center produces more than 250 units, they only 
23	have to test 60 units. 
24		DR. LEE:  Right. 
25		DR. KOERPER:  Is that "more than 250 units" a 

					102 1	month or a year?
	2		DR. LEE:  And as I've described this morning, I 
	3	left some room for facility-specific decision.  You can 
	4	define it as a month if you choose to, but you can define it 
	5	as three months, if that will suit your QC burden better.  
	6	But it cannot be any longer than a month.  There has to be
	7	some-- 
	8		DR. KOERPER:  It can't be longer than three 
	9	months. 
10		DR. LEE:  I'm sorry--any longer than three months, 
11	because there has to be an upper limit.

12		DR. KOERPER:  Right.  Exactly. 
13		DR. LEE:  If there is no upper limit, well you 
14	might say, "I look at it every year." 
15		DR. KOERPER:  Right.  That was the point I was 
16	trying to pull out, because that was what I was having
17	difficulty with. 
18		So, a center could say, "We produce 250 units a 
19	month--in three months--"-- 

20		DR. LEE:  Right. 
21		DR. KOERPER:  --"--therefore we only have to test
22	60." 
23		DR. LEE:  In that three-month period. 
24		DR. KOERPER:  In the three-month period. 
25		DR. LEE:  Right.  Of course a disadvantage of that 

					103 1	is that you are question-mark for that three-month period. 

	2	Until you close the loop of all of you're testing, you're 
	3	not exactly sure that you are at the 95 percent-- 
	4		DR. KOERPER:  Right. 
	5		DR. LEE:  --confidence level. 
	6		DR. KOERPER:  But on the other hand, you have to
	7	test at least one unit a week. 
	8		DR. LEE:  Right. 
	9		DR. KOERPER:  So-- 
10		DR. LEE:  That allows you to detect an 
11	unacceptable process earlier--

12		DR. KOERPER:  Right. 
13		DR. LEE:  --but in no way does it assure an 
14	unacceptable process any earlier, until you finish-- 
15		DR. KOERPER:  Right. 
16		DR. LEE:  --the entire period.

17		DR. KOERPER:  But on the other hand, this is a 
18	continual, on-going process, because once that three months 
19	is up, then you start the next three months, so you're going 
20	to keep doing your QC every week. 
21		DR. LEE:  That's correct, but--
22		DR. KOERPER:  And-- 
23		DR. LEE:  --it's a matter of product retrieval-- 
24		DR. KOERPER:  --it's a moving target. 
25		DR. LEE:  --it's a matter of product retrieval and 

					104 1	constancy notification.  When you discover an unstable

	2	process, what are the units that are expected by that 
	3	unstable process?  If you define your period short, then you 
	4	have less products to worry about. 
	5		DR. KOERPER:  Right. 
	6		DR. LEE:  If you define it with a long period,
	7	then you have more products to worry about. 
	8		DR. KOERPER:  But if you want to be totally sure, 
	9	then you would have to test every unit. 
10		DR. LEE:  That's correct. 
11		DR. KOERPER:  So I think that you have to
12	compromise with what's reasonable for the blood banks to do.  
13	And I'm thinking specifically of the hospital transfusion 
14	services --		      DR. LEE:  RIght. 
15		DR. KOERPER:  --that are not collecting as huge a 
16	number.  If they can at least aggregate over three months--

17		DR. LEE:  Right. 
18		DR. KOERPER:  --then that might lessen their QC 
19	burden somewhat. 
20		DR. LEE:  Right.  And at this point, we think that 
21	should be an option for small centers--right.

22		DR. HOLLINGER:  Dr. Fitzpatrick? 
23		COL. FITZPATRICK:  May I expand on Dr. Schmidt's 
24	comment for a minute, and ask the FDA to re-think it's 85 
25	percent recovery level? 

					105 1		DR. LEE:  Yes, I was trying to come back to that. 
	2	Go ahead, I don't want to-- 
	3		COL. FITZPATRICK:  If I could do an illustration 

	4	here: if we collect a unit at the top end of the scale--at 
	5	495 ml, with a 38 percent crit, and recover 85 percent, 
	6	we're recovering approximately 160 mls of red cells. If you
	7	recover 80 percent, you're recovering 150 mls of red cells, 
	8	but that's unacceptable.  And if you collect a unit of the 
	9	low end of the scale--at 405, at a 38 percent crit, you're 
10	recovering at 85 per cent 130 mls of red cells, but that's 
11	an acceptable unit.
12		DR. LEE:  Right. 
13		COL. FITZPATRICK:  And that's a disparity. 

14		I would encourage the FDA to act on other comments 
15	that I know they've received from other people to determine 
16	a minimum effective therapeutic does of red cells, and
17	establish that at 150 ml, 130 ml, or a grams of hemoglobin, 
18	and do away with the recovery thought process that is 
19	fraught with error anyway in many centers when you try and 
20	determine recoveries, because there's--depending on your 
21	method, there are difficulties in doing that.
22		And I think it would simplify the process a great 
23	deal. 
24		DR. LEE:  Thank you for the comment. 
25		COL. FITZPATRICK:  And then just another, I wanted 

			106 1	to support Dr. Sayers in his comment on sickle trait, and
	2	perhaps other hemoglobinopathies.  I think that is a 
	3	potential problem for many of us, dependent on our donor 
	4	population, and that prior to this becoming either a 
	5	standard of care or a mandated requirement, we need to be 

	6	able to deal with those donors and utilize them as either
	7	non-leukoreduced or leukoreduced products if an acceptable 
	8	method becomes available. 
	9		DR. HOLLINGER:  Yes, Dr. Ohene-Frempong? 
10		DR. OHENE-FREMPONG:  Yes, I just wanted to react 
11	to the last comment, about the sickle-cell trait donors.
12		Our sickle cell center, which I direct in 
13	Philadelphia, probably has the largest chronic transfusion 
14	program in the country.  We also, in addition, have a very 
15	aggressive partnership program with our local--regional 
16	American Red Cross center to increase African American
17	donors, specifically for our sickle cell disease patients. 
18		We--because we don't use sickle-cell trait blood 
19	for donations for sickle-cell disease patients, all the 

20	African American donors are--their blood, at least, is 
21	screened for sickle-cell trait.  So we know very well the
22	percentage of the donors who have sickle-cell trait. 

23		I just stepped out to check with the blood center. 
24	They have adopted universal leukoreduction now for a couple 
25	of years, and they tell me that they have not, up to this 

			107 1	point, even though they've heard about it, they have never
	2	had to reject any units because of sickle-cell trait 
	3	filtration.  So whatever the technical differences may be in 
	4	different laboratories in the past, it's worth checking.  
	5	But I just checked with them, and they're collecting several 
	6	thousand units from African American donors, and the fat
	7	that somewhere around 8 percent of them also may have 
	8	sickle-cell trait has not been a problem. 
	9		DR. HOLLINGER:  Thank you. 

10		Yes, go ahead, Dr. McCurdy. 
11		DR. McCURDY:  There have been several comments
12	about the potential loss of cells--red cells or 
13	platelets--when you filter those.  The 
14	Institute--NHLBI--supported two studies looking at some of 
15	the effects of leukoreduction.  One of them was the TRAP 
16	study trial to prevent alloimmunization to platelets, and
17	the other one was the VAT study--viral activation by 
18	transfusion. 
19		In both of those studies, they looked very 
20	carefully at the--how many units of red cells or platelets 
21	were given to these recipients, both leukodepleted arm and

22	non-leukodepleted arm, and there was no difference.  So that 
23	regardless of how much you use, this doesn't apparently 

24	filter through--if you'll pardon--filter through to the 
25	clinicians who actually order the transfusions.  They still 

				108 1	give approximately the same number of units, whether they're
	2	leuko-filtered or not. 
	3		DR. SCHMIDT:  I think the usual surgeon still 

	4	thinks he's giving a pint of blood every time he gives a 
	5	unit of red cells-- 

	6		[Laughter.]
	7		DR. SCHMIDT:  --and he calculates that out in the 
	8	quantity of fluids lost and replaced. 
	9		DR. McCURDY:  These were all medical patients.  

10	The VAT trial used patients with end-stage AIDS who required 
11	transfusion, and the TRAPs trial used primarily acute
12	granulocytic leukemia patients.  So they weren't surgeons.  
13	They were hematologists, oncologists. 
14		DR. LEE:  If I could just add a comment.  For red 
15	cells, the recovery--although I've stated 85 percent 
16	recovery--for red cells, the recovery is far higher than
17	that.  In fact, it's close to 99 percent. 
18		For platelets, there is probably more of a loss, 
19	but it's still well below 15 percent. 
20		DR. McCURDY:  Blaine, I have one more comment.  

21	The suggestion was made that we define a unit of red cells
22	as to how many ml of red cells, or something along that 
23	line. 
24		And that might be a reasonable thing to do.  On 

25	the other hand, there have been a number of people who have 

			109 1	made an attempt to define the transfusion trigger--that is,
	2	at what stage should you give a unit of red cells, of 
	3	whatever size, and that's proved to be a very, very 
	4	formidable task.  Nobody has been able to do the kind of 
	5	study that would clearly define at what stage should you 
	6	transfuse a patient with red cells.
	7		DR. LEE:  That question, of course goes--oh, I'm 
	8	sorry.  I'm speaking out of turn. 
	9		That question goes, of course, beyond the problem 
10	of leukocyte reduced.  It's just about blood, in general.  
11	And we could address it, at least in part, through leukocyte
12	reduction by defining the actual red cell content, or 
13	therapeutic cell content rather than recovery.  That's an 
14	option that we could go, as a partial solution to the bigger 
15	problem. 
16		COL. FITZPATRICK:  I'm not suggesting that we
17	standardize a unit of red cells and say "every unit is going 
18	to be 250 ml," but let's set a floor--a minimum level, 

19	knowing that there's going to be a range above that. 
20		DR. LEE:  Yes, with respect to leukocyte 

21	reduction, we could do that.  For instance, you could simply
22	take the weight and the hematocrit or platelet count of a 
23	post-filtered unit, and establish a minimum standard for 

24	that.  That's one alternative--one of many things that 
25	weren't particularly referred to in my talk. 

					110 1		DR. HOLLINGER:  Dr. Lee, is the process--the
	2	pre-storage leukoreduction, is that technician-dependent at 
	3	all, or is it device dependent, so that if you have 
	4	technicians who are doing this, and they change, that one 
	5	would--because it gets back to sort of what Jean was saying 
	6	about quality control. Is it--therefore is it
	7	facility-dependent and device-dependent more than 
	8	technician-dependent? 
	9		DR. LEE:  I'm afraid it is-- 

10		DR. HOLLINGER:  Afraid what is? 
11		DR. LEE:  Technician-dependent.

12		DR. HOLLINGER:  It's technician-dependent.   
13		DR. LEE:  Yes. 
14		DR. HOLLINGER:  Which means that if the technician 
15	changes--if you get a new technician in that's doing it, 
16	then that person needs to be validated in doing the
17	procedure then. 
18		DR. LEE:  That's part of training. 
19		DR. HOLLINGER:  Yes. 
20		DR. LEE:  Staff training. 
21		DR. HOLLINGER:  Ah--yes, Dr. Katz? You had a
22	comment. 
23		DR. KATZ:  I just wanted to give some data 
24	perspective on the sickle cell issue.  What's being seen at 
25	centers that are looking at the problem now is that, 

			111 1	depending on a variety of circumstances, as many of 50
	2	percent of sickle trait units will not go through a filter, 
	3	which is less problematic than the fact that those that do 

	4	go through the filter are not adequately leukoreduced. 
	5		We have no substantial data across the filter 

	6	manufacturers.  We have no substantial data across multiple
	7	centers.  And so it's an issue that's being looked, and 
	8	hopefully in time for the fall meeting so that we have a 
	9	clue. 
10		It doesn't surprise me that the Red Cross might 
11	not have recognized the problem.  The real issue is the
12	units that go through the filter, and when you count them, 
13	they've just got white cells in them. 
14		DR. HOLLINGER:  And when you find -- when you do 
15	quality  control, and you find something that is a 
16	problem--a validation--not a validation problem, but a
17	problem in the quality control, what do you do about the 
18	units that are--I mean, do you assume that only units that 
19	occur after that are going to be a problem, in terms of 
20	filtration?  Do you assume that units which are already in 
21	the facility haven't been used are a problem then, and do
22	you do something about those--or what? 

23		DR. LEE:  Well, that again sort of ties back into 
24	the concept of the manufacturing period.  The way we 
25	envision that working right now is that if you complete your 

			112 1	manufacturing period, and complete your full amount of QC
	2	testing that we require for that period, you've closed that 
	3	period off, and you're okay. 
	4		Let's say you discover an unacceptable unit at 
	5	some point in the middle of a period.  Then all units 
	6	manufactured since that period is subject to some question. 
	7	So for those units, you will have to either directly test 
	8	them, and re-label them properly--you'll have to first find 
	9	out what the process error is, and if you're able to narrow 
10	down the units that are affected by the identified process 
11	error, you may minimize the number of units that you have to
12	directly test. 
13		DR. HOLLINGER:  And should you change testing and 
14	QC based upon getting a new lot--on the basis of a new lot 
15	that comes in from a manufacturer or not? 
16		DR. LEE:   Right now there are no lot release
17	requirements. It's accepted for filters to perform in an 
18	equivalent fashion, and if a lot problem does creep in, that 
19	can only be detected through the quality monitoring process 
20	.  Hopefully, as a part of process investigation you will be 
21	able to narrow your problem down to the lot.  But right now,
22	after your initial validation of your process, you're 
23	strictly relying on your quality control monitoring on an 
24	ongoing basis to detect any problem in the lot. 
25		DR. HOLLINGER:  Because I would think that despite 

			113 1	the fact that there are lot releases, and so on, that are
	2	required, it's been my experienced, at least with 
	3	things--that you should probably test each new lot that your 
	4	getting out, at least in some respects, and not just--unless 
	5	you have a weekly frequency of doing things. 
	6		DR. LEE:  Well, with respect to lot-release
	7	testing, if lot-release testing is to be performed, it 
	8	should probably be performed by the filter manufacturer, and 
	9	not--under current 510(k) clearance mechanism lot release is 
10	not required. 
11		DR. HOLLINGER:  Okay.  Thank you.
12		Dr. Chamberland? 
13		DR. CHAMBERLAND:  That raises the question--and 
14	I'm not sure if FDA is planning to include this in its 
15	guidance document, but what do you do with those units who 
16	fail the filtration process, either up front--meaning, as

17	we've heard, some units just don't go through a filter--or, 
18	let's say in the middle of your three-month manufacturing 
19	period, or at the end of it, you discover that you have had 
20	some QA problem and, in fact, in your inventory there are, 
21	indeed, units that would not meet the required white blood
22	cell reduction level. 
23		In this time of inventory shortages and 
24	whatever--and let's say we move into an arena where, 

25	essentially, it's require to have leukocyte reduced 

			114 1	products, would there be a role for the use of non-leukocyte
	2	reduced if they were so labeled? 
	3		DR. LEE:  Sure.  Non-leukocyte reduced products 

	4	will continue to be available, and you can do one of three 
	5	things on the discovery of an unacceptable process, and 
	6	hopefully you are able to identify the number of units that
	7	were potentially affected by the unacceptable process. 
	8		Either those units have been released to 
	9	consignees and have been transfused, in which the consignee 
10	notification is all we can do; they have been released to 
11	the consignee and remain under the control of the consignee
12	and have not yet be transfused, in which case you can ask 

13	them to send them back; and, thirdly, the units are still in 
14	the control of the blood center, in which case you should 

15	directly test them.  And it's possible to label them as 
16	not-leukocyte reduced--simply label them as just regular
17	blood, because it failed QC testing. 

18		DR. CHAMBERLAND:  So FDA envisions that even if we 
19	carry this to sort of the regulatory step of this--a 
20	requirement for leukocyte filtration, FDA still envisions 
21	that there still would be use, on a day-to-day basis of
22	non-leukocyte reduced units. 
23		DR. LEE:  I think that product should still be 
24	available for physician choice. 
25		DR. CHAMBERLAND:  Okay.  Because I was going to 

			115 1	ask--well, then the next question I had in my mind is,
	2	practically speaking, will there really be--except for these 
	3	instances through QA failures or whatever--really be out 
	4	there available non-leukocyte reduced product if the 
	5	physician chooses to order such.  I mean, those of us who 
	6	sit at the Advisory Committee on Blood Safety and
	7	Availability heard testimony from a blood bank director that 
	8	he was, essentially, at this stage being forced into 
	9	accepting leukocyte reduced product, because that really was 
10	all that his source was sending him.  I think there was some 
11	sense of the concern stemming from some economic
12	considerations, that he wasn't going to get--his hospital 
13	wasn't able or willing to pay for this, and he didn't feel, 
14	at this point in time, that he needed a hundred percent 
15	inventory of leukocyte reduced product. 
16		So I'm just wondering, again, if you carry this
17	out down the road to its natural end--it sounds like the Red 
18	Cross, for example, isn't really going to have non-leukocyte 
19	reduced product available, unless it's through a QA failure 
20	or something like that.  So I'm-- 
21		DR. HOLLINGER:  Yes, Dr. Macik?
22		DR. MACIK:  And actually that was kind of some of 
23	the points that I wanted to get to, and these are more just 
24	comments, being a treater--clinician--predominantly and not 
25	a blood banker. 

			116 1		You know, until this issue came up recently,
	2	leukocyte reduced has not been a big focus issue outside of 
	3	this arena--or blood banking arena--as far as the general 

	4	clinician out there.  And I think if you would go out and 
	5	ask family medicine and various others, you know, "What 
	6	about leukocyte reduced?  Are you going to be in support or
	7	against this?"  I don't think they would know what you were 
	8	talking about.  And who orders the unit of blood?  The unit 
	9	of blood is not ordered by the blood banker, it is ordered 
10	by the physician who is treating a patient. 
11		And so I think there's been a lack of education
12	across the board, and instead--and I don't think it's 
13	entirely inappropriate that the people making the decision 
14	to use this or not use this, or to implement this or not 

15	implement this are--quote--"experts in the field."  But I 
16	think it's kind of being forced on the users without their

17	really even knowing it's coming.  They, however, do feel the 
18	impact--the financial burden--and there is absolutely no way 
19	you can separate out the financial component of this, even 
20	if you're going to say we're going to do it on scientific 

21	method.
22		You know, I don't--there's just no way that you 
23	can separate those two issues.  And I know that we've been 
24	told that we're working on three fronts and we're going to 
25	try to cover that. 

			117 1		So the concern I have is if--you know, what is the
	2	routine physician out there ordering?  Are we going to be 
	3	put in a position which was brought up and has been hitting 
	4	some of the press, that the decision is already going to be 
	5	made, because the only thing you're going to get is 

	6	leukocyte reduced when you order 15 percent leukocyte
	7	reduced and they send you 50 percent, you're going to have 
	8	transfuse that blood, and you're going to wind up being 

	9	caught in a bind about how are you going to pay for that 
10	blood, and how are you going to get people appropriately 
11	treated.
12		So, I have great concerns about how things are 
13	moving forward, and what's happening, and what's really 
14	available out there. 

15		I don't--I am for the purest product possible, but 
16	I also don't trust processes that supposedly help to
17	reimburse this, and I can see great problems coming along.  
18	Speaking just from the hemophilia standpoint, you know we 

19	all know there's a best product out there, and yet now 
20	facing government funding that says "We're not going to 

21	allow you to get the best product, because we're only going
22	to give you enough money to buy the second-best product."  
23	And if we have that on a small front, how do we know we're 
24	going to get covered in this big front, to provide the best 
25	product? 

			118 1		And I was not privy to all of  the information,
	2	you know, about why this is so clinically important, and so 
	3	much clinically better.  You know, I have to just take--we 

	4	weren't presented any of that information, because that was 
	5	in the, you know, previous Blood Products Advisory 
	6	Committees.  But, you know, I think there's a lot of
	7	information out there I feel like I don't know--being part 
	8	of the Committee now--that I've inherited from past 
	9	Committees, saying that this is obviously the best thing to 
10	go forward with. 
11		So--long-winded, but just some comments to make on
12	being a clinician and, you know, what kinds of things are 
13	happening here. 
14		DR. HOLLINGER:  Yes--Dr. Simon? 
15		DR. SIMON:  Kind of coming back to the 
16	beginning--because I think we've kind of gone around.  And
17	with Dr. Chamberland's comments, there seemed to be answer 
18	from FDA: yes, there would be leukocyte reduced blood 

19	available.  Well, I guess there is during the implementation 
20	phase, but this time I think I did understand the FDA 

21	position correctly, which is that at some point all red
22	cells, platelets--and now they've mentioned plasma as 
23	well--would be leukoreduced, and that would be the only 

24	component available to the clinician.  It won't be tomorrow 
25	or the next day, but at some point, if not by rulemaking, by 

			119 1	practice.
	2		DR. HOLLINGER:  I wasn't real sure why--did they 
	3	really say the plasma also?  I mean, with its less than 
	4	1x1.0 x 106-- 
	5		DR. SIMON:  I wrote that down.  Yes. 
	6		DR. HOLLINGER:  I mean, that would be kind of
	7	unusual, if--to me it seems a little unusual, if you're 
	8	going to require red cells to be only less than 1x1.0 x 106, 
	9	and my understanding is most plasma units are 1x104 or less 
10	for-- 
11		DR. LEE:  Yes, that's absolutely correct.  And,
12	initially, the Agency felt that there is no need to 
13	specially consider plasma components for leukocyte 
14	reduction. 
15		However, I think there is several groups that are 
16	concerned about being able to label a plasma unit as
17	leukocyte reduced; again, sort of pressure from 
18	international discussion of this topic, where other 
19	countries are recognizing plasma, leukocyte reduced.  And in 
20	order to sort of interact with them, we have to 

21	demonstrate--U.S. products have to be able to be
22	demonstrated as the same as the ones that are labeled as 
23	leukocyte reduced in other countries.  That's part of the 
24	reason. 

25		And also, manufacturing failures do occur.  If you 

			120 1	were to manufacture a plasma product in accordance with GMP,
	2	you should arrive at a product that's well below the 
	3	leukocyte reduction threshold already.  However failures do 
	4	occur.  You might consider them just as failures and treat 
	5	that separately as a failure case.  But you might also 
	6	consider, well, if you want to demonstrate that plasma, if
	7	it is indeed leukocyte reduced--as we assume--you might also 
	8	perform QC testing on them too, to ensure that some kind of 
	9	a GMP failure hasn't occurred. 
10		So it's possible to recognize products--plasma 
11	leukocyte reduced--based on the fact that if you perform the
12	appropriate QC testing as you would for other components 

13	that you can label it as such, but the method of getting 
14	there is no more burdensome than what you're using anyway 

15	for manufacturing plasma.  All you have to do is QC a few of 
16	them to make sure that you're under control  You don't have
17	to filter them.  We certainly don't want to encourage the 

18	extra use of filters just to filter plasma through, because 
19	it's not necessary. 
20		DR. HOLLINGER:  I think that's what--I mean, 
21	that's what my understanding was, that it's not necessary to
22	filter them-- 
23		DR. SIMON:  It wouldn't be necessary to filter, 
24	but I assume that you would want some kind of quality 

25	control program to make sure that you're meeting that 

			121 1	standard, if that's the case.  Is that correct?
	2		DR. LEE:  That's sort of the current thinking, 
	3	that you would subject these plasma units that are 
	4	manufactured under routine procedures, not using a special 

	5	leukocyte reduction step, but simply subject them to the QC 
	6	testing process, and demonstrate that you're in control for
	7	leukocyte reduction standards. 

	8		DR. HOLLINGER:  Yes? 
	9		DR. EPSTEIN:  Yes, I agree fully with what Dr. Lee 
10	has said. 
11		I wanted to come back to a different point about
12	sickle trait.  There are documented problems with 
13	leuko-filtration in the face of sickle trait, as Dr. Katz 
14	said, and also the experience in Europe.  But the idea that 
15	you have to routinely reject the donor may not be 
16	well-founded, because you can still prepare leukoreduced
17	platelet and plasma by apheresing the face of sickle trait, 
18	and also those donors may still be suitable for collection 
19	of peripheral blood stem cells by apheresis. 
20		So I don't think one has to think solely in terms 
21	of filtration--that's my only point.  Filtration is not the
22	only method of leukoreduction, although there's a recognized 
23	problem with filtration in such persons. 
24		DR. LEE:  If I might just add a comment to that 
25	topic. 

			122 1		One way to get at this would be just to screen red
	2	cell donors up front.  But there's no current thinking, at 

	3	this point, to require such sickle cell screening for 
	4	leukocyte reduction process.  Typically, though, I think a 
	5	sickle train donor will become apparent during the 
	6	filtration step.  I think we've heard something like 65

	7	percent of them will just not filter, and you'll--it's 
	8	apparent that this is a filtration process failure--right 
	9	there--and you'll be able to recognize that product. 
10		For the few units that do go through, I think the 
11	time that it takes for that filtration to complete is
12	variable, but it's going to be far in excess of the typical 
13	filtration time.  So what you might choose to do is specify 
14	a certain time limit within which the leukocyte reduction 
15	filtration process must be started and completed.  And 

16	typically a unit will filter easily within 15 minutes or
17	less.  In some cases, the filtration might be completed 

18	within half an hour without any particular reason for that, 
19	but in almost all cases, I think you will find that sickle 
20	cell donor will exceed those typical time limits and you'll 
21	be able to identify those units there.
22		So although you won't prevent the donation from 
23	happening--and the filtration from happening--you'll be able 
24	to retrieve the unit in advance of actually picking up them 
25	up through random quality control testing. 

			123 1		DR. HOLLINGER:  Yes--Dr. McCurdy?
	2		DR. McCURDY:  I have some incidental intelligence 
	3	that there's a representative of the American Hospital 
	4	Association that hadn't planned on commenting but might be 

	5	willing to.  Would you reopen the public hearing for that 
	6	purpose?
	7		          OPEN PUBLIC HEARING 
	8		DR. SAVER:  As indicated, I had not intended to 
	9	make a statement this morning-- 
10		DR. HOLLINGER:  Could you-- 
11		DR. SAVER:  My name is Mary Beth Saver, with the
12	American Hospital Association.  But I did want to take a 
13	couple of minutes to respond to some statements that have 
14	been made this morning. 

15		I will tell you that we have been hearing from our 
16	members--transfusion medicine specialists within some of our
17	major institutions--about their concerns with universal 
18	leukoreduced blood.  They have no problems, and they believe 
19	wholeheartedly in the targeted use of this blood, but they 
20	do not believe that ULR is scientifically indicated.  I know 
21	Dr. Epstein and others have made comments this morning, is
22	that because of cost? Is it because of the science? 
23		I can tell you, again, just what I'm hearing from 
24	the members that are calling me is they have definite 

25	concerns on the science, and they believe with limited 

			124 1	health care resources that the science should be followed.
	2		So I just wanted to comment on that. 
	3		In addition, I know we've talked this morning a 

	4	little  bit about reimbursement.  With $71 billion having 
	5	been cut out of the hospitals by the Balanced Budget Act, 
	6	contrary to what HCFA is saying, that we can cover our
	7	costs,  many of our hospitals cannot.  And on the 
	8	reimbursement front, we are working toward two different 

	9	avenues: once is a cost-securing campaign, which--two bills 
10	have been introduced.  One is in the House and one is in the 
11	Senate.  This is a 2.9 percent increase in the update for
12	hospitals.  The cost of blood is prominently featured in 
13	this campaign. 
14		In addition, we are working with the blood 
15	groups--AABB, ABC, American Red Cross--to come up with, 
16	also, a separate route just for blood.  And we believe that
17	is going to culminate in legislation, hopefully, that will 
18	be .5 percent increase in the overall update for blood. 
19		As Dr. Epstein commented, it is very difficult to 
20	target specific DRGs--it opens up the floodgates--and we 
21	believe this was a better route.
22		Going back to the cost-securing campaign, I can 
23	tell you that there is a lot of interest on the Hill.  There 
24	are 260 House sponsors of the bill.  There are 48--I believe 
25	48 Senate sponsors, which is pretty good for the Senate.  

			125 1	Typically, you may get 15, 20 co-sponsors on a bill.
	2		So, again, I just wanted to make these comments 

	3	from the reimbursement side, and also what we are hearing 
	4	from our members.  I will tell you that what drives AHA, 
	5	though, is first and foremost, is patient care and making 
	6	sure we're doing the right thing for our patients.  But we
	7	are hearing from our members: is this scientifically 
	8	indicated? 
	9		And the last question, if I might ask--and I go 
10	back to some confusion I have had--I believe Dr. Simon 
11	brought it up--is I'm still not understanding: will

12	leukoreduced blood, and non-leukoreduced blood be available?  
13	I know, for instance, with what the American Red Cross has 

14	been saying, they're converting all their manufacturing to 
15	leukoreduced blood.  And I suppose, I guess, a hospital 

16	that's dealing with American Red Cross could purpose their
17	blood from someone else if they want non-leukoreduced, but I 
18	guess that would just be a question I would like to pose, if 
19	that's appropriate. 
20		And thank you very much, and I'd be please to 
21	answer any questions.

22		Thank you. 
23		DR. HOLLINGER:  Thank you. 
24		Ahh - Marion. 
25		DR. KOERPER:  I just wanted to make a comment 

			126 1	about--first of all, I believe that we should have
	2	leukoreduced blood to the extent that it's possible, because 
	3	I think our charge is the safety of the blood supply.  And 
	4	while the financial considerations are, of course, 
	5	important, I think that--I applaud the way that this is 
	6	being handled in that, simultaneously, the Blood Safety and
	7	Availability Committee has been asked to comment on this, 
	8	and the bringing in of HCFA at an early stage in this, 
	9	rather than waiting until it's reached a rulemaking thing 
10	and then somebody saying, "Oh, wait a minute, we better 
11	change the reimbursement structure."
12		So, I'm very encouraged by seeing this sort of 
13	dualistic approach of two different agencies' trying to work 
14	on this at the same time. 
15		One comment about the requirement that it be 
16	filtered within 24 hours: talking with the director of our
17	transfusion service at our hospital, and also at the blood 
18	centers of the Pacific--one issue is that NAT testing takes 
19	three days to get a result back.  If the unit is 
20	unacceptable and has to be discarded, but has already been 
21	filtered, then there's--the blood bank has incurred an
22	additional expense that they can also not recover, because 
23	they filtered the blood that they're not going to be able to 
24	transfuse. 
25		So there's been some sentiment expressed that 

			127 1	perhaps the timing of the filtration could be long enough to
	2	allow for the results of NAT testing to come back, and the 
	3	units that were deemed acceptable could then be filtered at 
	4	that point.  So 72 hours has been suggested as a more 
	5	manageable time frame, to help with some of the 
	6	cost-containment issues.
	7		DR. HOLLINGER:  Well, Marion, it's my 
	8	understanding--I mean, if you just look at the numbers for 
	9	HCV, now it's like 1 out of 300,000 units--our policy.  So I 
10	think we're talking--and correct me if I'm wrong here--I 
11	think we're talking about pretty small numbers here.
12		DR. KOERPER:  Oh, I agree completely.  But this 
13	has been an issue that I've heard raised by at least two 
14	different blood center directors. 
15		DR. HOLLINGER:  Is there a problem--I mean, just 
16	on what Marion has just said, for the American Red Cross, or
17	somebody speaking from one of the organizations--is 24 hours 
18	a real problem for most blood organizations? 
19		Somebody might want to comment about that. 
20		DR. KATZ:  It's really going to depend on which 

21	specific center and system you're talking about, and how far
22	the unit has to move, physically, from point A to point B. 
23		I think there are some places in the Red Cross 
24	system--blood systems--where 24 hours might get pretty 
25	tight: small centers like mine, or medium-size centers like 

				128 1	mine, 24 is not really an issue.  But I think the big
	2	systems are going to have problems, and you're really going 
	3	to want to talk to the Red Cross, and blood systems in 
	4	particular--perhaps New York Blood Center--to find out the 
	5	real burden. 
	6		DR. HOLLINGER:  Somebody from the American Red
	7	Cross?  Can they just comment about that issue? 
	8		DR. CHAMBERS:  I think that's correct, that the 
	9	testing issues are going to be a drop in the bucket compared 
10	to just the practical issue of physically moving units that 
11	have been collected at remote sites back to a processing
12	center, and having them hit the processing center at a time 
13	when the component laboratory is prepared to do the 
14	leukoreduction.  48 hours is operationally many fold better 
15	than 24 in that regard, so that something collected, for 

16	example, late on a Saturday could be the first thing on
17	Monday morning collection, whereas a 24-hour limit would 
18	mandate that you be doing leukoreduction processing on 
19	Sunday. 

20		DR. HOLLINGER:  And I don't hear you saying that 
21	because somebody says it's going to be 48 hours, that
22	everything's going to be checked at 48 hours.  Probably the 
23	large majority-- 
24		DR. CHAMBERS:  No--correct. 
25		DR. HOLLINGER:  == of them would be tested much 

			129 1	earlier than that.
	2		DR. CHAMBERS:  Testing completed and 
	3	leukoreduction completed. 
	4		DR. HOLLINGER:  And it would allow you to do the 
	5	few that-- 
	6		DR. CHAMBERS:  I would encourage you to look very
	7	carefully at what is known about the point at which the 
	8	cytakines kick in and the cell degeneration becomes 
	9	substantial, and I think you'll be reassured that even 48 

10	hours builds in a large margin of safety, and is well early 
11	enough in the storage period that you haven't compromised
12	the effectiveness of the leukoreduction. 
13		DR. LEE:  There's actually three camps within the 
14	Agency as to the upper limit for leukocyte reduction.  One 
15	camp is to suggest a time limit that is consistent with all 
16	filters that are already on the market, already approved. 
17	They have--each filter came in with a particular 
18	instructions for using that filter, and the time limit for 
19	using that filter.  So, pick a time limit that's consistent 
20	with all the filters that are already out there--that's one 
21	suggestion.  And that would put the limit at something like
22	seven days. 
23		The other, second, camp is to choose 72 
24	hours--three days--and that's sort of the compromise 
25	position; recognize that operational complexity, but also 

				130 1	try to minimize the time period within which cell
	2	degradation and cytakine generation can be minimized. 
	3		The third camp is 24 hours.  That's the most 
	4	stringent one.  And if you do that, it's the best product, 
	5	but it obviously creates operational complexities. 
	6		So we're not decided, but certainly your comments
	7	are well taken. 
	8		DR. HOLLINGER:  Dr. Lee, have we answered many of 
	9	your questions?  I think most of the comments have been, I 
10	think important and pertinent? 
11		DR. LEE:  Thank you very much for the very helpful
12	insights. 
13		DR. HOLLINGER:  If that is all for today--I just 
14	wanted to ask--just a question of the Committee.  Well, no, 
15	it doesn't matter.  We'll discuss the time for the next 
16	meeting.  The next meeting has tentatively been set for the
17	usual time in September.  I think it's the 14th and the 15th 
18	for right now.  Is that a problem for anybody on the 
19	Committee? 
20		Well, be thinking about it. 
21		Yes--there's one person.
22		Okay.  Anyway, I want to thank again the Committee 
23	for its deliberations today, and we'll see you in September. 
24		Thank you. 
25		[Whereupon, at 12:20 p.m., the meeting was 

			131 
1	adjourned.]
2		- - -