1 DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION
CENTER FOR BIOLOGICS EVALUATION AND RESEARCH
		BLOOD PRODUCTS ADVISORY COMMITTEE

							67th MEETING
Thursday, September 14, 2000 8:00 a.m.
					Hilton Gaithersburg
		620 Perry Parkway Gaithersburg, Maryland

			2
PARTICIPANTS
Blaine F. Hollinger, M.D., Chairperson
Linda A. Smallwood, Ph.D., Executive Secretary
MEMBERS
	John M. Boyle, Ph.D.
	Mary E. Chamberland, M.D.

Richard J. Kagan, M.D. Jeanne V. Linden, M.D. Gail B. Macik, M.D. Daniel L. McGee, Ph.D. Mark A. Mitchell, M.D. Paul J. Schmidt, M.D. Sherri O. Stuver, Sc. D.
NON-VOTING CONSUMER REPRESENTATIVE Katherine E. Knowles
NON-VOTING INDUSTRY REPRESENTATIVE Toby L. Simon, M.D.
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.			5
Welcome and Opening Remarks			7
COMMITTEE UPDATES
Summary of PHS Advisory Commission on Blood Safety
and Availability Meeting, August 24, 2000:
		Stephen Nightingale, M.D.		12
Factor VIII and vWF Standards:
		Andrew Chang, Ph.D.		21
		Nancy Kirschbaum, Ph.D.		24
Blood Supply Update:
		Paul McCurdy, M.D.		26
Update on Donor Questionnaire:
		Jong-Hoon Lee, M.D.		30
		Kay Gregory			32
I. HIV p24 Antigen Testing of Plasma for Fractionation Potential Criteria for Discontinuation
Introduction and Background:
		Indira Hewlett, Ph.D.		36
Presentation:
		Michael Busch, M.D.		44
Open Public Hearing
		Presentations:
				NGI, Andrew Conrad, Ph.D.		74
Alpha Therapeutics, Charles Heldebrant, Ph.D. 86 Aventis, Charles Watson, Ph.D.		91
				Bayer, Barbara Masecar		94
				Baxter Hyland Immuno, Don Baker	102
				American Red Cross, Susan Stramer, Ph.D.	103
				Abbott Laboratories,
					Gerald Schochetman, Ph.D.	116
				Chiron Corporation, Chyang Fang, Ph.D.	121
				ABC, Celso Bianco, M.D.	129
				Alpha 1, Miriam O'Day	134
Questions for the Committee	139
Committee Discussion and Recommendations	140

							4
C O N T E N T S (Continued)
	II. Deferral, As Blood or Plasma Donors,
of Males Who Have Had Sex with Males
Introduction and Background:
	Andrew Dayton, M.D., Ph.D.	158
Epidemiology Presentation:
	Michael Busch, M.D., Ph.D.	165
Risk Assessment Model and Proposed Policy Options:
	Andrew Dayton, M.D., Ph.D.	200
Open Public Hearing
	Presentations:
		AABB, Louis Katz, M.D.	242
Gay and Lesbian Medical Association,
			Adrienne Smith, M.D.	251
		American Red Cross, Rebecca Haley, M.D.	256
		Committee of 10,000, David Cavanaugh, M.D.	265
		ABC, Celso Bianco, M.D.	268
		Hemophilia Treatment Centers,
				Derrick Robertson	271
Plasma Protein Therapeutics Association for North America, Dennis Jackman, M.D.	275
Committee Discussion and Recommendations	277

			5 1		         P R O C E E D I N G S
	2		   Statement of Conflict of Interest
	3		DR. SMALLWOOD:  Good morning and welcome to the
	4	67th meeting of the Blood Products Advisory Committee.  I am
	5	Linda Smallwood, the Executive Secretary.  At this time, I
	6	will read the conflict of interest statement.  I would just
	7	like to say that this statement is dedicated to Mary
	8	Gustafson who recently left us but never had the opportunity
	9	to hear it.
10		The following announcement is made part of the
11	public record to preclude the appearance of a conflict of
12	interest at this meeting.  Pursuant to the authority granted
13	under the committee charter, the Director of FDA's Center

14	for Biologics Evaluation and Research has appointed Dr.
15	Kenrad Nelson as a temporary voting member, and the Senior
16	Associate Commissioner of the Food and Drug Administration
17	has appointed Dr. Carmelita Tuazon as a temporary voting
18	member.

19		To determine if any conflicts of interest existed,
20	the agency reviewed the submitted agenda and all relevant

21	financial interests reported by the meeting participants. 
22	As a result of this review, the following disclosures are
23	being made.
24		In accordance with Title 18, United States Code,
25	208, Dr. Kenrad Nelson has been granted a general matters

			6 1	waiver which permits him to participate fully in the
	2	committee discussions.
	3		The following participants have associations with
	4	firms that could be affected by the committee discussions;

	5	Drs. Boyle, Chamberland, Hollinger, Knowles, Linden, Macik,
	6	McGee, Schmidt, Simon and McCurdy.  However, in accordance
	7	with Title 18, United States Code, Section 208 and 2635.502
	8	of the Standards of Conduct, it has been determined that a
	9	waiver or an appearance determination is not warranted for
10	these deliberations.
11		With regards to FDA's invited guests, the agency
12	has determined that the services of these guests are
13	essential.  There are reported interests which are being

14	made public to allow meeting participants to objectively
15	evaluate any presentation and/or comments made by the
16	participants.
17		They are as follows: Dr. Michael Busch is employed
18	by the Blood Centers of the Pacific.  He has received fees
19	and travel expenses from Chiron, Roche, Abbott and the

20	American Red Cross to speak at scientific meetings.  In
21	addition, he has a contract with Chiron, GenProbe for

22	laboratory work supporting the clinical trial of nucleic
23	acid testing and a past grant to the Blood Center of the
24	Pacific from Roche Molecular Systems.  Dr. Busch
25	collaborates on research with scientists from Alpha, the

			7 1	American Red Cross, Ortho, Abbott, Chiron, GenProbe and
	2	Roche.
	3		Dr. Dodd is employed by the American Red Cross,

	4	Holland Laboratory.  Dr. Sharyn Orton is employed by the
	5	American Red Cross.  Dr. Alan Williams is employed by the
	6	American Red Cross, Holland Laboratory.
	7		In the event that the discussions involve other

	8	products or firms not already on the agenda for which FDA's
	9	participants have a financial interest, the participants are
10	aware of the need to exclude themselves from such
11	involvement and their exclusion will be noted for the public
12	record.
13		With respect to all meeting participants, we ask,
14	in the interest of fairness, that you state your name,
15	affiliation and address and any current or previous
16	financial involvement with any firm whose products you wish
17	to comment on.
18		If there have been any omissions or oversights

19	concerning any of the committee members, would you declare
20	so at this time.
21		Hearing none, at this time, I would like to
22	introduce to you the members of the Blood Products Advisory
23	Committee.
24		      Welcome and Opening Remarks
25		DR. SMALLWOOD:  As I call your names, would you

			8 1	please raise your hand.  Dr. Blaine Hollinger, Chairperson. 
	2	Dr. Mary Chamberland.  Dr. Paul Schmidt.  Dr. Daniel McGee,
	3	who is a new member with the Blood Products Advisory
	4	Committee serving as our biostatistician.  Dr. Gail Macik. 
	5	Dr. Jeanne Linden.  Dr. John Boyle.  Dr. Sherri Stuver, who
	6	is also a new member of the Blood Products Advisory

	7	Committee serving us in the capacity of infectious diseases. 
	8	Dr. Paul McCurdy.  Dr. Carmelita Tuazon is serving as a
	9	temporary voting member.  Ms. Kathy Knowles, our consumer
10	representative.  Dr. Toby Simon, our industry
11	representative.
12		For this meeting, there are some members that are
13	absent or that will be late.  Dr. Norig Ellison, Dr. Marion
14	Koerper and Mr. Terry Rice will be absent for this meeting. 
15	Dr. David Stroncek will be absent today only.  He will be
16	here tomorrow.  Dr. Richard Kagan will be late this morning,
17	but he will be here for both of our sessions.
18		I would like, at this time, to recognize and

19	introduce to the committee as well as the audience the
20	Director of the Center for Biologics Evaluation and
21	Research, Dr. Katherine Zoon.  Dr. Zoon will come forward to
22	recognize Dr. Blaine Hollinger who will be leaving us as
23	Chairman of the Blood Products Advisory Committee.
24		Dr. Zoon?
25		DR. ZOON:  Thank you, Dr. Smallwood.  It is a

			9 1	pleasure to be here this morning.  I always am reminded,

	2	when I come to the BPAC--I see many faces that are very
	3	familiar that I have known for many years.  It makes me
	4	reflect on the enormous contribution of this advisory
	5	committee.  Having CBER involved in a variety of product
	6	areas in our center, I have to say the BPAC is the most
	7	active committee we have.

	8		Your agenda is always packed full.  The issues are
	9	always important or controversial and I think the
10	deliberations of this committee have been extremely valuable
11	in providing guidance and recommendation to the center on
12	many important policy issues.  So, as a whole, collectively,
13	I would like to thank all of you very much for the enormous
14	public-health contributions you have, are and will continue
15	to make.
16		In saying that, there is some special recognition
17	today for Dr. Blaine Hollinger.  I would want to say,

18	personally, his leadership on this committee has been
19	outstanding.  He has navigated through some very important
20	issues.  His endurance is admirable and his intellectual,

21	scientific contributions aiding the agency and the center in
22	making good blood policy has been enormously helpful.
23		With that recognition, I would like to provide you
24	with a couple of plaques of appreciation.  So if I could ask
25	you to come up.

			10 1		First, I would like to read a letter from Dr. Jane
	2	Henney, who is the Commissioner of the FDA, to you.  It
	3	says, "I would like to express my deepest appreciation for

	4	your efforts and guidance during your term as a member of
	5	the Blood Products Advisory Committee.  The success of this
	6	committee's work reinforces our conviction that responsible
	7	regulation of consumer products depends greatly on the
	8	participation and advice of the non-governmental health
	9	community.  In recognition of your distinguished service to
10	the FDA, I am pleased to present you with the enclosed
11	certificate.  Thank you very much."
12		In addition, we have a plaque from the center
13	saying, "For Outstanding Service and Leadership as the
14	Chairman of the FDA's Blood Products Advisory Committee for
15	the Years 1996 to 2000."  I am eternally grateful.  Thank
16	you very much.
17		[Applause.]
18		DR. HOLLINGER:  Thank you very much, Kathy. 

19	Really, this has been a great committee for me.  I have
20	thoroughly enjoyed it and, particularly, the members. 

21	Somebody once said, "Why would you ever do something like
22	this?  It is really something bad."
23		My wife reminded me with a story she told me the
24	other day.  It was about a wife who was spending all this
25	time with her husband who was in the hospital going in and

			11 1	out of coma.  She was by his side every day.
	2		One day, he woke up, after several months and
	3	looked at his wife and motioned her to come over closer to
	4	him.  She got by his side.  With tears in his eyes, he said,
	5	"You know what?"  He said, "You have been by me through all
	6	the bad times."  He said, "You were there when I got fired. 
	7	You were there to support me."  He said, "When my business

	8	failed, you were there at the time.  When I got shot, you
	9	were there.  When we lost our house, you were there.  And
10	now, when my health has failed, you are still there."
11		He said, "You know what?"  And she came closer to
12	him and sat down and said, "What, dear?" warmth sort of
13	increasing in her heart.  And he said, "You know what?"  He
14	said, "I think you are bad luck."
15		Actually, this has not been bad luck for me.  I
16	have got to tell you that.  I have certainly enjoyed this

17	committee.  We have a lot of work today.  This session today
18	is really--I think I have received more calls from the news
19	media about this meeting today than any other meeting I have
20	been associated with.
21		So, Kathy, thanks very much, from the agency's
22	standpoint, and we will get on with the meeting, then. 
23	Thank you.
24		DR. SMALLWOOD:  Thank you.  I just would like to
25	make an administrative announcement that any presenters that

			12 1	are using powerpoint for their presentations, if you would

	2	make sure that you see the AV technician that is over to my
	3	right with the white shirt on, sitting at the table there,
	4	so that he can be prepared for your presentation.
	5		I would also like to ask that everyone that will
	6	be speaking, anyone from the floor, please speak directly

	7	into the mike and announce your name and affiliation.
	8		We have a very full agenda today.  As you can see,
	9	we are a little late starting, getting into the official

10	business, but we would like to proceed accordingly and we
11	ask that you would govern yourselves as such.
12		At this time, I will turn the meeting over to our
13	Chairperson, Dr. Blaine Hollinger.
14		Dr. Hollinger?
15		           COMMITTEE UPDATES
16		DR. HOLLINGER:  We are going to start the meeting
17	today with some committee updates.  The first one is a
18	summary of the PHS Advisory Committee on Blood Safety and
19	Availability Meeting from August 24.  Dr. Nightingale will
20	give us an update.
21	   Summary of the PHS Advisory Committee on Blood Safety
22	         and Availability Meeting, August 24, 2000
23		DR. NIGHTINGALE:  Good morning.
24		[Slide.]

25		Thank you for giving me the opportunity to present

			13 1	the summary of the advisory committee meeting to you.
	2		[Slide.]
	3		The meeting of August 24 of the advisory committee
	4	arose because of a resolution of the advisory committee that
	5	was made on April 26.  The advisory committee said,
	6	"Recognizing the significant economic issues currently
	7	affecting the blood system, the advisory committee seeks to
	8	review the role of various considerations and decision
	9	making related to new and existing blood safety measures."
10		I hope, Dr. Hollinger, if your committee ever gets
11	control of its own agenda the way that mine has, that you
12	will show more respect for the English language.
13		[Slide.]
14		We paraphrased the resolution to what was the
15	serious business of the committee which is the question of
16	what are the principles on which a policy to assure a safe,
17	available and affordable blood supply should be based?
18		[Slide.]
19		The intellectual background or, perhaps, the
20	political background as well, of the committee's agenda is
21	this; there are, currently, two major ways in which policy
22	decisions have been framed before our advisory committee. 
23	One of the frames is, under a given policy, how much would
24	it cost to save a life and the alternative framing which

25	many of us see as functionally equivalent is, under a given

		14 1	policy, how many lives would be lost.  The jar between those
	2	two frames of the same question has been a recurrent concern
	3	of the advisory committee and of the blood community as a
	4	whole.
	5	          One of the answers to both of those questions that
	6	has been proposed by many parties has been the concept of
	7	no-fault insurance or compensation for unavoidable blood
	8	injury, which was proposed by the Institute of Medicine, the
	9	Krever Report and elsewhere, and it was adopted by the
10	advisory committee on April 26 when they said, "There is a
11	small but non-zero risk associated with the use of blood

12	products or plasma derivatives that cannot be eliminated
13	with current technologies.  The advisory committee,
14	therefore, supports the prior recommendation of the
15	Institute of Medicine and of others that a prospective
16	national system to compensate recipients for injuries or

17	death caused by blood products or plasma derivatives and not
18	associated with a reckless or intentionally harmful act
19	should be enacted and funded by Congress.
20	          While this is one alternative to proceeding under
21	the status quo, I think everybody in this room is aware of
22	the complexities of no-fault insurance in other arenas, the
23	complexities in implementing a fair and just no-fault--it is
24	easy to say we should have no-fault.  It is hard to do it,
25	and it is really in that context that I recommend that you

			15 1	read the response of the Secretary to that advisory
	2	committee recommendation.
	3		This was written on July 26 of this year.  "Dear
	4	Dr. Kaplan: in regard to your second recommendation," Dr.
	5	Shalala wrote, "The Department continues to feel that
	6	compensation issues are the responsibility of Congress."
	7		[Slide.]
	8		"The Administration stands ready to assist
	9	Congress as it considers such recommendations or
10	legislation."  This was, in fact, a reiteration of the
11	Secretary's testimony on October 12, 1995 before Congressman
12	Shays.  The summary, then, is that, current policy, we have
13	the competing frames of the same question which often
14	present those in, if not irreconcilable but at least
15	strongly competing, words.
16		The solution that has been proposed is not over
17	the political horizon yet.  That has led us to the
18	discussion of alternatives.
19		[Slide.]
20		One of those alternatives has been what is called,
21	rather than defined as, the precautionary principle.  The
22	precautionary principle was published by the European Union
23	on February 1 of this year.  The best legal statement of it
24	is here--it is in an environmental context--"Where there are
25	threats of serious or irreversible damage, lack of full

			16 1	scientific certainty shall not be used as a reason for
	2	postponing cost-effective measures to prevent environmental
	3	degradation."
	4		[Slide.]
	5		Again, a problem with the precautionary principle
	6	is that it is not well-defined in European or any other law. 
	7	It is one of those things that we all understand, kind of

	8	like group theory, but can't put our fingers on it.  The
	9	principles that are enunciated by the European Union on
10	February 1 were the application of the precautionary

11	principle should be proportional to the chosen level of the
12	protection, nondiscriminatory it its application, consistent
13	with similar measures already taken, based on an examination
14	of the potential benefits and costs of action or lack of

15	action, subject to review in the light of new scientific
16	data, and capable of assigning responsibility for producing
17	the scientific evidence necessary for a more comprehensive
18	risk assessment.
19		I think that you will see where I am going with
20	this talk is that there has certainly been some progress

21	towards discussion of these principles but that progress has
22	been, by no means, sufficient for action.
23		[Slide.]
24		I am sorry that screen does not have all of this
25	because, as I alluded to, the Rio Conference on the

				17 1	Environment was one statement of the precautionary
	2	principle.  The European Union's statement does not define

	3	it explicitly but there is what I am going to call a more
	4	stringent form.
	5		Dr. Epstein, who was, really, the leader of our
	6	efforts to get to this point, suggested that the principles
	7	that underlie blood safety could be ranked on the order of
	8	stringency.  Stringency is also an evolving concept but I
	9	think you will get what Dr. Epstein had in mind when you
10	read what Mr. Justice Krever wrote about the precautionary
11	principle.  This is also on the table, so to speak.
12		This one says, "Preventive action should be taken
13	when there is evidence that a potentially disease-causing
14	agent is or may be blood-borne even when there is no
15	evidence that recipients have been affected.  If harm can
16	occur, it should be assumed that it will occur.  If there
17	are no measures that will entirely prevent the harm,

18	measures that may only partially prevent transmission should
19	be taken."  Another definition that is on the table.
20		[Slide.]
21		The discussions that took place on August 24 have
22	been distributed to the advisory committee.  I did bring 24
23	copies of it.  It will be posted on the advisory committee's
24	website as soon as my deputy returns from travel because he
25	knows how to do it and I do not.

			18 1		That failing, that is the direct phone to my
	2	office.  That is my fax.  And that is my E-mail.  Those will
	3	be available outside the room afterwards.
	4		I think the one piece of the discussion that I

	5	specifically want to bring to the Blood Products Advisory
	6	Committee's attention is on the next slide.
	7		[Slide.]
	8		These are seven criteria for blood policy.  This
	9	is a very tight abstract of Dr. Epstein's presentation to

10	the committee and does not do that presentation full justice
11	but is what got into the ABC Newsletter.  It is a very
12	accurate reflection of a summary slide.
13		This is pretty much where we are in our own
14	thinking.  I, again, thank Dr. Epstein for the formulation
15	and praise it.  Acceptance of risk is a political decision. 
16	Acceptance of cost is a political decision.  Decision-making
17	must be transparent if it is to obtain public endorsement. 
18	Decision-making must include both risk assessment and risk
19	communication.  Decision-making must include ongoing
20	scientific input.
21		Blood-safety decisions should be considered in an
22	international context and, finally, individual contributors
23	to blood safety decisions should independently articulate

24	the scientific, economic and political bases of their
25	recommendations.

			19 1		There is far more thought behind these seven
	2	commandments, is what we are calling them informally, behind
	3	Dr. Epstein's back.  I recommend them to you for your
	4	thoughtful consideration.
	5		[Slide.]
	6		The question, however, of whether or not a
	7	sufficient foundation for blood policy can be identified is
	8	being debated, not only within blood policy but within
	9	broader realms as broad as law.  That will be coming into

10	our decision-making process; can you really find a set of
11	principles that you can enact a sound policy.
12		The argument on the left side is one of the

13	several competing--lists a few of the major competing
14	principles.  The argument on the other side, which is cut
15	off and really shouldn't be, because it is the argument not
16	only of Mr. Justice Holmes but of current legal scholars

17	like Richard Posner who are arguing for scientific or ad hoc
18	adjudication of political issues.
19		Most of you--the lawyers--will recognize, "The
20	life of the law has not been logic.  It has been experience,
21	the felt necessities of the time, the prevalent moral and
22	political theories, institutions of public policy, avowed or
23	unconscious.  Even the prejudices which judges share with

24	their fellow men have had a good deal more to do than the
25	syllogism in determining rules by which men should be

			20 1	governed."
	2		So the ultimate debater here is whether or not we
	3	can come up with a set of principles.  It is definitely
	4	worth trying.  But there are bright people who think that we
	5	are not going to succeed.
	6		[Slide.]
	7		Where the first challenges for this effort will be
	8	coming; the first will be in November.  We expect that there
	9	will be a meeting convened by the WHO of its Global
10	Collaboration for Blood Safety.  The general agenda items

11	are harmonization of blood-safety practices in developed
12	countries and promotion of blood-safety practices in the

13	developing ones and, in January, where I suppose the rubber
14	hits the road locally, where we have agreed that the

15	advisory committee should take up the issue of how the
16	government should respond to the current debate over
17	universal leukoreduction.

18		The last and very substantive point that I want to
19	make to this advisory committee is that the review by the
20	department's Advisory Committee on Blood Safety and
21	Availability is, by no means, a review or a second guess of
22	the deliberations of this advisory committee.
23		We have made it very clear that there is a
24	delineation of roles and the role of the advisory committee,
25	whatever it may be, is not to second-guess scientific

			21 1	decisions of a scientific panel.  We will continue in
	2	dialogue with you to assure that our roles are complementary
	3	and not competitive.
	4		I would be glad to answer any questions that
	5	anybody would like to have about them and apologize for
	6	running over a little bit.  I am done.
	7		DR. HOLLINGER:  Any questions?
	8		If not, thank you, Steve.
	9		The next update is on factor VIII and von
10	Willebrand factor standards.  Dr. Chang and Dr. Kirschbaum. 
11		     Factor VIII and vWF Standards
12		DR. KIRSCHBAUM:  Hi.  I am Nancy Kirschbaum from
13	the Laboratory of Hemostasis in the Division of Hematology.
14		Oh; that is Dr. Chang's talk.
15		Do you just want to go?
16		DR. CHANG:  Thank you, Mr. Chairman.
17		[Slide.]
18		For the next five minutes, I would like to give

19	you a brief introduction on the work in progress toward the
20	first international standard for von Willebrand factor 
21	concentrates.
22		[Slide.]
23		My name is Andrew Chang.  I work in the Division
24	of Hematology, CBER, FDA.  I would like to first start to
25	give you a message that is the good news, actually.  The

			22 1	first international standard for von Willebrand factor
	2	concentrates will likely to be available by the end of the
	3	next year.
	4		[Slide.]
	5		I would like to give you a brief, very brief,

	6	introduction on the process we have carried out for this
	7	first international standard.  We carried out this project
	8	in two phases; phase I is the initial characterization and
	9	phase II is the production and calibration phase.

10		In phase I, we selected five von Willebrand factor
11	concentrates from five different manufacturers.  There are
12	three organizations actually involved with this study; CBER,
13	FDA and NIBSC.  SSC stands for Science Standardization

14	Committee which is under the International Society for
15	Hemostasis and Thrombosis.
16		The goal for this study is to try to reach
17	agreement based on the scientific study to select two
18	candidates which are suitable for the international

19	standard.  The second phase is production and calibration. 
20	We decided to take two candidates into the phase II study
21	and filled 5000 ampoules for each candidate and then had a
22	panel of about twenty international laboratories around the
23	world in the calibration.
24		By the end, we will select one, the best one, as
25	the standard.

			23 1		[Slide.]
	2		Where are we now?  We have completed the phase I
	3	study and we presented our selection process to the SSC,
	4	Science Standardization Committee, in May of this year.  We
	5	are very happy the committee accepted our selections for two
	6	candidates.
	7		We are now on the second phase.  That is the

	8	production and calibration.  We have already filled one
	9	candidate.  We have 5000 ampoules ready for calibration. 

10	The second one is on its. way.  We already have the material
11	and are ready to fill.
12		We also distribute a survey form to about thirty
13	laboratories around the world.  We sent it out last month

14	and so far we have received sixteen of them committed to do
15	the calibration studies.  The calibration will be carried

16	out against the WHO Fourth International Standard for factor
17	VIII and von Willebrand factor plasma.  We envisioned that,
18	by the end of the study, we will have at least three
19	potencies which can be assigned to this standard; that is,
20	the von Willebrand factor level, von Willebrand factor
21	ritocetin-cofactor activity, and the collagen-binding
22	activity.
23		The final report for this project will be
24	presented to the Expert Committee of the Biological Standard
25	which is a committee under the World Health Organization in

			24 1	Geneva in October of next year.
	2		[Slide.]
	3		So, in conclusion, we have completed the phase I
	4	study and we selected the two candidates.  They are accepted
	5	by the SSC Committee and we are now under the production
	6	phase and are ready to distribute the candidate for
	7	multicentered international-wide calibration.  Hopefully, I
	8	think very likely, by the end of next year, we will have
	9	this first international standard for von Willebrand factor
10	concentrates available basically for the world.
11		Thank you very much.
12		DR. HOLLINGER:  Thank you.
13		Dr. Kirschbaum?
14		DR. KIRSCHBAUM:  I guess I will reintroduce
15	myself.  My name is Nancy Kirschbaum.  I am a senior staff
16	fellow in Laboratory of Hemostasis in the Division of
17	Hematology.
18		[Slide.]
19		Thank you for inviting me to present an update on
20	the development of Mega 2, which is the new U.S. working
21	standard for determination of Factor VIII activity.
22		[Slide.]
23		Mega 2 is being developed to replace the dwindling
24	supply of Mega 1 which is the current U.S. Factor VIII
25	working standard.  Phase I, in the development of Mega 2,

			25 1	was devoted to choosing a suitable candidate.  This was
	2	achieved through an international collaborative effort.
	3		The candidate that was chosen met stringent
	4	criteria of molecular integrity, linearity of dose response,
	5	stability and consistency of results within assays, between
	6	assays, and, importantly, between the two currently used
	7	test methodologies of the one-stage APTT assay and the
	8	chromogenic substrate assay.
	9		The candidate that was chosen is a plasma-derived
10	concentrate.  During phase II, the final fill of 100,000

11	vials was performed with direct participation by members
12	from our laboratory of hemostasis.  This particular final
13	fill was subdivided into two and these two sublots were
14	lyophilized in separate machines.

15		So, because of that fact, we conducted extensive
16	testing in our laboratory of hemostasis that demonstrated
17	the equivalence of the two sublots.
18		[Slide.]
19		Currently, we are collaborating with the European
20	Pharmacopoeia and the National Institutes of Biological

21	Standards and Control to organize the final phase of the
22	development of Mega 2 which is the assignment of potency. 
23	Forty-five laboratories from around the world have been
24	invited to participate.
25		The testing will involve the comparison of potency

			26 1	values determined for the candidate against current
	2	international standards.  The ones that we are going to
	3	include in our study are the WHO Fifth International
	4	Standard, the WHO Sixth International Standard and the
	5	European Pharmacopoeia Current Working Standard.
	6		In addition, a preparation of Mega 2 that has been
	7	filled in ampoules will also be tested for consideration as
	8	an international working standard.  Testing will also
	9	involve the comparison of potency values determined using

10	the two current test methodologies--that is, the one-stage
11	APTT assay and the chromogenic substrate assay.
12		[Slide.]
13		Finally, we plan to compete testing and data
14	analysis so that the new Mega 2 standard will be ready for
15	distribution next year.
16		Thank you.
17		DR. HOLLINGER:  Thank you.  Any questions for Dr.
18	Chang and Dr. Kirschbaum?
19		The next update; Dr. McCurdy will give us an
20	update on the blood supply.  Paul?
21		          Blood Supply Update
22		DR. McCURDY:  Good morning.
23		[Slide.]
24		At the last meeting of this committee, I provided
25	an initial brief description of what we have been doing.

			27 1		[Slide.]
	2		There have been, as I mentioned last time, for a

	3	number of years attempts and recommendations by a number of
	4	different groups that we do find out something about the

	5	blood supply in the United States.  It has been deplored
	6	that we know more about widgets than we do red cells and
	7	platelets.

	8		When the situation came up that it was necessary
	9	to defer donors who spent more than six months in U.K. from
10	1980 to 1996, and we were concerned about what might happen
11	to the blood supply, at the request of the Surgeon General,
12	the Heart, Lung and Blood Institute contracted with the
13	National Blood Resource Center to provide data on the blood
14	supply.
15		Initially, we selected a sample of twenty-seven

16	blood centers around the country.  These were selected to be
17	representative of the country as a whole, although there was
18	a bit more of a concentration in larger cities than small
19	rural centers primarily because one of our goals was to
20	detect shortages as they occurred or immediately afterwards,
21	and big cities are more vulnerable than small rural centers.
22		Twenty-seven were selected.  Six centers were not
23	able to participate and were replaced, and we had one late
24	dropout.  The final sample, therefore, was twenty-six.
25		[Slide.]

			28 1		This slide is a simplistic cartoon because I
	2	discovered that more people than I had originally thought
	3	were confused about what was released and made available for
	4	distribution, what the inventory level was and what was
	5	shipped or actually used.  What we are doing at the present
	6	time is getting information from the blood centers, from the
	7	sample of blood centers, on what was released for
	8	distribution and we are getting information on inventory the
	9	first and third Wednesdays of each month.
10		We do not have information on what was actually

11	shipped from the blood centers and, more importantly, we
12	hope to get information from a sample of hospitals about

13	what was actually used.  So keep in mind that that level of
14	inventory depends not only on what is put in but what goes
15	out at the bottom.

16		[Slide.]
17		These are a graph of the red-cell products
18	released from October through August.  As I mentioned last
19	time, we did not get information from all centers from the
20	very beginning.  Some were phased in as time went on and,
21	until August, we did not get information from every center

22	every month.  So we did a quick and dirty extrapolation from
23	the number that actually supplied to the total.
24		In August, we did get information very promptly

25	and from all twenty-six centers, and they are all to be

			29 1	congratulated for that effort.
	2		[Slide.]
	3		The next slide shows a regression line that I
	4	calculated.  The increase in blood made ready for
	5	distribution from October through August is significant at a
	6	p less than 0.01.  I am not quite sure what that means other
	7	than, perhaps, blood centers were able to cope with any loss
	8	of donors due to phasing in the variant CJD deferral period.
	9		[Slide.]
10		This is what happened to the inventory.  I started
11	the inventory slide in January because the retrospective
12	inventories, starting in October, there weren't enough
13	centers and we didn't think we could rely upon those data,
14	although it looks, perhaps, as though there is a progressive
15	downward trend on that.
16		[Slide.]
17		When one calculates a regression line, one can get
18	a negative slope.  But the p-value of this slope is being

19	different from zero probably because the variability is not
20	significant.
21		[Slide.]
22		The final slide shows information on the
23	inventories by blood group.  I am not sure how to interpret
24	this yet.  We have got, on this slide, the O's and the A's,
25	O's being characteristically in short supply all the time

			30 1	and A's being pretty adequate.  But we do get that
	2	information and we will be looking at it as time goes on.
	3		Thank you.
	4		DR. HOLLINGER:  Thank you, Paul.
	5		There is a person who would like to--Derrick
	6	Robertson from the Hemophilia Treatment Centers would also
	7	like to give us an update a little bit on the supply issue. 
	8	Is Derrick Robertson here?
	9		No?  I guess that was an interesting comment that
10	he had.
11		Any other comments about the supply issue?  Yes,
12	Paul.  Do have a comment for yourself?
13		DR. McCURDY:  I might comment that this really
14	does not speak to the issue of shortages which have been
15	widely reported in various different media, particularly the
16	newsletters of the blood-banking organizations.  With the
17	supply or the information about the blood put on the shelf,
18	one would suggest, but you can't prove, that there may have
19	been some increased demand over this period of time in order
20	to generate the shortages.
21		DR. HOLLINGER:  Thank you.
22		The final committee update is on donor
23	questionnaire.  Dr. Lee?
24		     Update on Donor Questionnaire
25		DR. LEE:  Good morning committee members and Dr.

			31 1	Hollinger.  I am here to not necessarily give you the full
	2	update on the donor questionnaire streamlining process but
	3	simply to give you a very brief background and introduce Dr.
	4	Joy Fridey to give the update.
	5		As Dr. Zoon mentioned this morning, the issues
	6	presented here are always controversial and important, and

	7	the donor interview process is no exception.  Blood safety
	8	and availability, at present, starts with selecting the
	9	right donor.
10		We intuitively know how important the interview
11	process is in safety and availability of blood, yet it has
12	been unclear for many years as to exact role of the donor
13	interview in assuring safety and availability.  There has
14	been ongoing internal discussion at the FDA for many years
15	as to how we might improve this.
16		The agenda of today's BPAC, especially the one
17	after lunch, speaks to our ongoing efforts in trying to

18	improve the current interview process and the questions used
19	in selecting the right donor.  More recently, the FDA has
20	charged the blood industry to get together as group to

21	analyze this in a more concrete fashion in an effort to
22	improve the donor interview process, particularly the
23	questions used in selecting the right donors.

24		Dr. Joy Fridey has graciously chaired this group. 
25	Dr. Joy Fridey will now give the update as to what the

			32 1	recent accomplishments have been from this task force,
	2	multiorganizational task force, led by AABB and give some
	3	specific goals as to what it is intending to do in the near
	4	future including a joint FDA-AABB-sponsored workshop
	5	currently scheduled for October 16 at Lister Hill Auditorium
	6	on NIH campus on streamlining the donor questionnaire.
	7		Dr. Friday?  I don't see Dr. Fridey.  I see Ms.
	8	Kay Gregory.  So I will now have the pleasure of introducing
	9	Ms. Kay Gregory.
10		MS. GREGORY:  Thank you.  There was a mixup in

11	communication and Dr. Fridey thought she was going to be
12	presenting tomorrow.  So I will try to fill in for her in
13	the meantime.
14		The American Association of Blood Banks has

15	established a new multiorganizational task force to evaluate
16	and develop recommendations to simplify the uniform donor
17	history questionnaire including consideration of an
18	abbreviated version for repeat donors.  The task force
19	appreciates the opportunity to make this advisory committee
20	aware of its activities.  We hope that this meeting will
21	also provide an opportunity to let the public and those with
22	a special interest on donor screening know the activities of
23	the task force.
24		The task force was formed in response to
25	information from the Food and Drug Administration that the

			33 1	agency would like to see a simplified questionnaire
	2	developed perhaps sometime in 2001 and would prefer to have
	3	a single initiative supported by the entire blood banking
	4	community.
	5		The task force, as you have heard, is chaired by
	6	Dr. Joy Fridey and is composed of representatives from the
	7	American Association of Blood Banks, American Blood
	8	Resources Association, America's Blood Centers, the American
	9	Red Cross, the Center for Disease Control and Prevention and
10	the FDA.  We will shortly be joined by representatives of
11	NHLBI and the Armed Services Blood Program Office.
12		The task force is intended to be the core group

13	guiding the effort.  But each organization will be active
14	participants assisting the task force with tasks such as
15	identifying member centers to pilot questions and generate

16	additional information or data as needed.  It is vital that
17	we include everyone in this effort including donors.
18		The task force charges are; to reevaluate the
19	scientific validity of all FDA requiring infectious-disease
20	questions in view of the most recent scientific data
21	including current testing technology; to identify and reword
22	questions for which the wording may represent comprehension
23	difficulties for average individuals--for example, do not

24	meet the eighth-grade reading comprehension guidelines for
25	written materials; to identify questions that can logically

			34 1	be grouped together and simplified; to reorder questions as
	2	appropriate and to evaluate methods and develop
	3	recommendations for administering the questionnaire, oral,
	4	written computer-based questioning, methods of handling
	5	recurring questions, et cetera; and, finally, to submit the
	6	document and proposal for its use for FDA approval when we
	7	finish the process.
	8		The task force will utilize pilot studies and
	9	other methods of obtaining information as appropriate.  This
10	is an active task force.  It was organized in June and has
11	already met three times by conference call.  Subcommittees
12	have also had numerous conference calls.  Sometimes, I have
13	talked to this group at least three or four times in one
14	week.
15		Activities currently underway include planning, as
16	you have heard from Dr. Lee, for a joint AABB-FDA workshop
17	to be held October 16.  We have also distributed a survey to
18	obtain information about questions currently in use to
19	selected blood centers, hospital blood banks and plasma-
20	collection facilities.
21		We have begun an AABB review of AABB-generated
22	questions.  There are some questions that we asked that were
23	generated by us and not necessarily by the FDA.  If we are
24	going to look at everything, we need to look at what we have
25	done, as well.

			35 1		Finally, the FDA is compiling information about
	2	questions most frequently cited in error and accident
	3	reports that they receive.  And then FDA is also putting
	4	together a list of nonnegotiable question items.  These are
	5	things that they believe are critical and must still be
	6	covered somehow in the questionnaire, although not
	7	necessarily using the exact wording that we are currently
	8	using.
	9		Again, I thank you for the opportunity to speak

10	today.  The task force is excited about the opportunity to
11	accomplish meaningful change and plans to provide regular
12	progress reports.
13		Thank you.
14		DR. HOLLINGER:  Thank you, Kay

15		Any questions?  I think that concludes the updates
16	for the committee at this time.  I want to thank the

17	individuals who have presented these updates today.
18		So we are actually back on time, but I will tell
19	you we will probably get out of time before long.
20		We are going to start the first open committee
21	discussion, which is a very important--all the topics,

22	actually, I think at these meetings here are important. 
23	This is another one.  This one is on HIV p24 antigen testing
24	of plasma for fractionation, the potential criteria for
25	discontinuation.

			36 1		Dr. Hewlett is going to give us an introduction
	2	and background to this proposal.
	3	   I. HIV p24 Antigen Testing of Plasma for Fractionation
	4		 Potential Criteria for Discontinuation
	5		      Introduction and Background
	6		DR. HEWLETT:  Thank you, Dr. Hollinger and good
	7	morning everyone.

	8		[Slide.]
	9		The topic for discussion this morning is the

10	potential discontinuation of HIV-1 p24 antigen testing of
11	source plasma.
12		[Slide.]
13		The specific issue that we want to focus on today
14	is whether FDA should permit manufacturers of plasma
15	derivatives to replace HIV p24 antigen testing with the

16	licensed minipool NAT method that has equal or greater
17	sensitivity.
18		[Slide.]
19		By way of background, I think would all agree that
20	there has been a dramatic and vast reduction in the
21	transmission of HIV by blood and blood products during the
22	past decade primarily due to the implementation of sensitive
23	tests for viral antibody antigen and, more recently, nucleic
24	acids under the IND mechanism and, in the case of plasma
25	derivatives, the use of effective viral removal and

			37 1	inactivation methods.
	2		[Slide.]
	3		The major sources of remaining risk are from
	4	window-period donations, viral variants that are not
	5	detected by currently licensed assays, atypical
	6	seroconversions and laboratory-testing errors.  According to
	7	recent reports, donations during the window period
	8	constitute at least 90 percent of the risk.  Therefore,
	9	measures to close the window period could further reduce the
10	low residual risk in HIV transmission by blood and plasma.
11		[Slide.]
12		In 1994, FDA held a workshop to discuss the
13	potential application of nucleic-acid-based methods to donor
14	screening for HIV.  It was felt, at the time, that, although
15	these methods were clearly very sensitive, they were not
16	ready for implementation on a large scale.
17		It was subsequently decided, in 1996, that p24

18	antigen testing could be adopted as an interim measure for
19	interdicting window-period donations until more sensitive
20	methods become available.  Despite the effectiveness of
21	viral clearance and inactivation procedures in the
22	manufacturer of plasma derivatives, FDA recommended donor
23	screening for HIV p24 antigen for plasma for fractionation
24	as an added safeguard since such testing would limit the
25	virus burden that may be present in a plasma pool for

			38 1	fractionation.
	2		[Slide.]
	3		Subsequent to implementation of HIV p24 antigen
	4	testing, the industry actively pursued development of
	5	nucleic-acid testing, or NAT, for screening blood and plasma
	6	donors.  NIH awarded a contract for development of NAT to
	7	screen individual donations of blood and plasma.  At this
	8	time, however, due to the high costs and the labor intensity
	9	of NAT, there was interest in testing minipools of plasma
10	rather than single units and, by 1997, some manufacturers in
11	Europe had voluntarily instituted NAT on minipools.
12		At about that time, the European Union had issued
13	a directive that, by July 1, 1999, HCV RNA testing would be
14	required in Europe for all plasma for fractionation and that
15	the requirement for HIV-1 RNA testing would follow at a
16	later date.
17		In the U.S., testing of minipools was first

18	introduced as an in-process control test for plasma for
19	fractionation.  However, the FDA position to regard pool-
20	sample testing by NAT as a form of donor screening and a
21	European directive which applied to both source and
22	recovered plasma provided impetus for rapid development of
23	minipool NAT for all blood and plasma donations.

24		FDA has taken the position that all NAT tests used
25	to screen blood and plasma are subject to regulation as

			39 1	biological products under the licensing mechanism.
	2		[Slide.]
	3		Since NAT screening of donors was expected to
	4	improve blood safety while not interfering with current
	5	measures of safety, FDA permitted the clinical study of this
	6	investigational technology on a large scale under an
	7	approved IND.  Such large-scale studies would be necessary
	8	to demonstrate the efficacy of NAT primarily because the
	9	frequency of window-period donations is low.
10		At the present time, virtually all source plasma
11	and whole blood collected in the U.S. is being tested by a

12	minipool NAT method for HCV and HIV-1 under an approved IND. 
13	FDA has not yet licensed a NAT method for use in screening
14	of donor blood and plasma including source plasma.
15		[Slide.]
16		With the implementation of NAT for detection of

17	window-period donations, the question of replacing HIV p24
18	antigen testing by NAT has been raised by many
19	investigators.  Since both tests are for direct markers of
20	the virus, it has been suggested that it may be feasible to
21	replace p24 antigen on the neat sample with minipool NAT if
22	it is found to be of equal or greater sensitivity.
23		At the BPAC meeting held in March of last year,
24	FDA defined criteria for discontinuation of p24 antigen and
25	replacement by minipool NAT.

			40 1		[Slide.]
	2		I will now briefly summarize the criteria that
	3	were presented at the time.  First, the sensitivity of the

	4	NAT method should be equal to or greater than that of p24
	5	antigen testing for the window period.  This could be
	6	established by testing all available and properly stored
	7	repository specimens that are p24-antigen-positive and
	8	antibody-negative and commercially available seroconversion
	9	panel specimens in the pooled method and the neat p24
10	antigen method.
11		Second, frequencies of NAT and p24 antigen
12	positivity in antibody-positive and negative specimens
13	should be evaluated in prospective studies.  Third, NAT and
14	p24 antigen should have equal sensitivity for detection of
15	the major HIV-1 subtypes.  Finally, weakly reactive p24-

16	antigen-positive specimens should be reproducibly detected
17	by the NAT method on multiple days by multiple operators and
18	for multiple kit lots and instruments.
19		[Slide.]
20		FDA also indicated that the NAT method would have
21	to be licensed before it could be used to replace the
22	antigen test.  FDA has published guidance on the validation
23	of NAT methods to screen plasma donors.  Among the major
24	considerations for the sensitivity of NAT on pools is
25	analytical sensitivity of the NAT method on the pool and the

			41 1	original donation as well as the pool size tested.
	2		FDA has defined a proposed sensitivity limit for
	3	licensure of 100 copies per ml for the pooled test and
	4	5000 copies per ml for the original donation.  FDA has not

	5	specified pool-size limits, thereby allowing manufacturers
	6	to set these limits based on the analytical sensitivity of
	7	their specific test.  Source plasma donations are currently
	8	being tested in pools ranging from 96 to 1200 donations.
	9		[Slide.]
10		To establish sensitivity criteria whereby p24
11	antigen can be discontinued, it is important to understand
12	the early dynamics of HIV infection and to establish and

13	determine a relationship between detectable levels of
14	viremia by p24 antigen versus minipool NAT.
15		Recent data, which will be presented later on in
16	this session and more in detail at the upcoming AABB
17	meeting, and which was shared with us by Mike Busch and his
18	coworkers, indicate that in studies where 146 serial
19	specimens from 48 HIV plasma-donor panels were characterized
20	by tests for HIV RNA, p24 antigen and HIV antibody, the mean
21	viral load at the time of p24 antigen seroconversion was
22	estimated at around 10,000 copies per ml.
23		Based on this estimate, NAT method should be able
24	to detect a minimum of 10,000 copies per ml or less in order
25	to replace currently licensed p24 antigen tests.

				42 1		[Slide.]
	2		In regard to plasma for further manufacturer, it
	3	is important to note that viral-inactivation methods provide
	4	an added measure of safety.  Since the end of 1987, there
	5	have been no transmissions of HIV by albumins, immune

	6	globulins or clotting factors.  Heat treatment used in
	7	albumin production has been shown to inactivate the
	8	infectivity of HIV-1 by around 7 logs, which is a least
	9	3 logs more virus than the maximum concentration reported in
10	the plasma of infected individuals, which is around 104
11	infectious units per ml.
12		The Cohn-Oncley method used to manufacture immune
13	globulins can remove greater than 10		               
				-5 infectious doses of
14	HIV per ml which is at least 11 logs greater than the
15	maximum circulating infectious doses per ml.
16		So, based on the rationale and criteria outlined

17	above, FDA is seeking the recommendations of the BPAC on the
18	potential discontinuation of HIV p24 antigen testing and
19	replacement by a NAT method for plasma collected for
20	fractionation.
21		[Slide.]
22		As outlined above, the two major considerations
23	are; one, that a NAT test is of equal or greater sensitivity
24	than the p24 antigen test and, second, that viral removal

25	and inactivation methods validated to remove and inactivate

			43 1	circulating levels of HIV detected by p24 or NAT are in
	2	place for plasma collected for further manufacturing.
	3		[Slide.]
	4		So, at this point, I will go ahead and read the
	5	questions for the committee.  I will put them up again at
	6	the time of the discussion.
	7		The first question is, "Do the committee members
	8	agree that HIV-1 p24 antigen testing of source plasma may be
	9	discontinued if, a), it is demonstrated that a particular
10	licensed NAT method can detect HIV at a level of
11	5,000 copies per ml or less in a unit of plasma even if the
12	donor sample is tested as part of a pool."
13		The second part of the same question, "Comparative
14	studies of the NAT method versus HIV-1 p24 are consistent
15	with the hypothesis that the NAT method is of equal or
16	greater sensitivity including the ability to detect major
17	subtypes."
18		[Slide.]
19		The second question is, "If committee members
20	disagree, we would like you to comment on an appropriate
21	alternative."
22		Thank you.
23		DR. HOLLINGER:  Thank you, Indira, for that nice
24	summary of what we are going to be discussing.
25		I think we will just move right now on.  Dr. Busch

			44 1	is going to now give us some initial data here, and then we
	2	have several presentations afterwards.
	3		Mike?
	4		              Presentation
	5		DR. BUSCH:  Thank you.
	6		[Slide.]
	7		I would like to take a moment to also acknowledge
	8	Blaine's leadership on this committee.  He has dribbled his
	9	way through all these problems.  Many of you may not know
10	that Blaine was actually on the basketball team with Wilt
11	Chamberlin at Kansas, about the year I was born.
12		Blaine is actually an amazing person in that every
13	time, for example, these committee meetings, when I would

14	send him material, and recently was a good example, about
15	two or three weeks before.  Now, FDA is quite religious

16	about getting material out to committee and, within two days
17	of sending that stuff out, I have about a four-page E-mail
18	from Blaine critiquing the data and with comments and
19	corrections on the material.  So he is a very conscientious
20	leader here.
21		[Slide.]
22		What I was asked to do is to review the issues

23	around p24 antigen in the blood and plasma-donor setting. 
24	My presentation will review the data briefly about what
25	really led to the introduction of p24 antigen.  I think it

			45 1	is an interesting brief review, particularly how we actually
	2	got into plasma-donor screening for p24 antigen.
	3		Then I will briefly summarize data that you will
	4	hear in much more detail later, the actual experience with
	5	p24 antigen, particularly in the whole-blood sector, because
	6	I think it was surprising in terms of the yield being
	7	substantially lower than predicted and some explanations
	8	around that.
	9		The most important part of the talk is really the
10	analysis that Indira alluded to, trying to understand the

11	relationship between viral RNA levels and antigen levels
12	during the early what we call ramp-up phase of viremia, the
13	pre-seroconversion phase, in order to get quantitative data
14	to base a decision to discontinue antigen on, in terms of

15	what level of sensitivity should a nucleic-acid test achieve
16	in order to confidently detect any antigen-positive units
17	during the window period.
18		Then I also added a little bit of data, at
19	Indira's request, in terms of the issue of viral subtypes,
20	both with respect to the distribution of non-B clade
21	infections in the U.S. donor setting and the sensitivity of
22	the NAT assay system's two different subtypes.
23		[Slide.]
24		So just briefly, there were early studies--
25	actually, Sue Stramer, who is now at the Red Cross was, I

			46 1	think, the first to publish in JAMA a major paper showing

	2	the detection of p24 antigen in early seroconversion using
	3	plasma-donor seroconversion panels.  Those panels remain a
	4	mainstay of our understanding of early dynamics of viremia.
	5		But this led to the clear evidence that, at least
	6	in the plasma-donor sector, individuals could give blood in
	7	an antigenemic phase detectable by p24 antigen tests prior
	8	to the development of antibody tests.
	9		That led to the initial concern around the
10	potential that antigen testing should be used to screen the
11	blood supply and led to two large-scale national studies to
12	evaluate p24 antigen.  This was back in the late '80s. 
13	There was a national study led by Harvey Alter that tested
14	over half a million donations on-line.  It was actually a
15	very large, the largest at that point, clinical trial.
16		Now, of course, NAT has long surpassed this.  But

17	over half a million donations were screened in parallel with
18	standard serologic tests and p24 antigen and no antigen-

19	positive antibody-negative donations were detected in this
20	study.
21		The second study, and these two papers were
22	published back-to-back in the New England Journal of
23	Medicine, was a study of high-risk donations given to the
24	Transfusion Safety Study just prior to the availability of
25	the HIV antibody assay.

			47 1		There were 200,000 donations to this repository. 
	2	What we did was to select about 8,500 that were from donors
	3	who were the right age males in zip codes which had the
	4	highest prevalence of HIV.  The rationale here was that we
	5	were going back to a time late in 1984 when the rate of new
	6	infections in the communities were much higher than in 1989
	7	and, therefore, we were selecting a population of antibody-
	8	negative samples that theoretically would have been enriched
	9	for early infections.  Yet, we found no p24-antigen-positive
10	donations.
11		So, these two studies at the time led to the
12	interim conclusion that antigen testing did not seem to have
13	any value for whole blood or blood donor screening.  Over
14	the subsequent several years, three case reports were
15	detected in the U.S. of antigen-positive antibody-negative
16	units through back testing of donors who seroconverted. 
17	These were associated in several cases with HIV
18	transmission.
19		So these were some anecdotal cases that suggested
20	that these earlier studies may not have been adequately
21	sized.
22		Then work from Ken Nelson, actually in Thailand,
23	demonstrated significant yield of p24-antigen-positive
24	antibody-negative donations in the blood-donor setting in
25	Thailand.  In fact, in Thailand, they introduced p24 antigen

			48 1	screening.
	2		If you extrapolate this to the U.S. donor setting,
	3	you would actually estimate about five to ten infections per
	4	year might be detected in the U.S. donor setting based on
	5	relative prevalence rates.
	6		Finally, the REDS modeling approaches sort of
	7	began to look at the issue of antigen screening.  Based on
	8	the duration of the antigen window and the incidence in the
	9	U.S. donor setting, estimates of about five to ten antigen-
10	positive antibody-negative donations per year were
11	projected.
12		[Slide.]
13		This is an interesting slide that was some of the
14	early model data based on seroconversion panels just to give
15	you some illustrations.  At the time, we had probably about
16	30 or 40 of these panels that were analyzed to estimate the
17	duration of the antigen-positive antibody-negative window.
18		As you will see, in many panels over the next,

19	probably, several days, the typical pattern is really very
20	consistently observed with a ramp-up of viremia, RNA load
21	increasing, then p24 antigen, and then the antibody tests. 
22	The green here is the new or third-generation assay which
23	has actually been around for now ten years in blood
24	screening--at the time, new--that pick up the early IgM
25	response.

			49 1		So you can see, in many of these panels, there is
	2	increasing signal in the more sensitive third generation

	3	antibody tests.  These tests have been estimated to close
	4	the antibody window by about two weeks compared to the
	5	earlier IgG-sensitive assays.
	6		So the improved antibody tests were thought to
	7	have made a dramatic impact on safety and, indeed, did. 

	8	But, nonetheless, the data was suggesting that there was an
	9	antigen-positive spike estimated at about five days prior to
10	antibody.
11		But one other thing this slide illustrates that we
12	didn't understand at the time is that people don't donate at
13	a consistent pattern over this period of early HIV
14	infection.  Again, these are plasma donors who are eligible
15	and usually give twice a week.  This was a slide that was

16	made back in the early 1990s before we knew the problem of
17	the yield being not as high as we now realize.
18		What this shows is that these donors often give
19	twice a week, twice a week, and then they skip a week;

20	again, twice a week, twice a week, skip a week; twice a
21	week, twice a week, skip a week.  This is consistently

22	observed across these panels that these plasma donors do not
23	give as frequently during the antigenemic spike.
24		We will come back to this because we think this is
25	the explanation for the lower-than-predicted yield of p24

			50 1	antigen testing.
	2		[Slide.]
	3		So, in any event, through the modeling estimates,
	4	we have estimated that the period of time prior to antibody
	5	that is p24-antigen-positive is approximately six days, and
	6	then there is about a five-day viremic pre-antigen phase. 

	7	It is these numbers that led to the predictions of about
	8	five to ten infections per year by combining this six-day
	9	antigenemic window phase with the incidence rate of new
10	infections in the whole-blood-donor setting, one can
11	estimate the rate at which people would give during this

12	transient seroconversion window period.  That ends up being
13	about five to ten per year.
14		[Slide.]
15		The other data that was addressed, and there was a
16	BPAC meeting back in the 1994 time frame where all of these
17	data were reviewed, the new evidence of case reports and the
18	yield projections.  At that time, also, in hindsight
19	probably a mistake, there was data presented on the cost-
20	effectiveness of p24 antigen screening derived by Jim
21	AuBuchon based on the projected yield of five to
22	ten antigenemic donations per year which would prevent ten
23	to fifteen infections at a projected cost range of $3 to $5
24	per unit, or probably in the range of $60 million per year.
25		Out of that analysis, Jim derived cost-

			51 1	effectiveness estimates for both antibody testing and

	2	antigen testing.  You can see that antibody testing is
	3	really quite cost-effective, about $3,000 per quality life
	4	year, relative to the usual benchmark of $50,000 considered
	5	procedures that are medically indicated.

	6		In contrast, p24 antigen at the time was estimated
	7	to have a cost-effectiveness of $2.3 million per quality
	8	life year, well out of the window of usual public-health
	9	measures.  That data was presented to BPAC.
10		[Slide.]
11		In addition, there was concern about what is
12	called the magnet effect, which is the concept that if there
13	is a new, better test available in blood banks, could you

14	actually recruit high-risk people who are seeking that test
15	at a rate that would actually offset the benefit of the
16	test, the idea that this was of concern early on in HIV in
17	the context of anti-core testing.
18		But, in any event, there was evidence that there
19	were donors who were infected who were seeking tests, both
20	HIV positive donors and seronegative donors, based on
21	surveys.  We knew that the antigen test would only reduce
22	the window partially, perhaps 30 to 50 percent.  So if you
23	more than doubled the rate of high-risk donors, you could
24	actually have a negative impact on blood safety by adding a
25	test that would only reduce the window period in half.

			52 1		At the time, though, the REDS group did a formal
	2	analysis that was published which actually concluded and,
	3	again, presented to the BPAC was the conclusion that it was
	4	extremely unlikely that any kind of magnet effect could
	5	offset the benefit of window-period closure with respect to
	6	adding the antigen assay.
	7		[Slide.]
	8		So, finally, at the BPAC meeting in June, 1995,
	9	this kind of all came to a head.  At that meeting, after all
10	of the data I just summarized was presented, there was
11	actually a vote of 9 to 6 recommending against licensure of
12	p24 antigen.  This resulted in an immediate backlash. 

13	Congressman Shays who was in charge of the oversight
14	committee of FDA at the time wrote a letter within a month
15	that explicitly indicated that the estimates that were
16	presented were gross underestimates of yield.
17		Somehow, he derived estimates of at least 50 to
18	100 per year would be interdicted and that it was
19	inappropriate and outside of the FDA's mandate to have
20	considered cost-effectiveness data and that there was too
21	much industry influence on the committee.
22		This led, within the next several weeks, to

23	basically complete revision of the membership of the
24	committee with all blood-banking members being excluded,
25	considered as industry representatives.  Then, a month

			53 1	later, FDA issued their memorandum.
	2		Now, up to this point of the FDA memorandum, all
	3	of the discussion that I was involved with and was aware of
	4	was focussed on the need to implement antigen potential need
	5	in the whole-blood sector.  As Indira mentioned, there had
	6	not been a transmission of HIV by a plasma derivative in
	7	over eight or nine years.  So everyone--at least I--assumed
	8	that the issue of plasma derivatives was safe as a
	9	consequence of the inactivation procedures and that the
10	discussion around adding p24 antigen was limited to the
11	blood-donor sector.
12		But, when the memorandum came out, it extended the
13	requirements to plasma donors as well.  That is really the
14	issue we are talking about now, which is considering
15	eliminating an assay which, in some context, was never even
16	indicated in the first place.
17		[Slide.]
18		The next comments are just in terms of, briefly,
19	the experience with yield.  Again, I think you will hear a
20	lot of data from the plasma industry as well as Sue Stramer
21	for the whole-blood sector that will give you much more
22	detail.  But the bottom line in whole-blood screening is
23	that the yield has been significantly less than predicted.
24		We have, I believe, detected five antigen-positive
25	antibody-negative donations now in approximately five years

			54 1	of screening.  So that is a rate of about 1 per 10 million,
	2	which is significantly less than the predictions of about 5
	3	per 10 million.  This reflects, in part, the declining
	4	incidence of HIV in the whole-blood sector but also what I
	5	alluded to earlier which is a bias, and that people probably
	6	do not give during that antigenemic phase of infection.
	7		There is also no evidence of a magnet effect, no
	8	evidence of a change in rate of HIV-positive donors giving
	9	during the pre- and post-introduction of antigen screening. 
10	The assay has performed relatively well in terms of
11	specificity but a 0.02 percent repeat reactive rate still

12	translates into thousands of donors being deferred annually
13	in the whole-blood sector.
14		In addition, one of the problems that Sue will

15	present is that we observed a moderate rate of donors who
16	were positive, not only on the screening assay, but

17	neutralized, meaning they were thought to be true
18	infections.  But, in fact, what we have realized is that the
19	assay is prone to false neutralization, false confirmation,
20	these donors are RNA-negative and are negative for other
21	studies to see if there might be some new or unknown
22	retrovirus present.

23		[Slide.]
24		Just a few comments here.  As I indicated, we
25	overestimated yield.  The bottom line is the models assumed

			55 1	a steady-state rate of donations during these phases of
	2	primary viremia.  But, in fact, what we now appreciate,
	3	through some formal analyses, is that that is not true, that
	4	there is a bias in that the rate of people giving during the
	5	per-seroconversion phase of HIV is significantly lower than
	6	the rate that these people give during other stages.  So,
	7	looking at individuals over time, the immediate pre-
	8	seroconversion phase, they tend to self-defer.
	9		This is probably related either to symptomatic
10	events of primary HIV syndrome or to risk behavior or to the
11	fact that we take temperatures of people at donation and
12	primary HIV during the antigenemic spike is often a febrile
13	phase.
14		[Slide.]
15		Now I am going to shift gears and present some
16	summary data on the modeling of RNA versus antigen.  As
17	Indira summarized, RNA tests are now routinely performed for
18	HIV and HCV, both in the whole-blood and plasma-donor
19	sector.  They have been phased in over the last two years. 
20	Retrospective studies have shown that the viral load the p24
21	antigen cutoff is about 10,000.
22		So, theoretically, any minipool NAT system that
23	can detect greater than 10,000 copies should be greater than
24	the capacity of p24 antigen.  I will show you a lot of data
25	to support that.

			56 1		In addition, as you will see from several
	2	speakers, I am sure, extensive prospective studies that have
	3	monitored the ability of these NAT screening programs to
	4	detect p24-antigen-positive samples have demonstrated
	5	consistent detection, both of sort of real-world antigen
	6	positives that are being screened in parallel but, also, a
	7	number of programs have conducted external control assay
	8	runs where every single run includes p24-antigen-positive
	9	controls that are literally set at the cutoff of the antigen
10	assay.
11		I am sure you will see data later that will show
12	that these are consistently deleted through minipool NAT

13	screening.
14		[Slide.]
15		What I want to present is a recent analysis that
16	we have done in the context of the REDS study group.  Ebi
17	Fiebig is the person who did the biostatistical analysis on
18	this.  It is based on 146 donations that were given during
19	the pre-seroconversion phase from 43 seroconverting plasma
20	donors.  These were plasma donors identified and collected

21	through the Alpha Therapeutics Program and the repository of
22	these plasma units was coordinated by Bioclinical Partners.
23		These donors were screened prospectively by p24
24	antigen using the Ortho/Coulter assay and the antibody tests
25	were performed both with Abbott and Genetic Systems on all

			57 1	of these panels.
	2		The PCR data is from NGI.  It is both qualitative
	3	and quantitative, but the data I will be compiling and
	4	showing is based on their quantitative PCR assay.  In the
	5	more refined model that I will show, there were 146 antigen-
	6	positive antibody-negative donations that were analyzed.  We
	7	actually truncated that dataset because, at the top end of
	8	the antigen spike, the RNA loads begin to flatten out.
	9		So, as we are trying to more precisely model the
10	cutoff and the relationship during the ramp-up phase, the
11	analysis was limited to 94 RNA-positive samples in the ramp-
12	up phase.  Those were then analyzed using a model that David
13	Wright at Westat developed called the multivariate
14	longitudinal regression model.
15		[Slide.]
16		This just illustrates the kind of panel data.  You
17	saw some earlier.  Again, what we are focused on now are
18	samples that are given during this very brief period when
19	RNA load is ramping up and we are looking at the
20	relationship on a sample-to-sample basis of the RNA load
21	versus the antigen level.
22		[Slide.]
23		This is actually an earlier dataset but it
24	illustrates that when you do a lot of these panels, you can
25	then compile the data from a lot of these panels on a single

			58 1	time line, either through extrapolation or other methods. 

	2	You can get a sense, then, of the difference in the ramp-up
	3	rates of viremia and then, after seroconversion, all of
	4	these people ramp down their viremia.  But we are focussing
	5	here on this early ramp-up phase of viremia.
	6		[Slide.]
	7		The first thing we did was to simply divide these
	8	samples up, these 146 samples, into those that were RNA-
	9	positive only versus those that were p24-positive.  This is
10	what is called a "box and whisker" plot which is just a

11	distribution of the RNA loads, the concentration of RNA,
12	during the RNA-only phase versus the p24-antigen-positive
13	phase of seroconversion pre-antibody.
14		What you see here are the summary statistics. 
15	Most important for this discussion is the viral load

16	distribution during the antigen-positive phase.  The
17	critical question to the committee is how good do RNA tests
18	need to be so that we can be completely confident that any
19	antigen-positive samples could be detected if we were to
20	discontinue the antigen test.
21		What this analysis indicates is that the median
22	RNA concentration during the p24 antigen-positive antibody-
23	negative phase is 140,000 genome equivalents per ml and,
24	most importantly, the lower bound of the 95 percent
25	confidence interval, if you will--the lower 2.5 percent

			59 1	inclusion limit is 7,300 copies.
	2		So if we have an assay system that can detect
	3	7,300 copies of HIV RNA, we can be confident, from a
	4	statistical perspective, that that would detect 97.5 percent
	5	of antigen-positive antibody-negative samples.
	6		Interestingly, these 85 specimens that have been
	7	derived from these selected plasma-donor panels represent
	8	something in the range of 20 years worth of whole-blood
	9	screening in terms of the rate of detecting antigen-positive
10	donations.
11		[Slide.]
12		We have also done a more sophisticated modeling,
13	as I indicated, based on these 94 samples during the ramp-up
14	phase using this statistical model.  This is what is called
15	a "spaghetti plot," which is plotting out the RNA loads over
16	time from the first positive RNA sample datapoint for these
17	94 panels.
18		From this analysis, you can derive a slope for
19	each of these seroconverters based on the RNA load increase
20	over time.  From that slope, you can derive a doubling time,
21	which is the estimate of the rate at which viral load
22	increases over time.  That is estimated at 21.5 hours.  So,
23	in other words, the concentration of HIV RNA increases in

24	plasma two-fold approximately every 21 hours.
25		[Slide.]

			60 1		What we looked at a moment ago was the
	2	distribution of RNA concentrations of p24-antigen-positive
	3	versus negative.  Another approach to get at what
	4	sensitivity should a test have in order to be comfortable

	5	discontinuing antigen is to try to estimate the cutoff at
	6	which all these seroconverters would break the p24 antigen
	7	cutoff level.
	8		In order to do that was this more sophisticated
	9	model, but basically the simple way to show this is to

10	express the concentration of RNA against the signal-to-
11	cutoff level of the p24 antigen assay.
12		So, in this graph, what we have done is to
13	express, on the X axis, the p24 antigen signal-to-cutoff. 
14	It is actually the log.  So zero is when each of these
15	seroconverters break the cutoff of p24 antigen.  Then, this
16	is the log of RNA concentration.  So this is a regression
17	plot of the RNA load relative to the p24 antigen signal to
18	cutoff.

19		The intercept of this regression plot tells us the
20	level of RNA at the point of p24 antigen seroconversion for
21	each of these seroconverters.
22		[Slide.]
23		The next slide summarizes the statistics on this
24	regression analysis.  The bottom line is that the p24
25	antigen assay cutoff, and this is based on the Coulter test

			61 1	and we have done this for the Abbott test as well and it is
	2	actually slightly higher, is almost exactly 10,000 genome
	3	equivalents per ml.
	4		So, again, so long as an assay achieves an RNA
	5	screening system, achieves the sensitivity of 10,000 genome
	6	equivalents per ml, it would detect antigen-positive
	7	seroconversion samples at the point where they actually
	8	achieve cutoff of the antigen assay.  So this is really a
	9	much more rigorous sort of approach to address the question
10	of what level of sensitivity should an RNA system achieve.
11		[Slide.]
12		Based on this analysis, I feel comfortable and I
13	think the FDA recommendation is even somewhat conservative,
14	that a p24 antigen test really should have a sensitivity of
15	at least 10,000 copies in order to recommend discontinuation
16	of p24 antigen and should, theoretically, if it can achieve
17	that sensitivity, detect additional yield beyond p24
18	antigen.
19		As you heard, I think FDA's requirement or

20	proposal is that systems achieve at least 5,000 genome
21	equivalents per ml, so they have sort reduced the level to
22	be more stringent.
23		[Slide.]
24		I want to just briefly talk about HIV subtypes. 
25	There is concern that these unusual subtypes, at least in

			62 1	the United States, may begin to traffic into the U.S.  As
	2	you will all, I am sure, know, the major subtype that seeded
	3	the epidemic in the U.S. was what is called clade B
	4	infection, group M, clade B.  That still amounts for the
	5	vast majority of infections in this country and, most
	6	importantly, the vast majority of new continued spread of
	7	infections is clade B.
	8		But, over the last five years or so, there has
	9	been documentation of non-B-clade infections including
10	group O and HIV-2 in the U.S.  Virtually, all of those
11	infections were imported, meaning that they were individuals
12	who had moved from or military personnel who had been
13	stationed in regions of the world where these non-B
14	infections are prevalent.
15		They were infected in those countries and then
16	moved to the United States.  So, again, we are talking here
17	about window phase so the real issue is what are the
18	incident infections, the newly transmitting strains.  Again,
19	a number of studies have shown that virtually all of the new
20	infections going on in this country remain clade B
21	infections.
22		[Slide.]
23		We have, under the support from the Center for

24	Disease Control, conducted a fairly large study to monitor
25	for unusual subtypes of HIV in the U.S. donor setting.  A

		63 1	paper is in press next month in Transfusion and will be
	2	published that characterizes the rate of unusual subtypes
	3	actually going back to samples from that early transfusion
	4	safety study testing samples from hemophiliacs who were
	5	infected in the very early 1980s from donors who undoubtedly
	6	were infected probably in the late '70s, moving on the very
	7	earliest infected donors found from TSS, 97 donors found
	8	through that repository as HIV positive and then continuing
	9	on to more contemporary samples from donors enrolled in the
10	CDC surveillance study, 400 donors from '93 to '96, and then
11	recently updated with an additional 265 donors from '97 and
12	'98.
13	          You can see that, in terms of non-B-clade
14	infections, none were detected in these early samples, but
15	we did begin to see a small percentage, about 1 percent, of
16	HIV-infected donors in the last two periods of time are
17	determined to be infected with non-B-clade infections.  We
18	have seen some As and some Cs.
19	          These are all individuals who have actually come
20	to the U.S.  They were infected in Africa and came to the
21	U.S. so were not acquisitions here.  They are more concerned
22	with the antibody tests than window-phase detection but it
23	does document that we are beginning to see, and there are

24	other studies in other settings as well that are
25	documenting--beginning to see infections by these unusual

			64 1	subtypes in the United States.
	2		So we do need to be proactive and assure that the
	3	tests are detecting these subtypes.
	4		[Slide.]
	5		The next couple of slide will just summarize, for
	6	several of the assay systems, the capacity of these new TMA
	7	and other kinds of PCR assays to detect subtypes.  This is

	8	some data that was shared with me by GenProbe.  GenProbe
	9	has, in their clinical trials, evaluated a large number of
10	both tissue-culture viral isolates as well as clinical

11	specimens from different subtypes of HIV, all HIV-1.
12		[Slide.]
13		In this analysis, where they looked at the CBER
14	subtype panel, they diluted--CBER has a panel of non-B-clade
15	infections.  These were diluted down to identify the
16	endpoint at which the assay goes from positive to negative. 
17	So, in each of these slides, you will see kind of two lines
18	that really flank the endpoint where the assay is
19	consistently detecting these samples as positive compared to
20	the next dilution where it begins to miss some.
21		The viral load is estimated at each of these
22	endpoints.  What you can see is, across each of these clade
23	infections, that the TMA assay is able to detect HIV at
24	dilutions that are equivalent in viral load to the range of
25	10 to 80 or so viral genome equivalents per ml.  So these

			65 1	assays do have high sensitivity to these variant infections.
	2		[Slide.]
	3		Additional data from GenProbe looking at some even
	4	more unusual subtypes, group O infection, some recombinant
	5	clade infections that have been recently characterized, and
	6	H.  Again, they ran these at both 300 and 100 copies per ml
	7	inputs and they had 100 percent detection of I think this
	8	was 20 replicates both in their combination multiplex
	9	screening assay as well as in the discriminatory test, so
10	excellent sensitivity to these HIV-1 subtypes.
11		[Slide.]
12		Finally, similar data that has actually been
13	submitted for publication from Roche on their HIV-1 donor-
14	screening assay system.  They actually had a number of viral
15	particles that were actually--the concentration was actually
16	characterized by EM particle count, so very precise
17	estimation of the concentration of virus.
18		What we are looking at here is viral
19	concentrations ranging from 20 up to 200 genome equivalents
20	or particles per ml and then they are looking at different--
21	this is actually a shortened version of their table just
22	showing two representative viral isolates for each of these
23	different subtypes.
24		What you can see--this is this bolded kind of area
25	here--is the endpoint of detection.  You can see that they

			66 1	consistently detect in the range of 30 to 75 genome
	2	equivalents per ml, they begin to get 100 percent hit rates. 
	3	So, again, both the major whole-blood screening platforms,
	4	either GenProbe and Roche systems, both seem to have
	5	excellent sensitivity to HIV-1.
	6		Both systems are HIV-1 specific.  They do not
	7	detect HIV-2.  But this is very reassuring data in terms of
	8	the concern around subtype detection.
	9		[Slide.]
10		I think the last slide, just a conclusion slide. 
11	What I have tried to summarize is a kind of history and then
12	to explain that I think, in fact, our early projections were
13	slight overestimates of yield in addition to cost
14	effectiveness needs to be revised because the yield was so
15	much lower that the cost effectiveness, at least in the
16	whole-blood sector would now come in at around $10 million
17	per quality life year.
18		We have had some unexpected problems in terms of
19	false-positive neutralization but, most important, I do
20	believe that the minipool match screening platforms that are
21	in place, both in the plasma and whole-blood sector, do make
22	p24 antigen redundant and that we should recommend
23	discontinuing this test so long as these systems achieve the
24	sensitivity standard recommended by FDA.
25		Thank you.

			67 1		DR. HOLLINGER:  Thank you very much, Mike.
	2		Are there questions now from the committee of Dr.
	3	Busch while he is here?  We can always bring up other
	4	questions later.
	5		DR. SCHMIDT:  Blaine, just to mention another
	6	relationship between the antigen and the FDA, the original
	7	report on the no findings in 500,000 donors was presented at
	8	a conference, a big conference, set up by the Institute of

	9	Medicine.  The real reason we got it set up that way was we
10	were trying to get the Institute of Medicine involved in

11	decision-making processes so there would be another big
12	voice out there that the FDA might listen to even though
13	they didn't have to.
14		Somebody got up in the audience and said, "Well,
15	if you just found one in those 500,000, maybe we could set
16	up some sort of system in the Institute of Medicine for

17	evaluation in the future," but the whole conference fell
18	through for that reason, that nothing was found.
19		DR. HOLLINGER:  Any other comments to Dr. Busch?
20		Mike, just a question--I don't want to dwell on it
21	because of the numbers and the time that these specimens

22	were collected.  I think a real important question is not
23	always just 97.5 percent and so on, but how many specimens
24	were actually below 5,000.  I saw one that is 596 that was
25	in there, but how many other specimens were in there that

				68 1	were below the 5,000 level.
	2		These are specimens collected over twenty years, I
	3	understand, in many cases.  They are specimens representing
	4	about 200, 300, samples of seroconversion specimens.  Of
	5	those that were antigen-positive, that were in the
	6	seroconversion period--that were antigen-positive and
	7	antibody-negative, how many were actually below 5,000?
	8		DR. BUSCH:  I would need to look at that.  I think
	9	I do have the dataset here so why don't I look into that. 
10	There was only really one sample that was an outlier.  In

11	fact, one seroconverter, as you noticed, had sort of three
12	values over time where that particular seroconverter had a
13	lower RNA to antigen ratio in their viral particles over
14	seroconversion.
15		There was one datapoint that may have approached
16	that 5,000 limit, but let me confirm that.

17		DR. HOLLINGER:  Okay.  I am always concerned about
18	outliers also because I am never sure about that sample and
19	so on.
20		Dr. McGee?
21		DR. McGEE:  On your regression slide where you
22	give the 10,000 point estimates, were the numbers in
23	parentheses the 95 percent confidence intervals?
24		DR. BUSCH:  Yes; I wish you hadn't noticed that. 
25	That was a confidence bound around the point estimate of the

				69 1	cutoff intersect.
	2		DR. McGEE:  The lower estimate for that was well
	3	below 5,000.
	4		DR. BUSCH:  Right.  It is important that you

	5	recognize that.  On the other hand, it is important, I
	6	think, that we put into context what we are saying there. 
	7	One, this is a statistical estimate of the point in time. 
	8	What we are trying to get at is, for all these different
	9	seroconverters, there is this five-day period or so or
10	antigen-positive antibody-negative ramp-up viremia.

11		For each of these seroconverters, we are trying to
12	back estimate the exact concentration for RNA at the point
13	where they theoretically--that moment where they cross
14	through the level of RNA to achieve antigen.  What we are
15	talking about is the confidence bound around our back
16	projection of that intercept.
17		To me, it would be ultraconservative to expect

18	that a system could detect every possible--and, again, the
19	numbers, the panels, et cetera, are not sufficient, perhaps,
20	to get a more precise estimate around that intercept.
21		DR. HOLLINGER:  Toby?
22		DR. SIMON:  I just want to clarify.  The question
23	that we have is to demonstrate that the particular licensed
24	NAT method can detect HIV at a level of 5,000 copies per ml. 
25	That is the question before the committee.  Based on your

			70 1	presentation, are you asserting that it should be 10,000
	2	instead of 5,000?
	3		DR. BUSCH:  There were two numbers that I think
	4	are critical.  One is the 10,000, which is the estimate of
	5	the cutoff level based on these seroconversion panel
	6	analyses, the level of RNA at which different seroconverters
	7	cross through the cutoff of p24 antigen.
	8		The other analysis was much simpler but perhaps
	9	much more straightforward and logical which is simply
10	looking at the distribution of the RNA load among all the

11	antigen-positive samples that were available.  That had a
12	lower, 2.5 percent, confidence inclusion bound of 7,500
13	copies.
14		So I think the FDA proposal of 5,000 is the

15	appropriate one.  It is also, I think, an achievable one. 
16	It is below both of those lower bound estimates.
17		DR. NELSON:  If there were an outlier that was
18	below that, presumably what you are saying is that outlier
19	would also be probably negative on p24 antigen test.  I

20	remember, there was a single case report in the JAMA a month
21	or two ago where there was an antibody-negative
22	transmission.
23		I can't remember what the NAT and--presumably,
24	that person was negative on both p24 and NAT.  I think what
25	you are saying is these two measures sort of travel

				71 1	together, isn't it?
	2		DR. BUSCH:  No; I think that is incorrect.  That
	3	JAMA paper, those samples were RNA-positive antigen-negative
	4	in that seroconverter.  The RNA tests are much more
	5	sensitive.  If you are asking a head-to-head comparison, RNA
	6	wins out hands down.  What you saw there was all of those
	7	other samples that were only detectable by RNA.
	8		So RNA buys us much more window-period detection
	9	than antigen.  But, in order to drop a test, I think we are
10	asking a somewhat different question; are we absolutely
11	confident that antigen will not miss anything that RNA might
12	have detected.  On a head-to-head comparison, RNA wins hands
13	down.
14		DR. NELSON:  I asked the question just to get to
15	the outlier issue; in other words, the outlier would also be
16	an outlier for p24, I suspect.
17		DR. HOLLINGER:  Although I think, Ken, that that 
18	outlier was p24-antigen-positive.
19		DR. BUSCH:  Right.  Again, it is theoretically
20	possible, and that one case suggests, that in some cases, it
21	is probably an issue of the primer pairs not accurately

22	amplifying up a particular sequence.  But, in some cases,
23	two specific assays, you can have, theoretically, levels of
24	detectable p24 antigen that break cutoff whereas the
25	amplification assay fails to amplify the RNA.

			72 1		Theoretically, it could be defective viral
	2	particles or something like that.  But, more likely, it is

	3	the primers.  Again, that particular case was based on the
	4	NGI system.  We actually haven't run that sample with the
	5	other platforms.

	6		DR. HOLLINGER:  I think we should not also forget,
	7	as Dr. Hewlett put up there, that there are other viral-
	8	inactivation-removal factors here for the plasma industry
	9	also.
10		Paul?
11		DR. McCURDY:  Mike, one of the take-home messages
12	I thought I got from that JAMA article was that pooled RNA
13	might not pick up samples like that one.  Is that correct or
14	am I misremembering?
15		DR. BUSCH:  That is correct.  We will be talking
16	later today a little about the issues around NAT and
17	individual versus pooled.  Individual donation would further
18	close the window for HIV by about four or five days.  So

19	there are definitely good examples of samples, as that
20	illustrated, and that are infectious, that are only

21	detectable consistently with single-donation NAT.
22		DR. HOLLINGER:  Dr. Epstein?
23		DR. EPSTEIN:  I guess it is important to recognize
24	here that we are talking about minipool NAT at this time

25	versus single-unit antigen at this time.  It is not an

			73 1	accident that the standard that FDA put forward for minipool
	2	NAT resembles the current sensitivity of antigen.
	3		The fact of the matter is that what we were trying
	4	to do--in other words, when the question presented itself,
	5	how shall we set a standard for minipool NAT.  We decided
	6	that it should be at least as good as what we were currently
	7	doing, which was antigen screening.
	8		The goal was not to overreach the currently
	9	available technology.  So now what is going on is--that was
10	all done in prospect.  Now we have datasets that we can
11	examine since we have had experience with the minipool NAT. 
12	So, in essence, we are really asking the question, did we
13	set the standard in the right place.
14		It is important to bear in mind that we have
15	clearly focused today's decision only on plasma for further
16	fractionation where there is the safeguard of viral
17	inactivation.  The goal in screening for p24 was to make
18	sure that there was a limit set on the viral burden that can
19	enter a fractionation pool.
20		What we are really asking is if you now do that

21	with minipool NAT, is that sufficient or do you still need
22	to do antigen besides.  I think the way we have to look at
23	it is whether we have achieved an equivalent sensitivity
24	standard.
25		It is not necessarily the case that they have to

			74 1	be identical on all samples tested.  It just has to be the
	2	case that, overall, it is as good or better.  I just thought
	3	it was important to point out that we may have a more
	4	stringent standard in mind when this question reemerges for
	5	whole-blood screening because you are not going to have the
	6	backup of viral inactivation.
	7		So it is comparability overall and a reason we are
	8	at the margin, comparing the two sensitivities, is because
	9	we tried to set the sensitivity requirement for minipool NAT
10	at the level of antigen sensitivity.  It looks like we got
11	very, very close.
12		DR. HOLLINGER:  Thank you, Mike.  We appreciate
13	that review.
14		Now, we have several presentations from a variety
15	of groups.  I would like to ask you to keep on the time that
16	you were asked to stay with.  The first one is Andy Conrad
17	from NGI.  Andy?
18		          Open Public Hearing
19		              Presentation
20		DR. CONRAD:  Good morning.
21		[Slide.]
22		I am here today to present the data, and my
23	associate from Alpha, Chuck Heldebrant, will also present
24	some of the secondary data from a follow-up study, about a
25	prospective study we conducted on pooled plasma to determine

			75 1	whether or not the polymerase chain reaction in these pools
	2	could detect HIV-positive samples prior to p24 testing of
	3	individual samples.
	4		[Slide.]
	5		So, basically, we understood that the blood-
	6	derived products had the potential to transmit virus and had
	7	in the past.  We wanted to see, under the system where
	8	donations are currently tested for a variety of antibodies
	9	and antigens, if we could use, as well as the p24, pooled
10	PCR to detect the HIV at an equal or earlier time point.
11		[Slide.]
12		Basically, that was our goal, the demonstration of
13	the plasma-pool testing system could beat the p24.
14		[Slide.]
15		So it was a prospective study.  It included
16	342,729 donations from approximately 48,000 donors collected
17	randomly over a three-month period.  Individual samples were
18	tested for anti-HCV, HIV antibody, HIV p24, HBV s antigen as
19	well as ALT levels.  So the standard tests were performed.
20		Samples from new donors--in other words, donors

21	that were just applying, had all these tests done prior to
22	the time that they were pooled in PCR but samples from
23	repeat donors or qualified donors were just immediately
24	pooled for PCR.  So you will see that some of these
25	donations have the possibility of being positive for these

			76 1	other markers because they were PCRed prior to being
	2	screened out for those other markers.
	3		[Slide.]
	4		Under our IND and our subsequent BLA and PLA
	5	submission, the mean sensitivity of this assay, with
	6	95 percent confidence, was 3.1 virions with a 95 percent hit
	7	rate of 5 virions.  So, in a pool of 512, you are talking
	8	about detecting individual samples with around 2,500 copies
	9	of HIV.  This becomes important later but you will see why.
10		[Slide.]
11		Essentially, for the last time, I will explain how
12	we do this.  We use automated robots called Tecan devices. 
13	I am sure you have all seen this many times.  This is just
14	what the Tecan looks like.  Essentially, 512 samples are

15	placed on the deck of this machine and the machine pipettes
16	them into a sort of a complex structure.
17		[Slide.]
18		Essentially, what that structure is is that, in
19	groups of eight, they are put into rows, layers and columns. 
20	So each row, layer and column pool will have 64 components.
21		[Slide.]
22		Essentially, what the model of this is is a giant
23	cube.  You can't see the little black lines of the cube
24	because my slide is bad, but it is a giant cube.  You test

25	all 512 members of the cube.  If it is negative, then you

			77 1	can infer that all 512 members are negative or at least
	2	below the cutoff of 2,560 that I just described to you.
	3		If it is positive, by testing the row, layer and
	4	column, you zero in on the positive sample.  So,
	5	essentially, to resolve a positive pool, it takes 25 PCRs
	6	instead of 512 to pick out the positive fellow.  It works if
	7	there are two, or if there are three.  It doesn't matter,
	8	the number.  It gets a little complicated if there are many
	9	more than that.
10		[Slide.]
11		So the rule, again, is if the master pool is found
12	negative, then all its components--and it is 25; I skipped

13	ahead there.  This is essentially what the assay looks like. 
14	It is a series of membranes with nucleic acids bound and
15	probed on them.  You can see that it is fairly digital, that
16	a positive is a positive and a negative is a white space. 

17	It is a dark band if it is a positive and the computer reads
18	these and does the analysis, picks out the row layers and
19	columns.  It is fairly automated.
20		[Slide.]
21		The results of the study.  Eighteen of 348,000

22	donations were found to be positive for PCR for HIV.  Of
23	these donations, ten were both antibody- and antigen-
24	negative.  That means they were pre-p24-positive.  Eight of
25	them were positive for either antibody or antigen, so they

			78 1	would have been excluded by the current system.
	2		These eighteen donations came from only four
	3	donors.  The donors in the plasma industry can donate quite
	4	frequently and, in the time it took for the donors to be
	5	rejected through the process, they had donated several more
	6	times, as you can see.  So there is about 1 in 12,000 donors
	7	were found positive by PCR.
	8		If you sort of take out the eight, it is probably
	9	1 in about 20,000 would have been negative for antibody and
10	antigen.
11		[Slide.]
12		We endeavored to enroll these donors into a
13	follow-up study to sort of see what we could get, see how
14	their seroconversions progressed.  From the two donors
15	enrolled, we got four of the ten donations.  From the two
16	not-enrolled donors, we got six donations.
17		[Slide.]
18		Here is the story of each of those four donors. 
19	Because they donated so many times, we saw a story.  This is
20	an interesting thing, and Mike Busch, I have got to talk to
21	you about this a little bit, because, in real time, in real
22	samples that were collected and were rather fresh and in
23	under fairly stringent conditions, here is the p24 status of
24	those individuals that we tested donations.
25		What you can see here is, here is the pool at 512

			79 1	if it was resolved naturally.  If we had already found the
	2	donor and this was a follow-up study, we diluted at 512 just
	3	to see if it would still have been positive or would
	4	continue to be positive.
	5		The most important number, I think, is over here,
	6	on this Donor No. 1, on the draw from 72997, he was positive
	7	in the naturally detected pool.  It was actually positive
	8	one donation before that with 20,000 virions, but he had
	9	750,000 virions.  This is an anomaly that sort of violates
10	the extrapolated graphs that we have been seeing.
11		In this case, the person turned positive here at
12	about 60,000 virions.
13		[Slide.]
14		The next slide is the other two donors.  This was
15	one of the eligible donors.  Actually, we caught him
16	positive a little bit lower than we would have expected to
17	have caught him positive.  Instead of 2,500, we caught it at
18	20.  But that is the 95 percent detection, so that was a
19	natural--and we never got him to follow up.  He vanished, so
20	we never found out if he would ever go p24-positive.  He was
21	repeat-positive on PCR.
22		The final donor, again, converted to positivity

23	around--it was negative at 40,000 copies and who knows when
24	he turned positive because there was a gap in between those
25	days.  So, at some point, he would have turned p24-positive

			80 1	lower than that.
	2		But those are the numbers.  And so we were alarmed
	3	to find out that there were actually cases when the HIV
	4	viremia was fairly high and the p24 on individual donors was
	5	negative.  So what we did at this point is we said we should
	6	go back and look at all of our donors in the past, in a
	7	retrospective study, that had ever turned HIV positive, get
	8	all of--because what happens is they donate so frequently
	9	that we probably have huge panels of this material.
10		So we went back to a retrospective study.
11		[Slide.]
12		What we did is we got 347 potential HIV donations
13	that came from people we know later had an HIV
14	seroconversion.  What this complicated graph sort of shows
15	is that we looked at what would happen if we tested those by
16	individual PCR, by pooled PCR, using p24 with Coulter or
17	Abbott, or the antibody test.
18		What you can see is that, indeed, there were 41--
19	here, there are 36 cases which would have been detected if
20	you use individual PCR.  However, here there are 41 cases
21	that would have been missed if you used the antigen test
22	alone.  If you would have used the antibody test alone, it
23	would have been 88 cases that would have been missed.
24		So, essentially, it shows that, indeed, individual
25	sample PCR is the best.  Chuck Heldebrant will talk to you

			81 1	about "best" as far as detection.  But with the plasma hold,
	2	it is probably unimportant and Chuck will demonstrate that.
	3		[Slide.]
	4		The next slide is just a different way of showing
	5	this same thing.  Graphically, basically, what you see is

	6	the difference between the undiluted, the diluted, pooled
	7	PCR.
	8		[Slide.]
	9		I think the next slide is the easiest way to
10	actually see.  I think this is the most important message. 
11	It is a two-by-two table.  This is PCR-positive, PCR-
12	negative.  There were 145 cases that were PCR-positive and
13	none that were PCR-negative whereas, if it is Coulter-
14	positive, Coulter or Abbott-positive, there were 81 cases
15	totally in this retrospective of these donations that were
16	found to be negative.
17		I think that that is an incredibly important

18	thing.  There was not a single case that PCR failed to
19	detect before p24.  In the whole retrospective or the

20	prospective study, we did not find a single case when p24
21	brought anything.  And this is a pool of 512.  So I think

22	that is a pretty significant statement about the efficacy of
23	the p24 in comparison with NAT testing.
24		[Slide.]
25		Anyway, those are the conclusions.  There wasn't a

			82 1	single case during the clinical trial where the p24
	2	individual testing detected a donation prior.  The
	3	specificity of the pooled PCR, and that is important because
	4	I think the specificity also is in question about the p24,
	5	how many false positives, there was not a single donor
	6	identified during the course of the trial or in subsequent

	7	trials that was false identified using the polymerase chain
	8	reaction.
	9		The beautiful thing about the matrix is that, as
10	you test the primary, and then you have to go down to

11	smaller and smaller pools, you are essentially really
12	reverifying any result.  It is very hard to get a false

13	positive.  You might get some of the PCR reactions, but that
14	doesn't, then, translate all the way to the donor.

15		Then there were 81 donations that were not
16	detected by p24 but that were found by pooled PCR in the
17	combined prospective and retrospective study we conducted.
18		[Slide.]
19		I would just like to thank all my colleagues at
20	National Genetics and at Alpha Therapeutics.  Thank you.
21		DR. HOLLINGER:  Any questions for Dr. Conrad? 
22	Andy, I have one and it has to do with the level of

23	sensitivity because that really gets back to what maybe can
24	or cannot be, to your confidence that you are going to be
25	detecting.  You mentioned that, at a level of 5, there is a

			83 1	95 percent hit rate.  That means 5 percent are going to be
	2	missed at that, presumably, if I understand that correctly. 
	3	I will ask my statistician over here to help me on that.
	4		DR. CONRAD:  It sounds about right to me.
	5		DR. HOLLINGER:  If that is correct, where are you
	6	at 100 percent?  At what level are you at 100 percent,
	7	because that gets back to the pool size, basically.
	8		DR. CONRAD:  The question is complex because what
	9	we do is we take multiple mls of material and prep it out. 
10	So when you see that it is 5 copies per ml, we also run it
11	with more reactions for the HIV, so it really is a matter of
12	how much you actually sample.
13		Although we can detect five copies per ml, I think
14	the statistics show that at around 18, it was 100 percent
15	detection.  That, again, translates here.  But, remember,
16	Blaine, the important thing about that is it is sort of an
17	interesting statistic in there because you saw the one that
18	we caught below the level.  So there is going to be a
19	continuum in there.
20		The important thing, and I think you will see
21	later, is that with the hold in the subsequent donors, there
22	is a system by which you could guarantee, because the HIV
23	sort of increases fairly rapidly.  It is a matter of
24	catching it, getting it out and at least identifying that
25	donor.

			84 1		So, although the numbers for the 100 percent
	2	detection is a weird math--and Chuck Heldebrant can talk a

	3	little more about it because it was a statistician who did
	4	it for us.  I think is was around 18.
	5		DR. HOLLINGER:  But, at 18, that would mean that
	6	you would really, then--to get 100 percent, you really need
	7	a pool size of about half of what you are doing, so instead
	8	of 512--to pick up 5,000.
	9		DR. CONRAD:  Yes; at 100 percent.  See, the

10	100 percent statistic is weird.  They don't like that
11	statistic.  They think it is very hard to derive.  They do
12	these strange curves and I think that they are inaccurate at
13	100 percent.
14		Dr. Epstein?
15		DR. EPSTEIN:  The negative p24s at very high
16	antigen load raise the question whether your p24 assays were
17	adequately sensitive in the trial.  Can you just comment on
18	the controls and did you use any external control reagents.
19		DR. CONRAD:  I will tell you that, during this

20	trial, it was not us doing the p24, it was an FDA-licensed
21	laboratory for Alpha that was conducting these, certainly
22	under the auspices of their licensure and following the

23	package insert.
24		In addition, what we did is we took the ones--if
25	they used Coulter, we would use Abbott.  In those particular

			85 1	samples, for some reason, we used both kits on them and
	2	found them to be negative.  We subsequently retested them at
	3	NGI.  So, again, we followed the package insert.  I don't
	4	know what the unique situation is.
	5		I want you to know that those particular samples

	6	are separate.  It is a split off the plasma leader.  There
	7	are two tubes dangling off of it and we took one of each. 
	8	So there may be issues about how they were stored or used,
	9	but certainly neither kit detected them.
10		DR. HOLLINGER:  Mark?
11		DR. MITCHELL:  Does that mean to imply that there
12	are some times when you get a positive test but you can't
13	trace it back to an individual donation and can you explain
14	why that is?
15		DR. CONRAD:  Early on, in the trial, and this was
16	done back in 1997--we are now seasoned, salty veterans of

17	the pooling wars and so it doesn't happen as much, but early
18	on, the decks of the Tecans--we had the samples arranged on
19	the deck in an interesting way, that the head of the Tecan
20	would pass over the already pipetted samples.
21		I think what was happening is there occasionally

22	would be a remnant on the outside of one that would drip in. 
23	There were four cases of that in the 596 pools that we did. 
24	There were four cases where we could see that there was--for 
25	example, an antibody-positive HCV sample and it dropped into

			86 1	another sample.  We could prove that with genotyping and
	2	sequencing.
	3		So we switched the configuration of the Tecans and
	4	it dramatically reduced that problem.  But most of it was
	5	sample-sample contamination that occurred on the deck of the
	6	Tecan.  It happened a lot in HBV early on in the IND because
	7	the donor centers needed to handle it.
	8		But the nice thing about is you can ask for a
	9	backup sample and identify it that way or it won't prove out
10	in the row, layer and columns if the pool gets contaminated
11	the same way.  The row, layer and columns won't line up.  So
12	it is very easy to see when something is anomalous and then
13	you can just test to find out where it happened.  It was 4
14	out of 596 times--early.  It was in the first month.
15		DR. HOLLINGER:  Thanks, Andy.  I appreciate it.

16		The next speaker will be Charles Heldebrant from
17	Alpha Therapeutics.  Dr. Heldebrant?

18		              Presentation
19		DR. HELDEBRANT:  May I have the first slide?
20		[Slide.]
21		I am going to talk about a comparison of HIV-1 p24
22	individual testing against pooled RT PCR in a source-plasma
23	screening program.

24		[Slide.]
25		We approached it from the idea of what are the

			87 1	criteria to replace individual p24 donation screening with
	2	pooled PCR in a source-plasma program.  The first criteria
	3	is that the HIV-1 PCR test of pooled samples has to be equal
	4	or superior to individual p24 and its performance in terms
	5	of sensitivity and specificity.
	6		[Slide.]
	7		As Andy alluded to, we conducted a prospective
	8	clinical trial and, for new donors, they were screened for
	9	HIV-1 p24 antigen and HIV-1/2 antibody and, if positive,
10	were excluded before PCR pooling.  For qualified donors, all
11	samples were tested irrespective of their subsequent HIV-1
12	p24 or HIV-1/2 antibody status.
13		We screened over 300,000 donations.  We used a
14	pool size of 512 for the master pool, which is the first
15	screen.  The row, column and layer are pools of 64 and all
16	suspect-positive donations were confirmed by individual PCR.
17		[Slide.]
18		In this study, again we tested 345,000 donations. 
19	We had 6 PCR-positive p24 and HIV-antibody-negative
20	donations.  These units comprised 7 times 108 genome copies
21	per ml.  The clinical specificity was 100 percent.  The
22	clinical sensitivity of PCR was 100 percent.  The
23	corresponding sensitivity of p24 antigen and HIV antibody in
24	this sample set was 27.8 percent.
25		The mean reduction of the window period estimated

			88 1	through some fairly complex work that was done with Mike
	2	Busch and Steve Kleinman is in excess of four days.
	3		[Slide.]
	4		Again, this is looking at the performance of an

	5	individual p24 antigen test.  This is taken from the Ortho
	6	p24 antigen package insert.  It shows a donor sample
	7	screening of about 300,000 donors.  Thirty-three samples
	8	found repeat reactive.  Of those, 31 were not neutralized. 
	9	They were Western Blot or PCR-negative and only two of them
10	were truly positive samples.  This is a reasonable
11	performance for all of the p24 antigen kits.
12		[Slide.]
13		Again, as Andy has alluded to, the proof of the
14	pudding is does PCR detect things that p24 does not detect
15	and vice versa.  Again, for undiluted p24 samples, using

16	basically the same data you have seen, there are no
17	instances where a sample is p24-positive undiluted and is
18	negative by pooled PCR.  There are a substantial number of
19	cases where the opposite case applies.
20		[Slide.]
21		So our conclusions were that, first of all,
22	substituting the HIV-1 PCR test of 512 pooled samples for
23	individual p24 in a donor screening detected virtually all
24	of the HIV-containing donations.  It increased the

25	specificity of screening and increased the clinical

			89 1	sensitivity of our screening.
	2		Our conclusion is that the PCR of pooled samples
	3	is superior to individual p24 antigen tests.
	4		[Slide.]
	5		The second criteria is that the performance of the
	6	entire screening program and its associated quality systems
	7	using the RT PCR with pooled samples has to be equal to or

	8	superior to the performance of that same donor-screening
	9	system when you use individual p24 as a component of it.
10		[Slide.]

11		This is a group of 288 HIV-infected samples, both
12	prospectively identified seroconversion panels and look-back
13	samples including a substantial number of low-titered HIV
14	samples.  Of these 288 samples, when they were evaluated
15	with pooled PCR, HIV-1/2 antibody and the look-back
16	inventory hold and qualified-donor standard quality systems,
17	we detected all 288 of those samples.
18		Similarly, had we used individual PCR with HIV-1/2
19	antibody, we would have detected all 288.  In this group,
20	individual PCR detected 285.  There were three samples which
21	were HIV-antibody-positive only.  They were PCR-negative and
22	p24-negative.
23		Pooled PCR with HIV-1/2 antibody detects 252, or
24	87.5 percent, of the samples emphasizing the need for the

25	look-back inventory hold and qualified-donor standard

			90 1	quality systems in the overall screening program.
	2		The addition of p24 antigen individual testing to
	3	pooled PCR plus HIV-1/2 antibody did not detect a single
	4	additional sample.  Again, 87.5 percent of the samples were
	5	detected.  p24 antigen and HIV-1/2 antibody alone detected
	6	only 200, or 70 percent, of these 288 high-risk samples.
	7		[Slide.]
	8		Our conclusion here is that the performance of the
	9	entire donor-screening program and its associated quality
10	systems, using HIV-1 RT PCR testing of pooled samples, is
11	superior to the performance of that same donor-screening and
12	quality systems using individual p24 antigen test.
13		[Slide.]
14		The benefits of PCR testing; the source-plasma
15	program coupled with the qualified-donor standard inventory
16	hold and look-back quality systems decreases the HIV-1 load
17	and manufacturing pools to the practical minimum.  Validated
18	viral-inactivation procedures inactivate any remaining HIV-1
19	during the manufacturing process of all plasma products.
20		[Slide.]
21		Why replace individual p24 antigen with a pooled
22	PCR?  Increased sensitivity; it detects more HIV-positive

23	donations; pooled PCR, HIV-1/2 antibody coupled with
24	inventory hold look-back and the qualified-donor standard
25	quality systems detects virtually all HIV-positive

				91 1	donations; and increased specificity.
	2		As Dr. Conrad told you earlier, and I am going to
	3	reiterate, the pooled PCR had no false positives.  There
	4	were no instances where donors were told that they had a
	5	positive or a reactive HIV test when it was not, in fact, a
	6	true test.
	7		Thank you.
	8		DR. HOLLINGER:  Thank you.
	9		Any questions?  We move on, then, to Dr. Watson
10	from Aventis.
11		              Presentation
12		DR. WATSON:  Good morning.
13		[Slide.]
14		I am going to report on our experience with PCR
15	testing and HIV antigen.  We did not design our IND to
16	specifically look at this question but I believe some of the
17	data we have is relevant for your consideration.
18		[Slide.]
19		We are going to first summarize what our test
20	system is.  We test all serology-negative samples for
21	hepatitis A, B, C, HIV and parvovirus B19.  Our first pooled
22	test comes in a pool size of 1,200.  With that, we use a

23	research-grade ultracentrifugation step.  So this is our
24	test system.
25		[Slide.]

			92 1		The results of that test system are summarized on
	2	our next slide which shows that, in this system, we have
	3	identified four donors and about 3.25 million samples, but

	4	those four donors come from 220,000 donors during the time
	5	period.
	6		So what we have identified here is approximately
	7	two donors per 100,000 donors where we find an NAT-positive

	8	and all serology markers are negative.  These donors donated
	9	six units and the frequency for that is 0.2 when you look at
10	the 3.25 million units per 100,000 donations.  That is just
11	a quick summary.  Remember that these are all serology-test
12	negative donations.

13		[Slide.]
14		The next slide shows a little more in depth the
15	donation history of the four positive donors.  I have tried
16	to show the donation prior to the PCR positive and then any
17	subsequent donations.  Notice, in the second and third
18	donors, there was approximately one month between the time
19	of the PCR-positive and they came back and it was antibody-
20	positive.
21		The fourth donor down here has two PCR-positives,
22	no antibody-positive, and that donor never returned, just
23	like the first donor never returned.  If you look at the

24	second donor here, and the fourth donor, you notice that
25	there are PCR-positives anywhere from two to four days prior

			93 1	to where an antigen might become positive if we assume a
	2	positive antigen on the next day.
	3		[Slide.]
	4		We then did some panel testing to see, in our pool
	5	of 1200, and if we ran that pool, what would we find based

	6	upon the serology tests and also based upon the HIV-antigen
	7	test.  We took the first antigen-positive sample and a
	8	sample prior to that on these panels to see what would
	9	happen.  Again, all of our testing is done in the pool size
10	of 1,200.
11		If you will notice, PCR found a positive on the
12	same day as the antigen-positive test and we found one pool
13	where we found a positive two days prior to the antigen-
14	positive.
15		[Slide.]
16		The next set of panels shows essentially the same
17	results where the antigen test is positive.  We have
18	discordant results here so we took the first one where both
19	were positive.  Wherever there was an antigen-positive, we
20	found a PCR-positive and, again, one out of three, we found
21	a PCR-positive, in this particular case, four days prior to
22	the antigen-positive.
23		So, to summarize this, basically, the panels that
24	we have run so far, we have found the PCR-positive signal,
25	even in our test system, to be the same day as the antigen-

			94 1	positive and, in addition, we found two of the six positive
	2	prior to the antigen signal.
	3		[Slide.]
	4		We also ran the HIV FDA panel, which is shown on
	5	the next slide, again using our test system by diluting it
	6	out because that is our first test.  In this test system, we
	7	found 5,000 copies positive, the 25,000 and the 250,000. 
	8	Based upon the data that we have, and I think the data that
	9	you are going to see from everyone that is presenting, we
10	believe that the PCR test process used in the plasma
11	industries could be a viable alternative to the p24 test.
12		Thank you.
13		DR. HOLLINGER:  Thank you, Dr. Watson.
14		Any questions?  If not, we will move on to the
15	next speaker, Barbara Masecar from Bayer.
16		              Presentation
17		MS. MASACAR:  Good morning.
18		[Slide.]
19		I would like to thank you for inviting me and I
20	appreciate this opportunity to give you this update from our
21	HIV NAT clinical study.
22		[Slide.]
23		First, I would like to start with a little bit of
24	background.  We filed our IND with FDA in August of 1999. 
25	It is a shared IND with Roche Molecular Systems.  We used

			95 1	the Roche Ampliscreen Microwell Plate method, not the Cobas. 
	2	we actually started testing in October of 1999, so we are
	3	coming up to that one-year mark.
	4		We use a minipool size of 96 individual donations. 
	5	In our system, that minipool is created, the nucleic acid is
	6	extracted and that sample is split.  Part goes to HIV
	7	testing and part goes to HCV testing.
	8		[Slide.]
	9		A few facts on assay performance in our hands, and
10	I will also give this in copies, since that is what we are

11	talking about today.  For the 95 percent test positivity
12	rate for this assay, it is 91 IUs per ml.  In our
13	laboratory, that is 10 to 20 copies per ml.  That calculates
14	up to detecting individual donations at 8,736 IUs per ml or
15	1,000 to 2,000 copies per ml in the individual donation.
16		We also run an in-house control with each assay at
17	40 copies per ml so we have assurance that we are detecting
18	individual donations at 4,000 copies per ml and above.
19		[Slide.]
20		Our donors that are discovered to be NAT positive
21	are divided into three major categories at the time of index
22	donation, that first donation that is positive.  The first

23	category, A, is those donors that are positive for NAT only. 
24	The second category is those donors that are positive by NAT
25	and p24.  And then the third category being those donors

			96 1	that are positive for NAT, negative for p24 but positive for
	2	antibody.
	3		We assume that this kind of correlates to the
	4	stages of infection, that those donors in category A are
	5	very early in infection, category B is a week to two weeks
	6	later, and then category C is after the donors have actually
	7	gone through the period of antigenemia and the antibody is

	8	now positive.  I will get back to those assumptions later.
	9		One thing that is not on this slide is those
10	donors that are positive for antigen only.  It is important
11	to this discussion to be able to say are we seeing any
12	false-negative NAT where the antigen is actually picking
13	them up.
14		[Slide.]
15		Although that category of donors, those donors
16	that may have a false-negative NAT test with a positive p24
17	antigen are described in our investigational plan.  We
18	didn't really build a process around that starting off to
19	really effectively capture that category of donors.  We
20	don't know of any donors to date that fall into that
21	category, but we are in the process of amending our IND to
22	more effectively capture that and to query the plasma
23	centers for that information.
24		So I don't have any information on donors that
25	could potentially be a false-negative NAT but we don't know

			97 1	of any in that category to date.
	2		[Slide.]
	3		So what is our data so far?  We have screened over
	4	2 million donations.  We have discovered eleven donors in
	5	category A that are positive for NAT only.  We have
	6	identified three donors in category B that were positive for
	7	antigen and NAT but negative for antibody and ten donors in
	8	category C where the antigen was negative but those donors
	9	were positive for NAT and antibody.
10		Going back to our assumptions of where these
11	donors fall in the viremia and the stages of infection, it
12	does fit in pretty well because those donors in category A,
13	we have found are fairly regular donors so we do have recent
14	prior negative donations on these donors.
15		The three donors in category B were absent from

16	donating, could be the self-deferral situation--I'm sorry;
17	that is category C.  In category B, also, they are fairly
18	regular donors but there is a longer gap in donation
19	frequency for those donors in category B.  So, typically,
20	for those three donors, they donated on day 1 and then they

21	were gone for two weeks, so they could have gone through the
22	period where they were positive by NAT only.
23		Then those donors in category C; actually,
24	category C is mostly comprised of applicant donors so they
25	have actually gone through the antigenemic period.  The

			98 1	antigen is now negative and they have come in to donate and
	2	their antibody is positive, and the NAT is positive.
	3		We intend to prescreen applicant donors from our
	4	studies but we have spotty compliance with those directives. 
	5	So we do get applicant donations that come in for NAT
	6	screening that have not been effectively prescreened by the

	7	viral marker test.  But, if we do identify them, we attempt
	8	to enroll them in follow-up studies.
	9		As far as the follow-up studies go, the most
10	useful perspective information to get from these donors is
11	those that are in category A, that when they come in, they
12	are NAT positive.  Can we enroll them and follow them up and
13	see when the antigen becomes positive.
14		[Slide.]
15		So for those eleven donors in category A, we do
16	have subsequent donation information on nine of them.
17		[Slide.]
18		So we have the nine donors here.  Most of these
19	donors actually had subsequent donation information that
20	allowed us to calculate the reduction in the window period. 
21	These three donors plus this donor here were actually
22	positive for p24 antigen the next time they came into the
23	plasma center.
24		Now, the NAT-positive test will defer these donors
25	but it is one to two weeks by the time we can turn the

			99 1	result around to the plasma center so the donor will
	2	continue to come in and donate without knowing that there
	3	are positive-sample result is coming.
	4		These two donors, A and C, actually did have one
	5	donation in between that was still NAT-positive, p24
	6	negative.  We did have three donors that were initially NAT-
	7	reactive.  They did not come in for subsequent donations. 
	8	We were able to enroll them, however.  By the time they came
	9	in which was approximately two months later, the antigen was
10	already negative. We assume it went through a positive and
11	then reverted to negative, but we don't have any data to say
12	that for sure.  But now the antibody is positive.
13		For these donors that we had the subsequent
14	donation information on, we did get donation information
15	that went to when that donor became antibody positive, 9 or
16	14 days after the initial NAT reactive.  And then we had
17	these three donors that we didn't see them again.  We had
18	that single subsequent donation.  They were antigen-positive
19	and NAT-positive at this donation and then we were unable to
20	enroll them into this follow-up study.
21		[Slide.]
22		This is the quantitative data actually on the
23	index donations for these nine donors.  You can see that the
24	range is 4,100 to 312,000.  As I said, we do run a control
25	with our assay that gives us assurance we are picking up

			100 1	donations in the magnitude of 4,000 so we are hitting things
	2	close to our detection limit.
	3		This may be an outlier.  It may also be in support
	4	of what Andy said where we have got donations that are
	5	really quite high in titer that are still antigen-negative. 
	6	All of these are antigen-negative.  This is the index
	7	donation that was positive for NAT only.
	8		So, even if you don't necessarily count this
	9	312,000, we do have several that are much higher than the
10	10,000 to 20,000 range and these are still antigen-negative. 
11	So it brings up some questions about the real robustness of
12	the p24 antigen assay.
13		[Slide.]
14		So the conclusions; we have seen the reduction

15	window period for those donors that are initially positive
16	by NAT relative to the p24 an average of 5 days, the range
17	being from 3 to 7 days.  Relative antibody test; we have

18	seen an average of 10.7 days with a range of 9 to 14 days. 
19	We haven't seen any false positives.  As I showed you on the
20	table, all the donors that we have been able to follow up,
21	or we have follow-up information on from subsequent
22	donations, we have corroborated that initial NAT reactive by
23	some other HIV assay.
24		So I think these data support that pooled NAT is
25	superior to individual donation testing for antigen.

					101 1		Thank you.
	2		DR. HOLLINGER:  Thank you.  I just had a couple of
	3	questions.  You said you had 2.1 million donations.  How
	4	many donors did that represent?
	5		MS. MASECAR:  We get a lot of applicant donations
	6	in there so it is probably in the range of 50,000 to 200,000
	7	donors but I don't have that exact figure.  I would say--
	8		DR. HOLLINGER:  50,000 to 100,000?
	9		MS. MASECAR:  50,000 to 200,000.  50,000 donors
10	would be conservative.
11		DR. HOLLINGER:  You initially, I think, said that
12	you did pools of 96 and a 95 percent detection rate of
13	91 copies per ml, I think you said.
14		MS. MASECAR:  No; in copies per ml at 95 percent,
15	it is 10 to 20 copies per ml.  91 IUs.
16		DR. HOLLINGER:  Okay.  Again, explain to me; you
17	had some samples in there that were 4,100 and 4,300, yet it
18	seemed to have detected those?
19		MS. MASECAR:  Yes, because our cutoff in copies
20	would be 4,000.  So we were detecting initial index
21	donations right around that cutoff.
22		DR. HOLLINGER:  So your lower copy level is what? 
23	How much is the copy level then from IUs?
24		MS. MASECAR:  That would be a multiple.  It is

25	somewhat of a range.  We have only done a couple of assays

			102 1	to correlate copies to IUs.  It is a factor of about 7, I
	2	think.  The scientist that did the work is here in the
	3	audience.  I can get an actual number for you.
	4		DR. HOLLINGER:  And the IUs are from the NIBSC
	5	standard?
	6		MS. MASECAR:  Yes; that's correct.
	7		DR. HOLLINGER:  Anything else?  Thank you.
	8		The next presentation, Don Baker from Baxter
	9	Hyland Immuno.
10		              Presentation
11		MR. BAKER:  One of the great things about these
12	meetings is the surprises.  One of the biggest surprises you
13	can get is to find that you are on the list as a presenter
14	when you were not expecting to be presenting.
15		I had attempted to provide the committee with a
16	written presentation which, I hope, was part of your
17	presentation materials.  If it wasn't, the fault is mine
18	because I was on vacation and I got it late.
19		I will attempt, if it is not in the presentation
20	materials, to summarize possibly the most pertinent point. 
21	Our PCR NAT IND was not constructed to directly address this
22	question of the relative sensitivities of p24 versus PCR
23	testing.  Our test system was designed, our IND was
24	designed, so that any donations which were--oh; good.  I see
25	the committee does have the materials.

			103 1		In that case, I am going to be sure that you have
	2	all read it.  And so are there any questions?
	3		DR. HOLLINGER:  Any questions?  I guess there are
	4	no questions.
	5		The next speaker is Sue Stramer from the American
	6	Red Cross.  Susan?
	7		              Presentation
	8		DR. STRAMER:  Thanks, Blaine.  I guess that was a
	9	hard act to follow.
10		[Slide.]
11		I represent the American Red Cross.  We do collect
12	plasma.  However, we also are one of the two major whole-

13	blood collectors in the United States.  In our IND for NAT,
14	we did include p24 antigen replacement.  So my presentation
15	today will focus on two areas, one, in collaboration with
16	Mike's presentation earlier.
17		The first thing you will note in this slide is I
18	included two dates because the topic of p24 antigen

19	replacement by NAT was addressed in an earlier Blood
20	Products Advisory Committee meeting on March 25. 
21	Unfortunately, I have a typo there.  I will not be here
22	presenting on Saturday.
23		[Slide.]
24		As part of background material; since the
25	implementation of HIV p24 antigen screening in March of '96,

			104 1	only six antigen-positive window-case donations have been
	2	identified at the Red Cross.  You will see later in the
	3	presentation--I read ahead--from ABC that they have
	4	identified four.  So, in the national experience since
	5	March 14, 1996, the date of licensure, in the whole blood
	6	industry we have identified ten p24-antigen-reactive units.
	7		Due to the low antigen yield and improved
	8	sensitivity of NAT screening for HIV-1, replacement of
	9	antigen with HIV-1 NAT should be possible.
10		[Slide.]
11		So, from the Red Cross side of the house, we have
12	screened 27.5 million donations.  You will see the same
13	27.5 million donations ironically enough from ABC, so we do
14	have an even split.  Of those screened, over 10,000 were
15	tested by neutralization; that is, they were repeat-
16	reactive.  This represents 7,500 plus index donations
17	totally to about a 0.027 percent repeat-reactive rate for
18	the test.
19		We do donor reinstatement for p24 antigen, so, of
20	these on index, about a third, 2,200, came in for follow up
21	to see that they remained antigen-indeterminate and then
22	were eligible for reentry.  However, reentry is a relatively
23	low yield proposition for antigen because you will see
24	higher numbers as well.  But, in our total study, 53 percent
25	of antigens who do present a second time remain antigen-

			105 1	indeterminate.  So there is a biological false positivity
	2	associated with the test.
	3		Of this total, we have 316 confirmed positive
	4	donations; that is, 3.1 percent of repeat-reactives or
	5	0.001 percent of the total screened.
	6		[Slide.]
	7		Of the 316 confirmed positives, this is the
	8	breakout.  And this breakout goes until August 31 of this
	9	year.  158 were false positives.  As Mike alluded to
10	earlier, false positivity is commonplace in this test.  We
11	defined these as false positive based on RNA-negativity, RNA
12	PCR testing performed by Mike Busch at Blood Centers of the
13	Pacific, lack of seroconversion in these donors, and
14	nonreproducible antigen-neutralization results.
15		In our SOP for donor counseling, we repeat the

16	antigen-neutralization test because most frequently the
17	false positives do not repeat.  So we can assure the donor,
18	"You are likely not to be infected."  We could not even
19	reproduce the antigen-neutralization result.
20		A subset of these 62 of the 158 were also tested
21	for reverse-transcriptase activity which would indicate the
22	presence of the retrovirus.  I will show you there was data
23	in detail, but none of those 62 were positive for reverse
24	transcriptase by a CDC-developed AMP RT assay.
25		Of the 316, 152 were antigen-positive and six, as

			106 1	I mentioned before, were recently infected seroconverting
	2	donors.  So the yield for the Red Cross is 1 in 4.6 million. 
	3	I should mention, one of these was an ABC donor, so if you

	4	add this one ABC to the four that ABC will show, that makes
	5	five from ABC, five from ARC, out of the same number of
	6	donations tested, so exactly an even split.
	7		Of these six, one was detected following NAT
	8	implementation.  We implemented in March of '99 and, since
	9	then, we did detect one donor who was both NAT an p24-
10	antigen-reactive.  I will also show you one donor that we
11	detected on index that was NAT-reactive but not reactive by
12	p24 antigen until we acquired follow-up samples.
13		As Dr. Busch showed, but I will show data also

14	collected from the Red Cross, we did not observe a magnet
15	effect with this test.  And that was done by looking at

16	increases in HIV antibody testing before implementation and
17	post-implementation.
18		[Slide.]
19		If you look at the two populations I have just
20	mentioned, antibody-confirmed positives and antibody-
21	negatives, and look at their percent neutralization results
22	for the 40 percent assay cutoff, you can see that antibody
23	positives have a higher percent neutralization than to
24	antibody-negative samples, or these are the false positives.
25		This subset here of 158 also includes the six

			107 1	window-period donations that I showed you.  So the median
	2	percent neutralization here was about 95 percent but you do
	3	see, and this represents one sample that we did have that

	4	was antibody-positive that did neutralize at a 40 percent
	5	neutralization.
	6		Here the mean neutralization was much lower, at
	7	51 percent.
	8		[Slide.]
	9		I mentioned before the false positives lacked
10	evidence of other retroviral infection.  Again, this was
11	performed using and AMP RT test developed by the CDC.  As

12	controls, we included 28 positive samples by HIV-1 RNA that
13	were also positive by the AMP RT test.  These included
14	antibody-positives and four seroconverters that we had from
15	our yield samples.
16		The false-positive samples, which were all
17	negative by HIV-1 RNA, were also all negative by the AMR RT
18	test.  So, again, these false-positive samples have no
19	evidence of other retroviral infection.
20		[Slide.]
21		One other question that we tried to address, Red
22	Cross in collaboration with the REDS study, is what is the
23	meaning of antigen-indeterminate donors.  Are these infected
24	with HIV?  So what we did was we took up subsets of the

25	donation screened, so we started with about 7 million

			108 1	donations screened, which resulted in 1,500, approximately,
	2	or 0.022 percent repeat-reactive indeterminate donors. 
	3	There is no criteria in the test for a negative.  You are
	4	either confirmed positive or indeterminate.
	5		We submitted available samples for PCR testing
	6	and, of those samples submitted for PCR testing, there were
	7	none that were positive by PCR.  So all indeterminates
	8	appear to be not infected with HIV.
	9		Of those that we had, 38 percent, who did provide
10	follow-up samples, those were antibody-negative and, in this
11	subset, actually, a higher number than the 53 percent I
12	showed earlier.  77 percent of these donors, on follow up,
13	remained antigen-repeat-reactive but did not neutralize.
14		[Slide.]
15		The question of the magnet effect was addressed by
16	looking at the antibody prevalence for the six months post-
17	implementation of p24 antigen and comparing that to six
18	months within the same--the same six months the year prior
19	to.  So we adjusted the data four times so that they were

20	the same six-month periods looked at pre-implementation and
21	post-implementation.
22		You can see the numbers of antibody-positives for
23	first-time donors and for repeat donors.  And you can see
24	the rates here, 7.3 per 100,000 pre-licensure, 6.8 per

25	100,000 post-licensure, and there was no significant

			109 1	difference so there was no antibody test-seeking that we
	2	could determine.
	3		[Slide.]
	4		The other part of this presentation will focus on
	5	what studies we have performed to show the redundancy or
	6	lack of a need of p24 antigen.  We have taken our antigen-
	7	yield samples and NAT-yield samples--actually, in the data I
	8	will show, there is only one, but we have subsequently added
	9	others.  We have diluted these 1 to 128 in RNA-negative
10	plasma.
11		The Red Cross IND had two phases.  One was a phase
12	in which we tested pool sizes of 128 and now we are testing
13	pool sizes of 16.  But all the work I will show you is a
14	pool size of 128 which actually represents worst case
15	because it is a eight-fold or greater dilution.
16		We have also looked at 25 commercial
17	seroconversion panels tested neat and tested at 1 to 128
18	dilution.  These were in our IND.  As an additional control,
19	with each run of NAT that we perform, we run a p24 antigen
20	external-run control sample.  Although we call this p24
21	antigen external-control sample, it is not reactive for p24
22	antigen.  That is because of the way it is prepared.
23		We have taken three antigen-positive antibody-
24	negative units and pooled then.  They had an S to CO 1 to 2
25	by Coulter but were actually negative by the Abbott test. 

				110 1	The pool of these three was diluted 1 to 16, and at this 1
	2	to 16 dilution, this pool was no longer reactive for p24
	3	antigen.  But it did have an RNA concentration equal to or

	4	greater, depending on the manufactured lot, of 2,400 copies
	5	per ml.
	6		We do not accept a NAT run for release unless the
	7	p24 antigen run control is reactive.  To date, at least to
	8	August 31, again, we have 6,674 runs.  No run has ever not
	9	been accepted because of a failure of this external-run
10	control.  So, in all of these runs, the p24 antigen control
11	has been reactive.

12		[Slide.]
13		Before I show you the dilutions, let me show you
14	our NAT yield samples or I should say, in this case, our
15	antigen yield samples.  These are the first five antigen
16	yield samples identified by the Red Cross.  These are the
17	days of follow up following the index donation.
18		This column is the RNA concentration and,

19	hopefully, these are visible.  These are p24 antigen signal-
20	to-cutoff ratios.  You can see, in gold, where p24 antigen
21	is reactive.  I have asterisked the peak antigen load.  You
22	can see that, in each case, it corresponds to the peak
23	antigen signal.  Even when antigen has a lower reactivity,

24	you can see at least 10	                
				4 and, in this case, 105 RNA copies
25	per ml.

					111 1		This is the percent neutralization.  This is the

	2	antibody results and Western Blot results, again antibody
	3	always come up after p24 antigen and NAT.
	4		[Slide.]
	5		This is the six antigen yield samples, same

	6	scenario, maximum antigen concentration, maximum NAT
	7	concentration, first positive 10		                
					5 copies per ml.  This
	8	sample here is our first NAT yield sample.  I show it
	9	because we did have follow-up samples here where this donor
10	did undergo the p24 antigen reactivity and then reversion to
11	negativity.
12		Here, the first antigen signal and an S to CO of 1
13	by the Coulter test did correspond to 4 times 10	                
		5 copies per
14	ml.  Again, here are the antibody results and Western Blot
15	results.
16		[Slide.]
17		If we took three of those samples, and actually
18	one that we got from southeast Wisconsin, the first antigen-

19	negative NAT-reactive sample identified since the NAT INDs
20	for whole blood were implemented, this one detected in a

21	pool of	24.  What we did was diluted these 1 to 128 then to
22	see if they were still reactive.
23		This is the initial viral load.  This one first
24	detected by NAT, therefore, having a lower viral load.  But
25	they were all detected at a pool size of 128 including the

			112 1	additional samples that we tested.  Here you can see the
	2	signal-to-cutoff ratio by the GenProbe TMA assay.  The one

	3	with the lowest viral load actually did have a little bit
	4	lower S to CO but, certainly, 7 is nowhere near the cutoff.
	5		[Slide.]
	6		This is the slide Mike showed, but I am going to
	7	show it for a different reason.  Here, you can see the two
	8	dates prior, NAT pickup prior, to p24 antigen.
	9		[Slide.]
10		This now adds the GenProbe NAT data, either a
11	single unit testing, which is in the solid symbols, or as a

12	pool size of 1 to 128.  Here the qualitative test by TMA was
13	a little bit more sensitive than quantitative PCR.  However,
14	quantitative PCR hit the same exact sensitivity as the
15	pooled NAT at a dilution of 128 both of which were a two-day
16	improvement over p24 antigen.
17		[Slide.]
18		If you look at all of the seroconversions that we
19	looked at for our IND, which totaled 25 individuals having
20	92 seronegative bleeds, and you look at the question of
21	assay reactivity by NAT versus p24 antigen--so, again, these
22	are all the seronegative bleeds--the green symbols show you
23	those that were positive both by NAT and by p24 antigen.
24		The yellow symbols here, the yellow circles, show
25	you those that were only positive by NAT and could not be

			113 1	detected by p24 antigen.  So, in this analysis, there were

	2	24 NAT samples, samples that were NAT-positive but negative
	3	for p24 antigen, and there were no samples in the reverse
	4	category; that is, antigen-reactive but NAT-negative.
	5		[Slide.]
	6		If you take these samples and dilute them 1 to
	7	128, you virtually get similar results, or identical
	8	results, with the exception that fewer samples remain NAT-
	9	positive.  Here 21 samples were NAT-positive but p24
10	antigen, but this is NAT at 1 to 128 dilution.  Again, no
11	samples that were antigen-reactive and NAT-negative.
12		[Slide.]
13		If you look at all of the samples in the panel--
14	that is, antigen-positive and antibody-positives--and we

15	tested by two lots of the GenProbe reagents, we detected 162
16	in one lot and a 167 NAT-reactive samples undiluted.
17		Performing a dilution of 128, we detected subsets
18	of this 162 of 145 or 90 percent and 148 or 89 percent on
19	the second lot.  If you look at the subset now that was p24-
20	antigen-reactive, only 57 or 55 percent of these samples
21	were p24-antigen-reactive.  The data on this side just shows
22	the similar relationship for ATL, that these tests are
23	really antiquated and we have probably no need to be doing
24	them.
25		[Slide.]

			114 1		Now, to address the external run-control sample,
		2	the Red Cross, in addition to running the p24 antigen run
		3	control sample with each run also runs and HIV and HCV and a
		4	negative member.  This is the concentration of our RNA NAT-
		5	reactive run-control samples.  Of four lots manufactured for
		6	p24 antigen, using this same target for manufacture, we have
		7	a range of copies per ml for this external run-control
		8	sample of 2,400 to 6,800.
		9		[Slide.]
	10		This shows you the distributions of those four
	11	external run controls.  Here are the negative samples.  Here
	12	are the HCV-reactive samples.  You can see that HIV, whether
	13	it is the NAT control or the p24 antigen control, virtually
	14	run very similarly.  Actually, the p24 antigen control runs
	15	a little bit hotter.

	16		[Slide.]
	17		So, in conclusion, from that data I have showed,
	18	high RNA titers corresponding to equal to or greater than

	19	10	                         4 copies per ml correspond with p24
antigen positivity. 
	20	There was no p24-antigen-reactive sample that was found NAT
	21	nonreactive even using a pool size of 128.  And we saw
	22	earlier detection and detection in HIV antibody-positives.

	23		So NAT, even using pools of 128, which we are no
	24	longer doing, is more sensitive than screening with the

	25	currently licensed tests for HIV p24.  According to these

			115 1	data, the antigen test could be replaced by the use of
	2	licensed pooled NAT.
	3		[Slide.]
	4		In combination with my data presentation, I am
	5	going to make the Red Cross position statement on the
	6	replacement of p24 antigen with NAT.  Red Cross seeks to

	7	support its patients with a blood supply of the highest
	8	quality and safety.  We also support the replacement of p24
	9	antigen testing--that is, when the discussion emerges for
10	whole blood--with NAT provided the following conditions are
11	met.
12		We have a licensed test.  The test is fully

13	compliant with all cGMP features.  It has full automation or
14	at least the maximum automation that we can obtain,
15	including positive sample ID and the test is at least as
16	robust as the current licensed screening tests we use today.
17		Thank you.
18		DR. HOLLINGER:  Thank you, Sue.
19		Any questions of Dr. Stramer?  Anyone?
20		Sue, again, just for my information, the p24
21	antigen, what was, again, the range for the copies per ml
22	for the p24 antigens that were positive and antibody-
23	negative?
24		DR. STRAMER:  From the six that we had?  They were
25	10	                         4 to 10 5 copies per ml.

					116 1		DR. HOLLINGER:  So those were fairly high.
	2		DR. STRAMER:  Yes.
	3		DR. HOLLINGER:  But there were only six that you
	4	had.
	5		DR. STRAMER:  Yes; right.  But that is why we did
	6	the larger sampling of the 92 seroconversion panels.
	7		DR. HOLLINGER:  And that ranged what?
	8		DR. STRAMER:  That ranged comparably to where we--
	9	well, actually, it covered the entire dynamic range because
10	we started with antigen-negative NAT-positive samples.  So
11	it covered the entire dynamic range.
12		I didn't do the regressions as Mike did so I can't
13	tell you what the antigen cutoff was, but I wouldn't be
14	surprised if it paralleled the data that Mike showed pretty
15	exactly.
16		DR. HOLLINGER:  Thank you.  Thanks very much, Sue.
17		The next presentation is by Dr. Schochetman from
18	Abbott Laboratories.
19			Presentation
20		DR. SCHOCHETMAN:  Thank you.
21		[Slide.]
22		As we contemplate whether to decide to continue or
23	discontinue antigen testing in the plasma fractionation

24	business, I would like to have you keep some things in mind. 
25	The first is that the current antigen assay is really not

			117 1	the ultimate in terms of sensitivity to which this assay can
	2	be driven.  The second is that, as we contemplate this and
	3	since it may take a certain amount of time to implement any
	4	possible discontinuation, that we don't send negative or
	5	disincentive messages to manufacturers so that they will not
	6	put the effort in to develop more sensitive single-unit
	7	antigen testing.
	8		[Slide.]
	9		Our goal, actually, or our objective, is to
10	develop more sensitive HIV antigen assays in the short term
11	to make these assays comparable in sensitivity to pooled NAT
12	testing and, in the long term, make this sensitivity
13	equivalent to single-unit NAT testing.
14		I should say--I gave a talk somewhat similar to
15	this at last year's BPAC meeting sort of giving the
16	alternative view.  I am getting to feel a little bit like
17	salmon going upstream, and that is it seems like possibly a
18	futile attempt, but you have this genetic urge that you must
19	keep doing this.
20		[Slide.]
21		What I want to do is share with you some data on a
22	research assay for our automated prism instrument that
23	already has increased sensitivity.  I should say that this
24	is, by no means, as far as this assay can be driven.
25		As you can see here, this is our current antigen

			118 1	assay that is on the market.  We estimate that the
	2	sensitivity of that antigen assay, using an internal Abbott
	3	standard, is in the neighborhood of around 7 to 10 picograms
	4	per ml.  If one makes the assumption that a picogram is in
	5	the neighborhood of 10,000 copies per ml, then we are
	6	looking at the ability to detect a sample with somewhere
	7	between 70,000 and 100,000 copies.
	8		At a dilution of 1 to 96, we would be looking at
	9	somewhere between 725 and 1,041 copies and, at a dilution of
10	1,200, we would be looking at 58 to 83 copies.  The current
11	research prism antigen assay is several-fold more sensitive
12	already and is in the range of 1 to 2 picograms which would
13	have an sensitivity, in terms of RNA copies per ml, of about
14	10,000 to 20,000 copies and a dilution of 1 to 96 would be
15	somewhere in the range of 100 to 200 copies and 1 to 1200
16	would be somewhere in the range of about 8 to 16 copies.
17		[Slide.]
18		Assuming the sensitivity of a picogram being about
19	10,000 copies of viral RNA, then, if you look at a NAT assay
20	with a sensitivity of about 50 copies per ml, then, at a
21	dilution of 1 to 96, that sample would have to have a
22	starting copy number of about 4,800.  If you are looking at
23	a dilution of 1,200, the starting copies would have to be in
24	the range of around 60,000 copies per ml.
25		[Slide.]

			119 1		What I would like to do is show you here some real
	2	data on early seroconversion samples from commercially
	3	available seroconversion panels.  What you can see here is
	4	samples from each of those panels.  The letter or the number
	5	after the slash represents the particular bleed.
	6		You can see here we selected these because they

	7	were all negative by the current Abbott test.  You can see
	8	here a signal to cutoff of less than 1 which would make it
	9	nonreactive.  Yet, in our research prism antigen assay,
10	these were easily detected.  You can see here the published
11	information on the NAT data for each of these specimens.
12		If you look at these specimens at a 1 to 96

13	dilution, the copies per ml range from about 122 up to about
14	1,000 copies per ml.  But, at dilutions of 1 to 1,200, we
15	are getting down into the range of 10 to about 80 copies per
16	ml and it begins to push the sensitivity of the NAT assays
17	as they currently exist.
18		[Slide.]
19		I think when one looks at an antigen assay such as
20	the one we have now and are continuing to drive the
21	sensitivity of that assay even further, that the advantages
22	of such an assay is that it is already a fully automated
23	system for antigen testing, and one gets really quite rapid
24	results.  There are already in place process controls for

25	enhanced GMP compliance.  There is really little or minimal

			120 1	sample preparation and, certainly, the issues of
	2	contamination or carryover that one potentially has with NAT
	3	testing are really virtually nonexistent.
	4		The ability to confirm using a neutralization test
	5	exists.  Certainly, for simplicity of implementation, there
	6	are no pools to dilute the sensitivity, no dissection of
	7	pools, no shipping of pooled specimens, et cetera, et
	8	cetera.
	9		[Slide.]
10		On the final slide, I think I would like to leave
11	you with sort of two messages.  One is that the gap between
12	individual antigen testing using more sensitive antigen

13	assays and NAT for pooled samples really may not be as
14	significant as we may like to think and that, as opposed to
15	thinking about discontinuation, I think maybe one ought to
16	really send a more positive message to manufacturers that
17	they should be encouraged to develop ultrasensitive antigen
18	assays with sensitivities equal to or greater than single-
19	unit NAT testing.
20		Thank you.
21		DR. HOLLINGER:  Questions?  I have a question. 
22	Have you had a chance to compare this with actually many of

23	the NAT-positive antigen-negative samples, a large number of
24	the ones which have now been positive by NAT and negative by
25	antigen, to see what percentage was actually picked up with

			121 1	the new technique, the prism technique, and so on?
	2		DR. SCHOCHETMAN:  We are trying to obtain some of
	3	those samples and we understand there is little, if any,
	4	available.  But we certainly would love to be able to look

	5	at those.  I think maybe something that we would certainly
	6	like to do is actually try to set up sort of a head-to-head
	7	comparison going into very high-risk populations where the
	8	incidence would be extremely high, probably in the 7 to
	9	14 percent range, and be able to look at many more early
10	seroconverters and to do probably a better study.
11		But we certainly would be happy to look at any of
12	the NAT-onlys.  We have, so far, been unable to really get
13	access to any.
14		DR. HOLLINGER:  Thank you.
15		We have two more.  Dr. Fang from Chiron
16	Corporation?
17		              Presentation
18		DR. FANG:  Thank you, Mr. Chairman
19		[Slide.]
20		I am Chyang Fang from Chiron Corporation, the

21	Blood Testing Division of Chiron Corporation.  Chiron
22	Corporation is a biotechnology company headquartered in

23	Emoryville, California.  We currently supply the NAT assay
24	for blood screening on more than 70 percent of the nation's
25	blood supply under an FDA-approved IND application.

			122 1		The Chiron TMA HIV-1 HCV assay is a multiplex
	2	assay for simultaneous detection of HIV-1 HCR RNA in human
	3	plasma.  This assay is developed and manufactured by
	4	GenProbe Incorporated located in San Diego, California.
	5		Today, I would like to present data in support of
	6	the notion of discontinuation of routine HIV-1 antigen
	7	testing after a NAT assay is approved by the FDA and
	8	implemented for routine blood screening.
	9		The first part of my presentation is to show that
10	all p24-antigen-positive donor specimens from three studies
11	were also positive with the Chiron TMA assay.  The second
12	part is to show the analysis of the Chiron TMA assay on
13	different subtypes of HIV-1.
14		[Slide.]
15		I collaboration with Professor Anton Hans of the
16	South African Blood Transfusion Service, we have conducted a
17	study in South Africa.  In South Africa, about 1 million
18	blood donations are collected annually by seven blood
19	centers; that is, one large center, two medium sized and
20	four small centers.
21		About 90 percent of the donations are from they

22	call it low-risk donors while the remaining 10 percent are
23	from high-risk donors.  The low-risk donors are many from
24	the white and the Asian population and the high-risk donors
25	are many from the black and colored populations.  These are

			123 1	the terms used in South Africa.
	2		The overall HIV prevalence was reported at
	3	0.21 percent in 1997 and 1998.  However, the rate among the
	4	high-risk group was more than 100 times higher than the low-
	5	risk group.  In 1994, the risk of HIV transmission through
	6	transfusion in South Africa was estimated at 2.2 per
	7	100,000.  This number was much higher than the United States
	8	and other developed countries.
	9		All donations are routinely screened for HIV-1,
10	p24 antigen, HIV-1 to HCV antibody, HBsAg and syphilis
11	serology with a double EIA strategy.  That means, a second
12	EIA test is used to confirm the initial reactivity instead
13	of neutralization, Western Blot or RIBA.
14		[Slide.]
15		For the study, about 10,000 samples from low-risk
16	donors and 10,000 samples from high-risk donors was
17	collected and shipped frozen to Johannesburg Laboratory for
18	TMA testing using the single-unit testing.  Samples were
19	provided by all seven blood centers, the contributions
20	proportional to their collection volume.  Routine laboratory
21	results and donor demographic information was collected
22	prior to the breaking of the linkage.
23		All serology and TMA-reactive samples have been
24	shipped to Dr. Michael Busch's laboratory at the Blood
25	Centers of the Pacific for further testing.

			124 1		[Slide.]
	2		A total of 20,620 donor samples have been TMA
	3	tested.  Of this, 54 percent are from the high-risk group. 
	4	62 percent is from male donors and 15 percent from first-

	5	time donors.  The higher percent of the first-time donors
	6	for the study population was mainly due to a higher
	7	proportion of the samples which were from the high-risk
	8	groups, particularly for the female high-risk groups.  We
	9	suspect that there is some test seeking in this group.
10		[Slide.]
11		For the purpose of this meeting, there were seven
12	HIV-1 p24-antigen-positive samples identified.  Those are
13	the TMA-positive and the p24-antigen-positive.  That group
14	is the TMA-positive, antigen-positive, but also antibody-
15	positive as a total of seven donor samples.
16		All of the seven samples are from high-risk
17	groups, six from males and one from females.  Five are also
18	positive for antibody and one was antibody-negative and

19	antigen-negative--no; I'm sorry.  One is also antibody-
20	negative but antigen-positive.
21		Although the additional testing has not been
22	completed yet in order to confirm this reactivity, but all
23	seven p24-antigen-positive samples were also positive in the
24	TMA testing.  In addition, there is also one sample from a
25	high-risk female donor which was positive only in the TMA

			125 1	testing.
	2		[Slide.]
	3		Data from this study will be presented at this
	4	year's AABB annual meeting in November by Dr. Nel.  The
	5	preliminary conclusion includes that the role of routine HIV
	6	p24 antigen testing should be reevaluated.
	7		[Slide.]
	8		In a second study, Professor Jean Pierre Allain of
	9	the Cambridge University in U.K. has collected donor samples
10	from Ghana and Durbin, South Africa, for single-unit and
11	pooled TMA testing.  Seroreactive samples were excluded from
12	the study.  However, some samples were identified as

13	positive for HIV-1 RNA by the TMA assay.  Most of the
14	samples were purposely included as a positive control.

15		This included four p24-antigen-positive for the
16	South African population and six antibody-positive from the
17	Ghana population.  Two additional samples from the Ghana

18	group were TMA-positive but negative for p24 antigen and
19	antibody.  All twelve HIV-1 RNA-positive samples were
20	confirmed by their in-house RT PCR methodology.
21		[Slide.]
22		A third study in the U.S. under the FDA-approved
23	IND, the AIBC is currently testing about 35,000 donor
24	samples monthly from 22-plus centers at the Citrus Blood
25	Bank in Florida using the TMA assay.

			126 1		From April, 1999 to August of this year, about
	2	600,000 donor samples have been tested in pools of 24.  Six
	3	samples were identified as positive for HIV-1 p24 antigen. 
	4	All six samples were also positive with the TMA assay.  All
	5	six were also reactive in the HIV antibody EIA, but only two
	6	were confirmed by Western Blot.
	7		[Slide.]
	8		A switch to the sensitivity.  In terms of the TMA
	9	sensitivity for different HIV subtypes, we have compiled
10	data from several assay performance evaluation studies
11	around the world.  Samples were from various sources and of
12	different origins.  Testing was conducted by six different
13	laboratories.  The viral load, or the copy per ml numbers,
14	were provided by the testing lab or measured against the
15	international standard.
16		This slide shows that the sensitivity of group M,
17	subtype A, specimens.  The data show that TMA could reliably
18	detect type A specimens below 100 copies per ml.
19		[Slide.]
20		This slide shows type B specimens.  Again, the TMA
21	assay can detect all samples including those at the 100
22	copies per ml.
23		[Slide.]
24		This again is type B specimens to show that TMA
25	can detect samples at a sensitivity less than 100 copies per

			127 1	ml.  The samples have been arranged in descending order of
	2	the copy per ml number at testing.  This column, basically,
	3	is tested once and then, again, positive results at the 1 to
	4	100 dilution and so forth.
	5		[Slide.]
	6		This lists all the type C specimens.  Again, TMA
	7	can detect samples at the viral load of 100 copies per ml or
	8	less.
	9		[Slide.]
10		This lists all the type B samples that have been
11	tested, down to less than 100 copies per ml.
12		[Slide.]
13		These are the type E specimens.
14		[Slide.]
15		This lists the type F, G and H.  For type H, only
16	two specimens were tested, once each by two different labs. 
17	Both samples had a viral load of higher than 100 copies per
18	ml.  This slide also shows that the TMA assay could detect
19	group or specimens at 100 copies per ml or less.
20		[Slide.]
21		This slide summarizes the data from the previous
22	seven slides.  Overall, data from the six evaluation studies
23	demonstrate that the TMA assay can reliably detect all HIV-1
24	subtypes at 100 copies per ml except for subtype H where
25	insufficient data were available.

				128 1		[Slide.]
	2		Finally, one of these evaluation studies also
	3	included 30 HIV-1 specimens with different recombinant
	4	subtypes from around the world.  The viral load of these
	5	samples were unknown.  However, all samples were detected as
	6	positive by the TMA assay.
	7		[Slide.]
	8		In conclusion, we have shown that, from these
	9	three studies, all 17 HIV-1 p24-antigen-positive specimens
10	were also positive in the Chiron TMA assay.  Second, the
11	Chiron TMA assay has a greater than 95 percent detection
12	rate at 100 copies per ml for HIV-1 subtypes.
13		Thank you.
14		DR. HOLLINGER:  Thank you.  Any comments?  Dr.
15	Nelson?
16		DR. NELSON:  We have seen all the various subtypes
17	of HIV-1.  How do both p24 antigen and PCR work for HIV-2?
18		DR. FANG:  TMA has no detection of HIV-2.
19		DR. NELSON:  Does p24 antigen?  Will the licensed
20	p24 antigen detect HIV-2?
21		DR. NELSON:  Dr. Schochetman?
22		DR. SCHOCHETMAN:  It can detect HIV-2 but not to
23	the limits that it does HIV-1.  We actually have some new

24	reagents that will detect all the HIV-1's and the HIV-2's
25	down to very low limits, now.

					129 1		DR. HOLLINGER:  An important point.  Thank you.
	2		DR. HEWLETT:  May I add something?
	3		DR. HOLLINGER:  Yes.  Dr. Hewlett?
	4		DR. HEWLETT:  I wanted to add that the licensed
	5	antigen assays don't have a claim for HIV-2.
	6		DR. SCHOCHETMAN:  Right.
	7		DR. HEWLETT:  So we really don't have a good sense
	8	how cross reactive they are with each other.
	9		DR. HOLLINGER:  I'm sorry.  I can't hear you.
10		DR. HEWLETT:  The licensed antigen assays are not
11	labeled for sensitivity for HIV-2 so, at this point, I don't
12	think we really have a good sense and good data to support
13	cross-reactivity for HIV-2.
14		DR. HOLLINGER:  Thank you.
15		The next presentation is by Dr. Bianco from the
16	America's Blood Centers.  Celso?
17			Presentation
18		DR. BIANCO:  Thank you, Blaine.
19		[Slide.]
20		Thank you for the opportunity to present our
21	experience here.

22		[Slide.]
23		America's Blood Centers is an association of 75
24	not-for-profit community-based blood centers that collect
25	about half of the blood supply from volunteer donors.

			130 1		[Slide.]
	2		The results that I am going to present are
	3	summarized--these results were a survey or our centers. 
	4	There were actually two surveys that were carried out in
	5	September.  The period that they cover is from the
	6	introduction of HIV-1 p24 antigen.  That was March, 1996, to
	7	August, 2000.
	8		We received reports from 74 of the 75 centers in

	9	the survey about the detection or identification of HIV-1-
10	p24-positive antibody-negative donors.  This represents

11	27,525,000 collections.  That is 98 percent of the total
12	whole-blood and apheresis collections that these centers
13	have for these periods.
14		I have more detail in the survey from 60 ABC
15	centers.
16		[Slide.]

17		These 60 centers tested 22 million donations over
18	the period.  There were 3,425 samples that were repeatedly
19	reactive for p24 antigen.  Of those, 174 samples were

20	positive on neutralization representing about one in each of 
21	twenty samples that were tested, that were repeatedly
22	reactive, were positive on neutralization.
23		[Slide.]
24		This is just a pie chart representing more or less
25	the same thing; that is, a very proportion of the samples

			131 1	that are repeatedly reactive become positive on
	2	neutralization.
	3		[Slide.]
	4		This is a breakdown per year.  You can see that it
	5	has been a more or less constant set of data.  We have
	6	between 4.4 and 5 percent or 6 percent variation in terms of
	7	repeatedly reactive samples that neutralize.  There were
	8	four among those centers' samples that actually were
	9	antigen-positive antibody-negative among those 174
10	neutralized samples.

11		[Slide.]
12		This is a bar graph just representing the same
13	thing in the distribution per years.  There was one sample
14	identified in 1996, two samples identified in 1999 and one
15	sample identified early this year.
16		[Slide.]

17		These samples came from all areas of the country,
18	two from the Pacific, one from the Northeast and two from
19	the Southwest.  The last sample was detected after the
20	introduction of NAT testing for HIV and so the sample was

21	tested for both.  The donor did not come back for follow up. 
22	All the other donors seroconverted, were neutralization-
23	positive and two of them were PCR-positive.
24		[Slide.]
25		So the yield between March, 1996 and August, 2000, 

			132 1	of over	27.5 million donations were four positive
	2	individuals for HIV-p24 antigen-negative on antibodies.  So
	3	the ratio, the yield, here, is one in about 6,880,000
	4	samples.
	5		[Slide.]
	6		In summary, HIV p24 was introduced as an interim
	7	step for shortening the window for HIV until molecular
	8	assays became available.  And we heard very good summaries
	9	from Dr. Hewlett, Dr. Busch, and also from Sue Stramer.  ABC
10	identified one in 6,880,000 as window cases detected by the
11	p24 antigen; thus, the yield is very small.
12		[Slide.]
13		In conclusion, NAT for HIV is much more sensitive
14	than p24 antigen even when performed in pools of 16 to 24
15	specimens.  NAT has been successfully performed under FDA-
16	approved INDs and ABC centers support the elimination of the
17	requirement for HIV p24 antigen screening when NAT for HIV
18	is performed either under an approved IND or with an FDA-

19	licensed test.
20		We understand that the position of FDA is for an
21	FDA-licensed test but we would like to request that, for
22	donor pools of 16 and 24 samples, that the same
23	consideration being given to source plasma be given to
24	whole-blood donations and apheresis.
25		Thank you.

			133 1		DR. HOLLINGER:  Thank you, Celso.
	2		Any comments for Celso?  Questions?  Thank you.
	3		This concludes the individuals who have asked to
	4	speak to the issues here, but I am just going to open it up
	5	for a second to the public for anyone else who wishes to
	6	present any information on this aspect of the question.  If
	7	there is someone else that wants to speak about something, I
	8	will get to that in a minute.
	9		Does anyone else wish to make a comment?
10		DR. CONRAD:  I just think it is very important--I
11	don't know if the issue of the false-positivity--it struck
12	me as remarkable that that is the other side of this
13	equation.  I think that the polymerase chain reaction or TMA
14	is very sensitive, but I also think the specificity
15	shouldn't be overlooked and that some of the slides that Dr.
16	Bianco and Dr. Stramer showed, there was an enormous number
17	of people being told that they are potentially at risk for
18	having HIV and that are not being confirmed.
19		I think many of those donors are permanently
20	deferred.  That is a pretty terrible position to be in.  So
21	it is not just whether or not NAT is more sensitive and
22	imparts safety on the blood supply.  It is also that it is
23	probably more specific and imparts piece of mind on the
24	donors.
25		DR. HOLLINGER:  Thank you.

			134 1		I want to get to just one final presentation and

	2	then we are going to take a break.  Alpha 1 wants to make a
	3	presentation on the availability of therapeutic products. 
	4	This is going to be Ms. Miriam O'Day.

	5		              Presentation
	6		MS. O'DAY:  Hi.  First of all, I wanted to say
	7	that I am here today--I have changed my affiliation.  I am
	8	Miriam O'Day.  I am Director of Government Relations and

	9	Regulatory Affairs for the Alpha 1 Foundation.  Thank you
10	for the opportunity to comment today regarding the
11	availability of therapeutic products for the treatment of
12	alpha 1 antitrypsin deficiency.
13		The Alpha 1 Foundation is a national not-for-
14	profit organization whose mission is dedicated to providing
15	leadership and resources that will result in increased
16	research, improved health, worldwide detection and a cure
17	for alpha 1.  The Alpha 1 Foundation works closely with the
18	Alpha 1 Association to promote awareness and further
19	advocacy goals.

20		AAD is a single-gene defect leading to the loss of
21	one serum protein requiring augmentation therapy. 
22	Currently, the AAD protein is replaced with an intravenous
23	plasma-derived product which is produced by a sole
24	manufacturer.  Because extreme product shortages have been
25	experienced within the alpha 1 community, with supplies

			135 1	decreasing to between 40 to 80 percent of the prescribed
	2	dosage, the Department of Health and Human Services Advisory
	3	Committee on Blood Safety and Availability passed a number

	4	of resolutions to recommend strategies for amelioration of
	5	this crisis.
	6		On August 24, the Foundation provided a report to
	7	the advisory committee regarding the status of their
	8	recommendations which I will summarize for you.  First, the
	9	advisory committee recommended that methods be developed to
10	optimize and standardize allocation of available product in
11	an equitable manner including the management of emergency

12	supplies and programs that distribute products directly from
13	manufacturers to registered consumers.
14		Distribution of Prolastin, the AAD augmentation
15	therapy, was addressed by the alpha 1 community which
16	included the Alpha 1 Association, the Alpha 1 Foundation and
17	the Foundation's Medical and Scientific Advisory Committee.
18		In response to consumer requests, they have
19	implemented a direct-distribution strategy.  Prolastin is no
20	longer sold to distributors.  It is allocated directly from
21	the manufacturer to the consumer insuring that the fully

22	prescribed dosage is available to each alpha as long as
23	there is product available.
24		All alphas enrolled in the program have received
25	their full prescription at 28-day intervals since November

			136 1	of 1999 resolving the need for reduced dosages or increased
	2	intervals between infusions.  In addition, over 200
	3	consumers that did not have access to augmentation therapy
	4	prior to the establishment of this program are currently on
	5	product.  Direct distribution of a one-product, one-
	6	manufacturer, community has resolved inequities and directly
	7	related to the decrease of the severe shortages.
	8		The direct distribution from manufacturer to

	9	consumer has proven beneficial with regard to safety as
10	well.  Direct distribution has allowed for the swift and
11	accurate notification of recalls and withdrawals.  For
12	example, information regarding the recent recall of

13	CliniPads due to the confirmation of bacterial contamination
14	within some lots reached all alpha-1 consumers within 48
15	hours.
16		I would like to note that the Foundation continues
17	to support the voluntary patient notification system and per
18	capita has the greatest number of consumers enrolled in the
19	PNS.  Second, the advisory committee recommended that
20	industry explore with the FDA strategies for reallocating

21	partially processed plasma materials from one manufacturer
22	to another in order to optimize production of alpha-1
23	antitrypsin and other plasma derivatives.
24		The Foundation was able to work closely with

25	industry on this issue and, on behalf of the alpha-1

			137 1	community, we would like to thank the American Red Cross and
	2	Baxter for working with Bayer in a cooperative relationship
	3	to provide enough raw materials to reach full production
	4	capacity at both of Bayer's manufacturing facilities.
	5		We caution, however, that this does not indicate

	6	that the end product or the throughput will satisfy demand
	7	nor does it resolve the uncomfortable feeling within the

	8	alpha-1 community of reliance on one manufacturer.  This
	9	dependency leaves us vulnerable to possible GMP problems and
10	accentuates the delicate balance between supply and demand.
11		Third, the committee recommended that NIH and

12	industry should immediately evaluate alternative dosing
13	schedules and alternative delivery systems for alpha-1

14	therapy including prophylaxis strategies and strategies for
15	treatment during acute exacerbations of disease and
16	accelerate development of gene-based products and gene-
17	directed therapies for alpha 1.
18		This resolution supported the evaluation of new
19	delivery technologies and expedited development of new and
20	non-plasma-derived options including aerosol and inhaled
21	delivery systems.  Currently, there are three manufacturers
22	in various stages of development with an aerosol product
23	including one transgenic product.
24		The hope is that aerosol will prove more
25	efficacious because it delivers the drug directly to the

			138 1	lung.  It is also hoped that the aerosol products will
	2	provide increased access to a greater number of consumers,
	3	perhaps up to five times as many individuals with the same
	4	raw material and be more cost-effective.
	5		In conclusion, the current situation with one
	6	manufacturer and one product causes concern about the
	7	inevitable situation when demand will exceed supply.  Within
	8	the next few months, we anticipate a delay in dispensing

	9	causing a delay in serving all consumers enrolled in the
10	direct-allocation program.
11		Providing the alpha-1 community with therapeutic
12	alternatives should be a top priority for the FDA and the
13	agency has been very cooperative in addressing issues
14	relating to clinical-trial design and INDs.  The Foundation
15	hopes that this progress will continue and we are very
16	encouraged that we have an opportunity for further
17	discussions with the agency at a meeting that is scheduled
18	at the end of the month.
19		Thank you very much for your time today.
20		DR. HOLLINGER:  Thank you, Ms. O'Day.

21		We are going to take a break now until noon and we
22	will meet back here for committee deliberations and to deal
23	with the question.  Thank you.
24		[Break.]
25		DR. HOLLINGER:  We have most of the committee

			139 1	members here, but not all of them.  Is Dr. Hewlett still
	2	here?  Is there anyone here from the FDA?  Are we by
	3	ourselves?  We can create anything we want now.
	4		Dr. Hewlett, could you go over the question again,
	5	please?
	6		      Questions for the Committee
	7		DR. HEWLETT:  At this point, I am going to read
	8	the questions.  The first question for the committee is, "Do
	9	the committee members agree that HIV-1 p24 antigen testing
10	of source plasma may be discontinued if: a, it is
11	demonstrated that a particular licensed NAT method can
12	detect HIV at a level of 5,000 copies per ml or less in a
13	unit of plasma even if the donor sample is tested as part of
14	a pool, and b," as it is written here.
15		I am going to go ahead and read this question, but
16	we have had some discussion about whether to rephrase it. 
17	The question, as written, is, "Comparative studies of the

18	NAT method versus HIV-1 p24 are consistent with the
19	hypothesis that the NAT method is of equal or greater
20	sensitivity (including the ability to detect major
21	subtypes)."

22		However, we would like the committee to focus on
23	whether the data you have heard this morning are adequate
24	for you to make a recommendation that it is acceptable to
25	replace p24 with the NAT method.

			140 1		The second question is, "If committee members

	2	disagree, please comment on an appropriate alternative."
	3	         Committee Discussions and Recommendations
	4		DR. HOLLINGER:  Except for fractionation being
	5	misspelled.  I am going to open this up to the committee

	6	now--we have closed the open session--and ask the committee
	7	members to deliberate on this a little bit about the
	8	question, any comments that anybody wants to make, any
	9	discussions and so on before we actually vote.
10		Who would like to start?  Dr. Simon?
11		DR. SIMON:  I basically agree with the question. 
12	I had two comments I would like to make.  Number one, at

13	least from my point of view and I think, perhaps, we will
14	hear this from several others, it would seem that we could
15	go to both source plasma and whole blood.  There must be a
16	reason why the FDA wanted this restricted to source plasma,
17	but it would be appear that the data would be very
18	supportive of making the substitution for whole-blood donors
19	as well.
20		Secondly, I did read--it was in packet, and there
21	wasn't much more said about it--the Criteria for
22	Discontinuation, Current Thinking.  I just wanted to express
23	a concern, given the data that we have heard which seems to
24	be very strong, that the NAT will, if anything, improve

25	safety over what might be now and allow us to eliminate a

			141 1	test that has caused us to lose many noninfectious donors,
	2	that the FDA not be too onerous in its requirements.
	3		Some of the things here seem to go beyond what is
	4	in the question, for example about the reference to new
	5	clinical trials or clinical trials done by the companies. 
	6	As was stated by at least one of the presenters, some of the
	7	companies didn't have this, per se, as a question in their

	8	clinical trials but their data show overwhelmingly that the
	9	NAT test is more sensitive in detection of potential window
10	donors than is the p24 antigen.
11		So I would hope that data based on meeting the

12	sensitivity limits set by the FDA as well as demonstrating
13	in the various panels that the detection is possible would
14	allow this approval to occur, because I think this
15	potentially would be if not a significant advance certainly
16	a step forward by eliminating a test that we do not need and
17	utilizing the NAT technology that is coming along so well.
18		DR. HOLLINGER:  Thank you.
19		John?
20		DR. BOYLE:  I would just like a clarification on
21	question 1 because I don't know enough about the test
22	variability for NAT testing, but does detecting at 5,000
23	mean all, some or any?
24		DR. HOLLINGER:  Can you rephrase that a little
25	bit?

			142 1		DR. BOYLE:  In other words, "can detect HIV at a
	2	level of 5,000 copies."  Does that mean in all cases, some
	3	cases or any cases?
	4		DR. HOLLINGER:  I would presume it would be in all
	5	cases.  Dr. Hewlett?
	6		DR. HEWLETT:  At least 95 percent of the time.
	7		DR. HOLLINGER:  Dr. Fitzpatrick is not here, but
	8	he did send an E-mail and I would like to read into the
	9	record, at least his comments.  It is fairly short.  He
10	says, "I agree with the recommendation of the FDA but would
11	encourage the committee to ask the FDA, on record, to
12	discuss each of the prerequisites for dropping the test that
13	the FDA, itself, had outlined.  All of these have not been
14	addressed in the preexisting materials.  One of the most

15	important is a licensed NAT test for HIV.  I know you all
16	will follow up with them on the others," and so on.
17		His question just is, apparently, there are some
18	reasons for dropping a test and one of them is that you
19	would use another test for it like the NAT test.  I think
20	what he is just saying is since there are no licensed NAT
21	tests at the present, how are you going to deal with that?
22		DR. HEWLETT:  The issue that we would like to
23	stress, one of the points that we would like to stress, is
24	that replacement at the present time--our consideration is

25	that it will not happen until a NAT method is licensed.  So,

			143 1	in other words, although data are being accumulated and
	2	certain manufacturers may, in fact, have analyzed their data
	3	to demonstrate utility or greater sensitivity of the NAT
	4	method, that particular manufacturer would get licensed and
	5	would be allowed to replace the HIV antigen test with their
	6	licensed NAT method when they get licensed for the NAT test.
	7		So that is the current thinking at the FDA in
	8	regard to how it is going to be implemented.  Obviously, the
	9	issue has been raised as to whether the industry as a whole
10	can move towards a specific test.  We need to recognize that
11	the NAT testing, the pool testing, has been implemented in a
12	somewhat different way than most of the other tests have. 
13	They have been implemented under IND primarily to gather
14	data to support the efficacy of the test.
15		So in allowing manufacturers to do that, I think
16	we have gone a long way.  Another modification under IND I
17	think would probably not serve us as well.  So what we are
18	looking at at this time is to go with specific licensed NAT
19	methods and to allow manufacturers to replace p24 with their
20	specific and particular method when it becomes licensed.
21		DR. HOLLINGER:  Thank you.
22		Dr. Nelson?
23		DR. NELSON:  I don't completely understand the
24	licensure procedure given the fact that there is a lot of
25	data on NAT testing.  Have none of the manufacturers applied

			144 1	for licensure yet or, if they have applied, what is the
	2	procedure, what else needs to be done?
	3		DR. HEWLETT:  Obviously, our tongues are tied in a
	4	certain way in regard to what we can disclose, but I think
	5	you have heard from at least one manufacturer today that
	6	they have submitted an IND, they have submitted a BLA which
	7	is under review.
	8		The review process, just to give you a two-minute
	9	summary of how it takes place; we review, we send them
10	letters.  We go through the deficiencies, do an inspection. 
11	So there is a lot of review and inspection and establishment
12	issues that need to be addressed as well in addition to test
13	validation and clinical-trial issues.
14		DR. HOLLINGER:  At least in my opinion, I think it
15	is clear that the nucleic-acid testing is clearly more
16	sensitive than the p24 antigen testing.  I don't think there
17	is probably anybody here who would disagree with that.
18	I think that the levels that have been selected are probably
19	a reasonable selection.  5,000 copies per ml seems, at least
20	to me, to be a reasonable one.
21		I would like to ask, just for the record because I
22	know what the answer is, but I would like to have someone
23	discuss from industry or from people who are doing the
24	tests--we talk a lot about false-positive tests.  That is
25	not really the issue.  The false-positive tests are no

			145 1	problem.  If you get a positive test, you look at the
	2	individual samples to see if any of them are positive or
	3	negative.
	4		What is really important are the false-negative
	5	tests, and how often does false negative come into
	6	existence.  The difficulties of potentially sucking up the

	7	DNA, the pellet, or something like this in which you will
	8	get a pool that is negative which is, indeed, truly
	9	positive.
10		So I would like somebody to discuss what things
11	are being done, such as controls and so on.  That is why I
12	am really bringing it up.  Also inhibitors, when you pool
13	things, the potential for inhibitors that might inhibit a
14	positive test that are in there.
15		Andy, why don't you go ahead and do that.
16		DR. CONRAD:  For us, one of those manufacturers
17	has submitted those BLAs.  Of course, all of our samples
18	that are actually tested, contain an internal control, and

19	that internal control--I know that TMA has it, as well, and
20	I know that the Roche system that Bayer uses as well.  So
21	all of the current manufacturers I think that are in the

22	process of this all have internal controls which would
23	indicate inhibitors either from an individual sample or in
24	the pooled context--would indicate a preparation error where
25	the nucleic acids weren't carried forward to the

			146 1	amplification reaction.
	2		So the issue, just from our clinical experience,
	3	during our INDs which we have conducted with several
	4	manufacturers, there was not a single case in which a donor
	5	seroconverted where we had a prior donation that we did not
	6	find positive.  So there were no false negatives.
	7		There are individual donations that are not
	8	detected in pooled PCR but that is different than a donor
	9	passing through the system undetected.  I am sure the story
10	is true with TMA as well as the Roche system used by Bayer. 
11	So false negativity due to inhibition or extraction errors
12	cannot be brought forward because the internal controls and
13	the sensitivity prevents false negativity in the sense that
14	truly positive donors are missed.
15		DR. FANG:  Like Andy said, the TMA also has
16	internal controls.  TMA has been used for screening over
17	10 million donations.  It is very rare cases that internal
18	control may have a very low signal or suspect of inhibition,
19	or whatever.  But none of those samples can be repeated; in
20	other words, it is all due to technical errors rather than
21	due to inhibitions because when we retest the samples, the
22	internal control was fine.
23		Secondly, because of pool testing, we also suspect
24	that there may be some samples have an inhibitor and then,
25	when you do the pooling, the inhibitor--and therefore you

			147 1	can't detect it.  But when you do the single-unit testing,

	2	you may have inhibition reaction and you missed it.  So we
	3	take some of the pool reactive when we can and find any
	4	single samples in the pool that turn out to be reactive, we
	5	suspect whether there is any inhibitor and we do some
	6	testing.
	7		Data, so far, is showing that there is no
	8	inhibition whatsoever.  Data will be presented at the AABB
	9	this year.
10		DR. HELDEBRANT:  In a similar system using PCR to
11	screen HCV, because of the European requirement to test
12	manufacturing pools for HCV, you have an independent
13	confirmation as to whether there are any false negatives
14	getting through the system.  In our experience, we have had
15	absolutely no false negatives when we have been screening
16	for HCV with pools of 512 and then assaying the
17	manufacturing pools made from that screened material.
18		So, as of yet, we have yet to see false negative
19	get through the system.
20		DR. HOLLINGER:  Thank you  I would like to ask,
21	also, the FDA whether--you say that you want to detect HIV
22	at a level of 5,000 copies per ml.  I wonder whether that
23	ought to be modified somewhat to say at a level comparable
24	to 5,000 copies per ml because I imagine that, somewhere

25	down the line, you are going to go to an international unit,

			148 1	most likely, whether it is WHO standard 1, genotype 1--I
	2	mean, I'm sorry; that is for HCV--or whether it is for HIV,
	3	some other standard.
	4		Is that correct?  Am I assuming--and is that an
	5	issue if we make that to say something at a level comparable
	6	to 5,000 copies per ml?
	7		DR. HEWLETT:  Yes; I think that is a reasonable
	8	modification.  In fact, we are looking at moving towards the
	9	international unit.  The CBER release panel is being
10	calibrated against the international unit as we speak, so we
11	hope that when those numbers come in, we will actually be
12	able to adopt that in the future.  But, at this time, we are
13	going to stick with copies.
14		But adding the word "comparable" I think is a good
15	suggestion.
16		DR. HOLLINGER:  I think having a standard that all
17	the manufacturers have to shoot for gets away a little bit
18	about pooling and so on.  One of the issues often is how low
19	a test is, how sensitive a test is, can you detect 5 at 95
20	percent, can you detect 15 or 20 and so on.
21		The real issue is if you are going to use
22	something like this, can you detect a particular standard or
23	proficiency panel that is set out in a way that will
24	reassure us that you are not going to miss any main samples.
25		DR. HEWLETT:  I think we agree.

				149 1		DR. HOLLINGER:  Dr. Chamberland?
	2		DR. CHAMBERLAND:  I have a question for the FDA. 
	3	It is a bit of a side bar to the main question that we have
	4	been asked to vote on.  But if, in fact, industry elects--if
	5	there are licensed NAT tests available and industry elects

	6	to replace p24 with them, I was just wondering if there had
	7	been at least any preliminary discussion about would it be
	8	possible to entertain bringing back into the donor pool

	9	donors who had tested--would appear to be biologically false
10	positives with the p24 antigen assay when you have a
11	situation now where donors would be screened, let's say,
12	with NAT.
13		I was curious if that was something that had come
14	up for any preliminary discussion.
15		DR. HOLLINGER:  Comments from the FDA?
16		DR. HEWLETT:  I think that is a good suggestion. 
17	In fact, that is something we may want to look at as we go
18	further along.  At this point, for example, you are talking
19	about reentry of false positives.  That is obviously
20	something that can be evaluated in clinical trials and so on
21	in the future.
22		DR. SCHMIDT:  Wouldn't the answer to that be there
23	aren't any?  I mean, we are talking about a dozen people and
24	what would be the value of running a big protocol just for
25	them.

			150 1		DR. CHAMBERLAND:  What I was referring to were

	2	individuals and maybe Sue Stramer could--I was speaking
	3	about individuals who were deferred currently from donation
	4	because they tested positive on a p24 antigen screen and
	5	neutralization and other workups seem to indicate that they
	6	were most likely false-positives.  Sue, can you maybe give
	7	us some ballpark of numbers that we are talking about?
	8		DR. STRAMER:  For the Red Cross, we have seen,
	9	since March of 1996, 158 of those donors.  The numbers are
10	not high but if ABC has a comparable 158--174.  Okay; not
11	exactly, but the same.  We already have a litany of test
12	results that show that these individuals are not infected
13	with HIV.  But they are listed as permanently deferred in
14	our donor-deferral registry.
15		DR. HOLLINGER:  Dr. Kleinman?
16		DR. KLEINMAN:  I think Mary's concerns should be
17	broadened though because there is a whole group of donors
18	who are p24 repeat reactive and don't neutralize that then
19	fail the current reentry algorithm because they are still
20	p24 antigen repeat reactive.  That is a half of the repeat-
21	reactive rate.  What was the repeat reactive rate?  About
22	0.027.  So that is 0.013 percent of people, so about one in
23	10,000 donors are out because they can't requalify on
24	antigen test.
25		So that would potentially be a very much larger

			151 1	yield for a reentry algorithm.  So I would agree with your
	2	suggestion and encourage FDA to think about, once licensed
	3	occurs, different kinds of reentry algorithms for people who
	4	have been disqualified because of p24 antigen.
	5		DR. HOLLINGER:  Dr. Nelson?
	6		DR. NELSON:  When p24 antigen was replaced by NAT
	7	testing and then they came in again and were not tested by

	8	p24, wouldn't they automatically reenter?  They would meet
	9	their criteria.  They are on the permanent deferral.  I see. 
10	Okay.
11		DR. HOLLINGER:  Dr. Simon?
12		DR. SIMON:  There is one other comment I need to
13	make and it is not on point as to whether the committee
14	should or should not support the question per se, but just
15	to make people both from the agency and members of the
16	committee and the public aware that if a single fractionater
17	were to be approved and there were a plasma-donor collection
18	center that supplied more than one manufacturer, and one of
19	the manufacturers was approved and the others were not for

20	their NAT to replace p24 antigen, then that collector might
21	still be in a situation where they were doing p24 antigen in
22	all their donations.
23		So there is a logistical issue here.  Obviously,
24	if all the manufacturers were approved, then that problem
25	would go away.  But as it is on a one-by-one basis, we would

			152 1	find at least a portion of the plasma industry that might
	2	have to keep doing the test.
	3		DR. HOLLINGER:  Also, Toby, just one question, is
	4	there a problem with eliminating the test in terms of Europe
	5	or other places also?
	6		DR. SIMON:  That was brought up also.  My
	7	understanding is that Europe does not require it so one
	8	would think it would go away.  However, it is in some of the
	9	filings that the companies have done for their product in
10	Europe, so those would have to be changed, the various
11	claims and filings and so forth.
12		So, unfortunately, while I support the question

13	and would like to see us take this step and don't want to
14	say anything discouraging, I just want people to know that
15	there will be, then, an evolutionary process afterwards to
16	actually implement it.  It will be a little bit more
17	difficult to implement than it would seem.
18		Now, if there is a manufacturer who is totally
19	self-sustaining and gets all its donations from its own

20	centers, that manufacturer could probably go ahead.
21		DR. HOLLINGER:  Thank you.  Again, as I say, we
22	are talking about plasma here and, of course, plasma also
23	has removal and activations procedures as well as another
24	major safety.  So I would like to make a motion, actually,
25	for myself to change just that 1a), which would say, "It is

			153 1	demonstrated that a particular licensed NAT method can
	2	detect HIV at a level comparable to 5,000 copies per ml or

	3	less in a unit of plasma even if the donor sample is tested
	4	as part of a pool."
	5		Can I have a second to that?  Mark?
	6		DR. MITCHELL:  Second.
	7		DR. HOLLINGER:  Any discussion?  All those in
	8	favor of that change, raise your hand.
	9		[Show of hands.]
10		All opposed?

11		[No response.]
12		Let's, then, go ahead and vote with that change in
13	mind on 1a) and b) since they are interchangeable.  Mark?
14		DR. MITCHELL:  Before we do that, I have another
15	question.  If we vote on this, does this mean that the--we
16	heard previously that there is an effort to improve the
17	specificity of the antigen testing, itself, and that it may
18	become similar to the NAT testing.  Does voting on this mean
19	that they would have to switch completely to NAT testing, or
20	can they also have the p24 antigen testing if it is similar
21	in sensitivity?
22		DR. HOLLINGER:  I would think they would have to
23	show comparable sensitivities.  Dr. Epstein?
24		DR. EPSTEIN:  I think the way we would look at it
25	is that they need to be doing a test of equal or greater

			154 1	sensitivity to the current p24.  So the question is if they
	2	are approved for NAT, and that is determined to be a test of
	3	equal or greater sensitivity than p24, then they can
	4	discontinue p24.  But we would not be saying you cannot do
	5	p24.
	6		So, if a future test comes about which is, for
	7	argument's sake, equivalent to NAT or better than NAT, then
	8	we would simply argue that that becomes an acceptable test. 
	9	What we are really trying to move toward here is a
10	sensitivity standard for the HIV screen, the direct viral
11	screen.
12		DR. HOLLINGER:  So we will go ahead and vote on
13	1a) and b).  Do I need to read it fully?  I will read, then,
14	1a) and b).  It says, "Do the committee members agree that
15	HIV-1 p24 antigen testing of source plasma may be
16	discontinued if, a), it is demonstrated that a particular

17	licensed NAT method can detect HIV at a level comparable to
18	5,000 copies per ml or less in a unit of plasma even if the
19	donor sample is tested as part of a pool and, b),
20	comparative studies of the NAT method versus HIV-1 p24 are
21	consistent with the hypothesis that the NAT method is of

22	equal or greater sensitivity?"
23		The parenthesis you want in there or not in there? 
24	Parenthesis, "Including the ability to detect major
25	subtypes."  End of parenthesis.

				155 1		With those in there, all those in favor of, the
	2	committee members agree, that it may be discontinued under
	3	those circumstances, please raise your hand.
	4		[Show of hands.]
	5		All those opposed?
	6		[No response.]
	7		DR. HOLLINGER:  You realize this is a momentous
	8	occasion here.  I think there should be music playing in the
	9	background now or something for this.
10		The consumer representative?  Kathy Knowles?

11		MS. KNOWLES:  Yes; I vote in favor of it, too.
12		DR. HOLLINGER:  And the industry representative?
13		DR. SIMON:  Yes.
14		DR. SMALLWOOD:  The results of voting are as

15	follows: there were unanimous "yes" votes of 13 votes. 
16	There were no "no" votes, no abstentions, and both the

17	consumer and industry representatives agreed with the "yes"
18	votes.
19		DR. HOLLINGER:  Thank you.
20		[Applause.]
21		DR. HOLLINGER:  Actually, we are finished fifteen
22	minutes early.  I don't know what to do.  But we are going
23	to take a lunch break until 1:45.  This afternoon is going
24	to be a lot of discussion here.  I hope we finish somewhere
25	near midnight, but we will move forward.  I think it will be

				156 1	an interesting session.
2		So we are adjourned until 1:45.
3		[Whereupon, at 11:45 a.m., the proceedings were
4	recessed to be resumed at 1:45 p.m.]

			157 1	         A F T E R N O O N   P R O C E E D I N G S
	2		                                       [1:45 p.m.]
	3		DR. HOLLINGER:  Thank you.  I think we are going
	4	to convene.  I talked to somebody just before the meeting
	5	and they said you should always try something different.  If
	6	you keep doing the same thing over and over again, you keep
	7	getting the same results.  And he told me this story.  So I
	8	will tell you another story.
	9		It was about two avid moose hunters.  These moose
10	hunters, every year, chartered a plane to take them up to
11	the Canadian back woods to hunt moose.  This was an
12	exceptionally good year this year.  They got their moose
13	within a few days, so they radioed the pilot to come and get
14	them.
15		Well, the pilot returned and looked down there and
16	saw these huge moose that they had gotten and he said, "You
17	know, I can't carry those in my plane.  They weigh too
18	much."  And the guy said, "We have had such a wonderful hunt
19	this year."  He said, "We really want to take these moose

20	back.  And besides, the pilot we hired last year didn't
21	complain about the mooses' weight."
22		So the guy, after arguing a little bit more, he
23	finally boarded the moose on board his plane as well as

24	himself and the plane sort of took off, and it just sort of
25	hovered in the air a little bit, lost altitude and crashed

				158 1	into the mountain.
	2		The two hunters sort of got themselves out from
	3	the wreckage and one of them looked at the other hunter and
	4	said, "Where are we?"  The other one said, "About a mile
	5	farther than we got last year."
	6		So maybe we can do the same thing here today, get
	7	a mile farther than we got a couple of years ago.  Andy
	8	Dayton is going to give us an introduction and background on
	9	deferral, as blood or plasma donors, of males who have had
10	sex with males.
11	     II. Deferral, as Blood or Plasma Donors, of Males
12			Who Have Had Sex with Males

13			Introduction and Background
14		DR. DAYTON:  That is a rather inauspicious
15	introduction, but I know it was not ill-intentioned.

16		We are going to reexamine the issue of deferral of
17	men who have sex with men from giving blood.  I am going to
18	give a short introduction to remind the committee and the

19	audience where we have been on this issue over the last
20	several years.  Then I am going to very briefly give the
21	outline of the theoretical structure of my talk.
22		Then Mike Busch is going to summarize a lot of
23	extremely interesting data in the field that is relevant. 
24	Then I will come back and, using data which has been

25	provided to me by many tremendously cooperative people, both

			159 1	inside the FDA and outside, and I will try to develop a
	2	model that will give us some idea of the consequences of
	3	projected changes in this policy.
	4		I should also begin by thanking the audiovisual
	5	staff.  They couldn't solve the slide advance problem, so I
	6	have a little slide projector thing.  I push it and it makes
	7	a noise and he advances the slide for me.  I think this is
	8	tremendous dedication and greatly appreciated.
	9		[Slide.]
10		The HIV epidemic in the United States is generally
11	recognized to have started just after 1977 and, as a
12	consequence of that, currently, MSMs, or men who have sex
13	with men, are deferred for MSM behavior which has occurred
14	even one time since 1977.
15		In 1997, to this committee, the FDA presented an
16	analysis of the potential effects of relaxing the MSM
17	deferral policy to either one year or five years; in other
18	words, the one year meaning if you have had any MSM activity
19	within the last year or the five-year meaning if you have
20	had any within the last five years.
21		At that time, we were only able to take the
22	analysis so far.  The summary of a very complicated analysis
23	was that blood-banking errors of various types were poorly
24	quantified at the time, but they were considered the most

25	significant risk to changing the policy.  The conclusion we

					160
	1	were able to reach at that point was that we don't know, in
	2	terms of exact numbers, what exact risk we are taking.
	3		We get roughly 10	                
				3 HIV-positive units into the
	4	blood banks which are then interdicted by tests.  We
	5	calculated that, under some MSM relaxation standards, we
	6	might double or triple that number of units which got into
	7	the blood banks and which we hope to be interdicted by
	8	tests.
	9		And we didn't know the failure rate but we
10	estimated that we would be tripling whatever the risk was

11	that we were willing to take, given the knowledge at the
12	time.
13		[Slide.]
14		In November of 1998, we hosted a workshop on donor
15	suitability.  It was a fantastic workshop and a lot of very
16	good data on incidence and prevalence was presented.  In
17	December of 1998, we summarized that data for this committee
18	and I will rely heavily upon that data during my
19	presentation.
20		[Slide.]
21		Why are we reexamining this policy at this time? 
22	Well, the widespread adoption for nucleic-acid testing for
23	HCV and particularly HIV provides, amongst other benefits,
24	redundancy.  Now, I am not talking about the reduction of

25	the window period here.  The NAT tests are run as entirely

			161 1	separate tests from the ELISA tests, for instance, and the
	2	idea is, let's say you have a pipetting error.
	3		If you have two tests and you make a pipetting
	4	error in one of them, it is unlikely you will make a
	5	pipetting error in the second of them.  So the two are
	6	redundant.  That gives you a tremendous protection against
	7	errors of certain types.
	8		The other reason we are reexamining this issue is
	9	that we have not a complete but at least a better
10	understanding of blood-bank error rates, their types and
11	their frequencies, and I do hope that at least some of that
12	improved understanding was, at least in part, the result of
13	the highlighting of blood-bank error rates in the 1997 BPAC
14	presentation on MSMs.
15		[Slide.]
16		I am going to go through, briefly, the logic
17	behind my subsequent presentation which will come after Mike
18	Busch's talk.  Diagrammatically, this is how bad things
19	happen.  This is how errors are made.  Infection gets into
20	potential donors and then, from potential donors, it gets

21	into the blood supply.
22		Now, our primary line of offense against bad
23	things getting into the blood supply are blood-screening

24	tests.  However, there are ways that the system gets--or bad
25	things circumvent the tests and happen, or agents can

			162 1	circumvent the tests and get through to the blood supply.
	2		Examples include undetectable strains which can't
	3	be picked up by the tests; blood-bank errors, which I have
	4	already mentioned; primary test failure, which is more of a
	5	theoretical problem than a practical problem because the
	6	tests--it doesn't seem to be a problem.  And, finally, there
	7	are window-period donations in which no current tests are
	8	able to pick up certain agents very early in the infectious
	9	process.
10		So we build redundancy of another sort into the
11	system and we try to stop infections from getting into the
12	blood supply by the introduction of a questionnaire.  That
13	is to reduce the number of potential donors that even have
14	their units taken, and those units are sitting around in the
15	blood supply waiting for test.
16		So it is very much like a forward chemical
17	reaction in the sense, and the math is--it really is just

18	arithmetic--is the same.  Of course, questionnaires are not
19	perfect.  They can be bypassed by several mechanisms
20	including ineffective risk identification which means we

21	have not really identified correctly the risks that should
22	be screened out.  Test-seeking behavior; for instance,
23	somebody may know they are in a high-risk group but they may
24	seek to get a test anyway because they want to know what
25	their serostatus is.

			163 1		Peer pressure; that is an obvious one.  And
	2	misunderstanding of questions, which is a major problem in
	3	designing a questionnaire.  Finally, we also have at this
	4	position here self-deferral which is mediated by appropriate
	5	education.
	6		[Slide.]
	7		Most of what I am going to focus on today is in

	8	this second half of the equation and the consequences of
	9	getting people to this step and what might happen.  We can
10	break the relevant issues into prevalence issues and

11	incidence issues.  I will talk about them somewhat
12	separately in my talk.
13		The prevalence issues involve errors allowing
14	undetectable strains or blood-bank errors or test-failure

15	issues, and I will go through this in more detail later on. 
16	Incidence includes primarily the window-period issues.
17		[Slide.]
18		To summarize where I am going to go; if we
19	consider changes in the deferral policy which result in a

20	new group, a new population, a new set of donors appearing,
21	we want to know how many errors--in other words, in this
22	case, how many infected units could conceivably get through
23	the system with a new population of donors.
24		The way we are going to calculate that is the new
25	errors--now, this means the new units that get through that

			164 1	we don't want getting through the system--in other words,

	2	infected units that might sneak through all of our testing
	3	and questionnaires.  That is going to equal to the size of
	4	the newly donating population--how many new donors do we
	5	have coming in--times the overall error rate.
	6		I will just briefly show what that equation looks
	7	like.  It is really quite trivial.  The newly donating

	8	population is merely the change in population.  The new
	9	errors I just simply wrote here as delta errors.  And then
10	there is a term here, and I will go through that in more
11	detail in my later talk, which calculates the error rate. 
12	All that is is the prevalence issues plus the incidence
13	issues.
14		[Slide.]
15		At the end of my second talk, and when the
16	committee is ready to approach questions, we are proposing
17	that this be the question the committee entertains.  Of

18	course, it will probably be rewritten.  But, as it stands
19	now, what we are going to be asking you is do the available
20	scientific data support the concept that men who have sex
21	with other men, MSMs, can be deferred from donating blood
22	for a period of five years following MSM activity rather

23	than being deferred for any MSM behavior since 1977.
24		That is the end of my introduction.  Now we are
25	going to have a very interesting talk from Mike Busch. 

			165 1	Mike, I don't know if you have the neat slide connection
	2	that I have arranged, but you are welcome to it.
	3		       Epidemiology Presentation
	4		DR. BUSCH:  Thanks, Andy.  Those were great
	5	slides, by the way.  I would really like to get some of
	6	those E-mailed.
	7		[Slide.]
	8		What I was asked to do sort of evolved over the

	9	last couple of weeks but was to present kind of mostly the
10	impact of new testing to give you confidence that, with
11	these new tests, we really understand risk and the risk is
12	exceedingly low, which gives a certain level of comfort in
13	terms of relaxing the deferral criteria as discussed.

14		But I have also been asked to add to the talk
15	discussion of HHV-8 as kind of a prototype new and emerging
16	virus that is prevalent in the gay community.  So I will

17	review some data that has been generated by several groups
18	looking at HHV-8 and the potential for its transmission by
19	blood transfusion and a preliminary study to document the
20	prevalence in the donor pool.

21		Finally, just a couple of days ago, I was asked to
22	address some new data, recent data, from San Francisco on
23	the increasing incidence of HIV in gay men.  So I will
24	present a colleague's talk addressing that topic at the end.
25		[Slide.]

			166 1		Basically, this is just the historical risk.  The
	2	committee--I apologize; I did E-mail the slide presentations
	3	recently, but you received some handouts, some chapters and
	4	stuff.  There is a slide like this in there.  Basically,
	5	this is just to emphasize really the very dramatic reduction
	6	in risk that was achieved from the mid-80's through the mid-
	7	90's through the discovery of several of these viruses and
	8	the introduction of progressively enhanced antibody tests.
	9		[Slide.]
10		Basically, as Andy indicated, what we have tried
11	to do in the last five years or so was to understand risk in
12	the context of the element sources of risk.  We have
13	dissected the risk into the four what we think are relevant
14	activities or issues.  One is the window-phase donations. 
15	The second is viral variance.  These are divergent viral
16	strains that the test could miss and, as we talked about
17	earlier, it is critical that we understand the prevalence of
18	these variants and fix the test to detect them.
19		A fourth source is what have been termed atypical
20	or immunosilent infections where people do not form antibody
21	or the markers we are screening for even though they are
22	persistently infected.  This is more of a red herring
23	because, although they do exist, they are extraordinarily

24	rare and a lot of the concern around immunosilent carriers
25	arose from early studies that really were reporting false-

			167 1	positive PCR results.  So these are extremely rare for all
	2	of the major viruses.
	3		Then, finally, testing error which is, as Andy

	4	indicated, is an important contribution to the potential
	5	impact of relaxing the deferral criteria because if test
	6	error occurs on an increasing frequency of prevalent

	7	infections, it can allow these prevalent infections to sneak
	8	through.
	9		So, with the REDS group, and particularly Steve

10	Kleinman and myself, what we have been trying to do is to
11	quantify each of these sources of risk.  What this table
12	does is to actually put hard numbers on the risk per

13	10 million donations.  So this is essentially the frequency
14	that infected units would potentially enter the blood supply
15	per year, because we screen about 12 million.
16		You can see, this is actually post-p24-antigen but
17	pre-NAT.  We will talk about, in a minute, the impact of
18	NAT.  So you can see that, for HIV and HTLV, the two
19	retroviruses, we are dealing with risks in the range of 1 in
20	750,000.  For the two hepatitis viruses, pre-NAT, we were
21	dealing with risks in the range of 1 in 100,000.
22		You can also see that most of that risk, we
23	believe, is due to window-phase infections.
24		[Slide.]
25		I wanted to just spend a moment on the test-error

			168 1	issue because that is, I think, going to be a major driver
	2	in the decision here.  There are two recent studies that
	3	have estimated error rate in routine blood-bank screening. 
	4	One of them is a study that we did in the REDS group that
	5	was published six months or so ago.
	6		In this study, what we did was to track serial

	7	donations from routinely screened blood donors.  What we
	8	looked for was donations that were initially scored as
	9	confirmed positive where the donor gave another unit.  That
10	may seem to be an odd thing.  Why would a donor be allowed
11	to give again after they had given a prior confirmed
12	positive donation.
13		But that is allowed for autologous donors.  So

14	people who are giving for themselves can give sequential
15	donations even though they were positive because the blood
16	is exclusively used for that person.  So, through this

17	analysis, we were able to quantify the rate of error by
18	looking at the frequency of negative subsequent donations
19	where we had over 2,000 donations that had previously been
20	confirmed as seropositive.
21		On first cut, we had eleven donations that tested
22	non-reactive on the follow up.  It turns out ten of those
23	were actually early test configurations like first-

24	generation HCV tests or HTLV-1 tests that were missing--they
25	were actually subtype problems where they were missing HTLV-

			169 1	2 or relatively less common subtypes of HCV, where the
	2	initial sample was borderline reactive and the follow-up

	3	bleed that tested nonreactive was actually just below the
	4	cutoff.
	5		So these were not actually what we would construe
	6	as test errors.  These were actually problems with subtype

	7	detection that have since been fixed.  But we did detect one
	8	frank test error which, when put over the denominator,
	9	yielded an error rate of 5 per 10,000.  We then applied, in
10	the paper, that error rate times prevalence to calculate, as
11	on the previous slide, the frequency of risk due to errors.
12		It turns out they are a very small contributor to
13	risk.  But this is one of the estimates that we have on
14	error rate.
15		The second actually comes from the NAT screening. 
16	This is data from Sue Stramer's NAT program where over the
17	first approximately six months of NAT screening, in the Red
18	Cross system, they detected three donations that were
19	antibody-negative for HCV but scored NAT-confirmed positive.
20		As they routinely do, when they reflex tested
21	these samples again to confirm the antibody-negative status,
22	in three cases, the antibody was actually positive.  It was
23	a testing error where the initial screening serology was
24	incorrect.  That yielded--over that period of time, they had
25	about 2,300 HCV seropositive donors.  So that illustrates an

			170 1	independent measure of error rate in routine serology of
	2	about 0.1 percent, so, similar to this other estimate.
	3		In fact, two points.  The Red Cross has not seen
	4	any more test errors in the subsequent almost year of
	5	screening.  So if we updated this, we would estimate that
	6	the error rate is probably more comparable to this
	7	0.05 percent because the denominator would go up about
	8	three- or four-fold.
	9		Another point is this is the redundancy that Andy
10	spoke to.  This is NAT picking up a sample that was a test
11	error serologically.  So this is really a good illustration
12	of the important advance that having these two highly
13	sensitive redundant technologies offers in terms of test
14	error.
15		[Slide.]
16		As we talk about the major risk, though, it is
17	window phase.  An important distinction here; a lot of those
18	risk estimates that we report for window period assume that
19	individuals are infectious from the point of exposure and
20	infectious exposure to when the antibody becomes positive.
21	But what we have come to understand, through various
22	studies, is that there are actually two phases of the window
23	period, the pre-seroconversion window period.
24		There is what we call the eclipse phase, which is
25	the period after an infectious exposure but before one can

			171 1	detect any evidence of the virus in the body by any nucleic-
	2	acid tests or any methodology.  Then there is the phase

	3	where we can detect viremia and where clearly people are
	4	infectious.
	5		So our risk estimates, because we want to be
	6	conservative, assume that this entire phase could be
	7	infectious when we calculate out the pre-seroconversion
	8	window period.  But, as I will show you, actually we have
	9	pretty good evidence that this early phase is probably not
10	infectious, so our risk estimates are, perhaps,
11	overestimates.
12		Then, obviously, with NAT, we are essentially
13	eliminating this pre-seroconversion viremic phase.
14		[Slide.]
15		Just a little bit of data on the overall window
16	period from exposure to seroconversion.  That is derived

17	from modest studies typically of parenteral exposures where
18	you have an individual who has a discrete exposure who is
19	then sampled at some modest frequency until they
20	seroconvert.
21		For HIV, the best data comes from a CDC
22	compilation of HIV-infected healthcare workers who acquired
23	the infection from a needle-stick accident, so you have a
24	discrete date of exposure.  Then these people were sampled
25	at irregular intervals and, through an analysis by Glen

			172 1	Satten, he estimated that the time from exposure to
	2	seroconversion with sort of early-generation assays was
	3	about 46 days.
	4		We know that contemporary, particularly blood-
	5	screening assays, have closed this antibody window by about
	6	two weeks so we typically talk about a 25-or-so-day period
	7	from exposure to antibody seroconversion on the new third-
	8	generation assays that we screen the blood supply with.  And
	9	you see the confidence bound.
10		For HCV, from post-transfusion hepatitis cases,
11	the data supports, from several groups, approximately a 70-
12	day incubation period from exposure to antibody.  For HBV,
13	on very limited data, it is 59 days.  For HTLV, again,
14	fairly limited data, about 50 days.
15		So this is where we get our number that we use for
16	the exposure to seroconversion window period.
17		[Slide.]
18		For each virus, I am going to just show you a
19	summary slide of what is an enormous amount of work to
20	characterize the durations of the viremic and other
21	characteristics of the window phase.  We talked about HIV
22	earlier today.  For HIV, as I indicated, it is about twenty-
23	five days before the high sensitivity antibody tests detect
24	infection.
25		Viremia is detected by high sensitivity NAT about

			173 1	ten days prior to antibody with this doubling-time parameter
	2	reflecting the rapid ramp-up of viremia.  And then p24
	3	antigen comes in about halfway through.  From this data, we
	4	can calculate the overall potentially infectious window
	5	period as well as the portions of that window period that
	6	can be closed through adding antigen or RNA testing, as
	7	discussed earlier.
	8		[Slide.]
	9		With HCV, it is quite a different dynamics in that
10	the virus ramps up very rapidly--the next slide will show
11	it--but the very rapid doubling time of well less than a day
12	and then reaches a very high-titer plateau phase that is

13	readily detectable either with single-donation or minipool
14	nucleic-acid testing.
15		This lasts, as a plateau phase, for, on average,
16	almost two months, about sixty days.  And then antibody
17	become detectable.

18		[Slide.]
19		Through analysis of large numbers of these panels,
20	we have derived similar summary curves that again show that
21	typically, within about ten days of exposure, you develop

22	rapid ramp-up viremia doubling time about 17 hours and then
23	there is a plateau phase that lasts about 57 days prior to
24	antibody seroconversion.
25		[Slide.]

			174 1		HBV; I am not going to go into it.  We have talked
	2	about it at the last meeting.  But the summary statistics
	3	are here so the number of cases that have been studied,
	4	plasma-donor panels for HCV, we have this unique phenomenon
	5	of this high-titer plateau phase.
	6		We have these different doubling times ranging
	7	from 17 hours to 20 hours to about three days, so a slower

	8	ramp-up for HBV.  Another interesting observation recently
	9	is prior to the what we call definitive ramp-up phase, in a
10	proportion of these plasma panels, we do detect very low-
11	level transient viremia a week or two prior to the ramp-up.
12		This is a subtle point when we talk about the

13	impact of single-donation NAT but studies are ongoing to
14	understand what this is and is this pre-ramp-up transient
15	low-level viremia infectious.
16		[Slide.]
17		So, as we talk about the decision on NAT, we can

18	use those numbers to estimate the window-period closure that
19	could be achieved by moving into minipool versus individual-
20	donation NAT.  You can see that, for HCV, because it has
21	that rapid ramp-up and plateau phase, we are going to
22	dramatically--or we have dramatically--reduced the
23	potentially infectious window period by almost two months
24	through introduction of minipool NAT.
25		We would only add a modest, about three-day,

			175 1	further window-period closure by moving to single-donation
	2	NAT assuming that that intermittent low-level viremia is not
	3	important.
	4		For HIV, minipool NAT relative to antibody closes
	5	about nine days.  You would close another four days.  For
	6	HBV, if you have a NAT assay and minipool which has about
	7	1,000-copy sensitivity, you would close by about six days. 
	8	If we theoretically moved to single-donation NAT with
	9	50 copy sensitivity, we would close about 17 days.
10		[Slide.]
11		We have introduced HIV and HCV NAT, as you heard
12	from Sue Stramer.  This is a first-year experience of whole-
13	blood screening, over 10 million donations screened for HCV
14	and almost 7.6 million screened for HIV.  The yield was 42
15	HCV viremic seronegatives and 4 HIV.  That yield observed

16	yields of 40 per 10 million and 5 per 10 million for the
17	minipool screening.
18		I would just juxtapose this, and this is a slide
19	from Steve Kleinman's analysis, with what we predicted the
20	yield would be based on the those model projections.  You
21	can see that the predictions were that we would pick up

22	something in the range of 50 to 80 for HCV--we picked up 40-
23	-and something in the range of 7 to 8 for HIV--we picked up
24	5.
25		So the yields are a little bit lower but, really,

			176 1	very consistent and, in fact, our projections were
	2	conservative.  We slightly overestimated the observed yield. 
	3	So I think this is very important to give us confidence that
	4	the model bases of estimated risk are accurate, that we are

	5	proving out essentially what we predicted based on these
	6	models.
	7		In addition, for HCV, these cases can be broken up
	8	into whether they were window-period yield, test-error yield
	9	or immunosilent infections.  What you see down here is that
10	essentially, as predicted, 84 percent of these cases that
11	were evaluated turned out to be window period
12	seroconverters.  12 percent, I mentioned earlier, those
13	three cases that were test error, and one case proved out to
14	be a long-term nonseroconverter.
15		So, again, not only the overall yield but the
16	distribution of types of risk were quite consistent with the
17	model projections.
18		[Slide.]
19		In terms of the risk now, and these are Steve
20	Kleinman's slides, for HCV and HIV, we projected the impact
21	of NAT on reduction of risk.  As I have summarized, we think
22	the current window estimate was about 70 days.  We believe
23	that NAT has closed it something in the range of 42 to
24	58 days, probably more in the range of 58 days, and so a 60
25	to 80 percent reduction in the window period

			177 1		When we run that through the incidence rates, the
	2	new risk estimate would be in the range of 1 in 250,000 to 1
	3	in 500,000 for HCV.  That assumes that the entire pre-
	4	minipool NAT-positive phase, the so-called eclipse phase, is
	5	infectious.  So this is almost certainly a worst-case
	6	scenario that is an overestimate of risk.
	7		[Slide.]
	8		The same for HIV.  We can look at the overall
	9	window and we have closed it by adding minipool NAT.  So, if
10	we calculate out the new risk for HIV based on a residual,
11	about a ten-day theoretical window phase which is mostly,

12	probably, noninfectious eclipse, we estimate the risk at
13	around 1 in 750,000.

14		[Slide.]
15		So we are really dealing with extremely low risks
16	now for HIV and HCV as a result of NAT screening.  There is
17	a lot of discussion about, in the very near future, and some
18	of the plasma industry has already implemented HBV NAT,

19	again probably not indicated in the whole-blood sector as
20	discussed by your committee but, certainly, in the plasma

21	industry, again, there is a move to add B19 and hepatitis A.
22		There are studies looking at the potential role of
23	NAT screening for these other agents that we are currently
24	aware of and are concerned about.
25		[Slide.]

			178 1		But, perhaps, more important is the availability
	2	of a direct-virus screening platform like NAT as we uncover
	3	new agents.  This is important because most of the new
	4	viruses that are being discovered are being discovered by
	5	genome-based methods.  I will talk about that in a moment. 
	6	So, therefore, it is often a year or two between the time
	7	where we have nucleic-acid assays for these newly discovered
	8	viruses before we have a serologic test that can detect
	9	antibody or theoretically antigen.
10		So if we need to move quickly, the assay that

11	would be available will probably be a nucleic-acid-based
12	system well before there is a serologic test.  More
13	importantly, the nucleic-acid testing strategy is much more
14	rational.  It directly detects infectivity rather than a

15	serological response.  For many of the new agents, like
16	hepatitis G and TTV, when people seroconvert, they have
17	usually cleared the viremia.

18		So, to detect the infected donor, a direct virus
19	NAT system is much more appropriate.  So we can avoid the
20	problems with antibody testing by going straight to a
21	nucleic-acid test system.
22		[Slide.]
23		This slide is actually from Jean Pierre Allain

24	which was a nice sort of capsulization of how, over the last
25	several decades, the discovery of viruses has really tracked

			179 1	the evolution of new technology.  So HBV was discovered
	2	through electron microscopy, HTLV through culture and early
	3	PCR, HIV mostly through PCR, and then HCV through
	4	immunoscreening strategies.
	5		Then, over the last few years, new methods, like
	6	representational-difference analysis, PCR screening
	7	strategies, have led to the discovery, every year, of a new
	8	putative blood-borne agent.  So we have to anticipate that
	9	this is going to continue.
10		We have to have rational strategies for detecting
11	and assessing the importance of these new agents.
12		[Slide.]
13		What I will be using in the moment is HHV-8 as an
14	example of how these studies need to address these key
15	issues.  We need to determine the prevalence of the agent. 
16	Since we are not screening, it is really the prevalence
17	which will tell us how many units are actually being
18	transfused from infected people.
19		If we start screening, and also just in general,
20	we also want to understand the incidence because that is the
21	critical factor that tells us the rate of new infections and
22	addresses the issue of window-period risk.
23		Optimally, we would like to understand these

24	parameters both today, but also in the donor pool and in
25	general historically because that gives us a sense of

			180 1	whether this is a new and spreading infection which could

	2	be, like HIV, creating a huge problem in the blood supply
	3	and transmitting to recipients.
	4		If it is a virus that has been prevalent forever
	5	and we, obviously, don't have a lot of transfusion
	6	recipients dying of unknown diseases, then it is probably
	7	not as significant a factor.  So both studying historical

	8	repositories as well as current donors is a critical issue.
	9		Obviously, the question of transmission is
10	critical both by looking at linked donor recipient samples,
11	high-risk patients like hemophiliacs who have been exposed,
12	and also animal-transmission studies.  If transmission is
13	observed, then the question of disease is important and, as
14	we will see, a number of the recent "hepatitis agents" have
15	turned out to not be disease-causing at all.  They are
16	transmitted by blood but they have proven to be not
17	associated with any disease.  So, obviously, we don't need
18	to screen for a background nonpathogenic agent.
19		Finally, if we do want to screen, the approach to
20	screening needs to be understood.
21		[Slide.]

22		This is just a summary slide that looks at several
23	of these new recently addressed agents, hepatitis G, HHV-8,
24	TTV, SEN-V through in variant CJD in terms of the question
25	of whether these established persistent infections in

			181 1	asymptomatic donors.  The answer is yes.
	2		There is data on the prevalence rates of these

	3	agents in the donor pool.  Some of them are really quite
	4	prevalent and we will focus on HHV-8 in a moment.  But some
	5	of them are 10, 20 percent of our donors are actually PCR-
	6	positive for several of these viruses.

	7		Many of these are transmitted by transfusion, the 
	8	so-called hepatitis viruses, but, in contrast, as we will
	9	talk about in a moment, HHV-8, the evidence at this point
10	does not support transmission by blood transfusion.  There
11	is highly debated transmission of the CJD agent.
12		In terms of pathogenicity, again, several of these
13	hepatitis viruses turn out not to be pathogenic.  Clearly,
14	HHV-8 does cause disease and then what screening strategy
15	would be appropriate, I think for all of these agents,
16	actually, a direct virus or pathogen assay makes a lot more
17	sense than some indirect marker of exposure.
18		[Slide.]
19		Moving directly to HHV-8, this is the virus that
20	causes Kaposi's sarcoma.  That has unequivocally been
21	established.  It also causes several other disease, lymphoma
22	and several other phenomenon.  It is typically prevalent

23	either in gay men or in certain endemic populations around
24	the world such as SubSaharan Africa and in southern Italy.
25		This summarizes prevalence estimates for HHV-8

			182 1	based on antibody assays, either immunofluorescence of

	2	ELISA-type assays.  You can see that, in patients with
	3	Kaposi's sarcoma, 80 to 95 percent test positive for HHV-8
	4	antibodies.  In HIV-positive homosexual men who do not have
	5	KS, it ranges from 30 to 65 percent depending on the
	6	population in the assay; HIV-negative homosexual men, 15 to
	7	30 percent.

	8		In injection drug users, the rates are really much
	9	lower, background rates.  In general, there is not a lot of
10	evidence, and we will review some recent CDC data for
11	injection drug-use transmission of HHV-8.
12		In women and donor donors, the rates are quite
13	low, again, depending mostly on the assay.  We will look at
14	some hard, new data on this issue.  In southern Europe, the
15	rates are quite a bit higher, again, in, I think, Spain and
16	Italy.  Quite a bit more of this virus is present in these
17	populations.  Also, some studies from the Middle East and

18	from Africa that show very high rates.
19		[Slide.]
20		This show prevalence in gay men in San Francisco
21	by year.  You can see here that, in gay men, the rates
22	increase over time from younger individuals fairly
23	dramatically reaching rates of 30 to 40 percent whereas in
24	other populations, there is no evidence of increased
25	prevalence over time in women or injection drug-using men.

			183 1		[Slide.]
	2		Also, we know that this virus has been around for
	3	a long time in gay men.  This is a study from Jeff Martin
	4	collaborating with several of the cohort studies in San
	5	Francisco that look back at samples collected from gay men

	6	in the late '70's, in the mid-'80's and in the mid-'90's. 
	7	You can see that the prevalence rates of HHV-8 are
	8	essentially identical over time, both in the HIV-positive
	9	and HIV-negative.
10		So this is not a new emerging agent.  This has
11	been around in the risk population at a fairly stable rate
12	over time.
13		[Slide.]
14		In terms of the virus in the body, this slide

15	summarizes data on the prevalence rate in different body
16	compartments.  This is direct virus detection now with PCR-
17	type assays.  What you can see is the virus is present
18	peripheral blood lymphocytes.  It is a herpes virus so it is
19	predominantly a cell-associated virus in leukocyte
20	compartments.
21		In KS patients, at least half of KS patients have
22	circulating virus in their leukocytes.  In non-KS patients
23	who are seropositive, in the range of 15 to 25 percent have
24	positive PCR on their mononuclear cells.  That does not
25	necessarily mean that this is an infectious compartment of

			184 1	the blood.  It could be a noninfectious circulating viral
	2	byproduct.
	3		Also, this is a fresh PCR analysis which doesn't

	4	necessarily reflect infectivity.  We will talk about that.
	5		Interestingly, several studies, including studies
	6	from our lab and in collaboration with Jeff Martin in the

	7	San Francisco gay cohorts, have documented very high rates
	8	of HHV-8 virus in saliva, much higher than are present in
	9	semen.  So there is probably a significant mode of

10	transmission of this virus through salivary virus shedding.
11		[Slide.]
12		This is data comparing, again in our San Francisco
13	studies, the prevalence of HHV-8 in peripheral blood

14	leukocytes in different populations, in blood donors
15	including a small number of HHV-8 seroreactive donors.  We
16	have never detected HHV-8 by RPCR studies in healthy blood
17	donors.
18		In HHV-8 seronegative gay men, again, no evidence
19	of peripheral-blood PCR positivity.  In HHV-8 seropositive
20	gay men without KS, peripheral-blood lymphocytes are
21	positive about 24 percent of the time and, in KS patients,
22	in our studies, 43 percent.  So there is evidence in
23	seropositive and, particularly, symptomatic patients of
24	virus in the blood, in the lymphocytes.
25		[Slide.]

			185 1		But is it transmitted by blood transfusion?  There
	2	are several studies that address this.  The problematic
	3	study was published from Jay Levy's group in Lancet three
	4	years ago.  What happened here was they were actually
	5	getting blood from our blood bank from healthy donors to use
	6	as controls and as seeded cultures for trying to grow HHV-8.
	7		So they had 72 donors who were being studied over
	8	a period of several years just getting buffy coats.  Low and
	9	behold, what happened was they were stimulating these cells
10	and then adding cells from infected patients to try to

11	transmit the virus from HHV-8-infected patients but they
12	would also grow the normal donor cells in the absence of

13	seeding in infected patient samples as controls, as sort of
14	background lab controls.
15		Lo and behold, they detected one donor who, on
16	coculture, or on stimulation and then coculture with
17	additional normal cells, they indicated had evidence of
18	infectious HHV-8.
19		Now it turns out, and this was reported in Lancet,
20	it turns out we have brought this donor back on a series of
21	occasions and the donor was actually seronegative and HHV-8-
22	negative on follow up.  So my personal bias is that this was
23	actually a contamination.
24		But the bottom line is this paper alluded to the
25	potential risk of transmitting HHV-8 from a healthy blood

			186 1	donor because they could demonstrate in vitro transmission
	2	from a donor through another donor's lymphocytes.  So this
	3	is the paper that has raised the greatest concern about
	4	blood safety.
	5		On the other side of the coin, if you look at the
	6	epidemiologic data, there is no evidence for transfusion
	7	transmission of HHV-8.  KS is virtually unheard of in HIV-
	8	positive transfusion recipients or hemophiliacs.  The
	9	seroprevalence of HHV-8 in a variety of studies is virtually
10	identical or essential background levels in hemophiliacs and
11	transfusion recipients versus blood donors from the same
12	regions tested using the same assays.
13		In studies from the TSS, none of 14 recipients who
14	got transfused with blood that was HIV- and HHV-8-positive,
15	none of those recipients developed HHV-8 infection even
16	though 13 of the 14 acquired HIV.  There are several other
17	studies that have looked at transfusion recipients.  There
18	is a total of about 30 transfusion recipients who have

19	gotten known HHV-8-positive blood who have not become
20	infected.  So this data supports, albeit in small numbers,
21	lack of transmission.
22		[Slide.]
23		There is, however, evidence for transmission by
24	allograft transplant.  So renal transplantation studies, a
25	paper in the New England Journal a few years ago, showed

			187 1	that a series of transplant patients had significantly
	2	higher HHV-8 seroreactivity following transfusion than
	3	before transfusion, and the seroconverters predominantly
	4	received blood from donors--organ donor; the kidney, itself,
	5	was HHV-8 positive.
	6		So it is, I think, clear that kidney transplants
	7	do transmit this virus.  Of course, kidneys have a lot more
	8	than blood, and this virus is predominantly--may have a
	9	significant compartment in vascular tissue as well as
10	lymphocytes.
11		So all of this has led to a study which Phil and I
12	are leading to look at the prevalence of this virus in

13	healthy blood donors, and then some other studies are
14	planned to look at the potential transmission question.

15		This study has just completed a first large phase
16	of testing which involved a panel of 1,040 specimens going
17	to six different laboratories with extensive published
18	expertise in HHV-8.  The panel included 40 positive control
19	patient samples, known KS-positive patients, and all of the
20	labs picked all those up.  Essentially, there was one QNS
21	sample that was missed.  So all the labs demonstrated
22	excellent sensitivity.
23		But when we then looked at 1,000 normal donors,
24	what we saw was dramatically different rates on identical
25	samples ranging from labs that reported only a handful of

			188 1	positive EIA-reactive results, 0.5 percent rates, to labs
	2	reporting 7 percent of these healthy donors being
	3	seroreactive.
	4		It turns out only one of the samples was positive
	5	in all of the laboratories.  We asked, then, how many
	6	samples were positive in two labs, three labs, four labs. 
	7	We sort of made a cut that if at least two labs called a
	8	particular donor sample positive, we would at least consider
	9	potentially positive and do PCR, et cetera.
10		So, overall, there were 3.6 percent of the donors
11	that were reactive in at least two labs.  All of these
12	samples were PCR-negative.  So, in truth, these are probably
13	false-positive serologies.  There are studies underway to
14	further characterize that.
15		[Slide.]
16		The last data on HHV-8 is actually Phil Pellett's
17	data, who is here, in a cohort.  This is important because
18	it is sort of the newest data that raises another small
19	concern regarding potential transfusion or parenteral
20	transmission.  This is a cohort called the HERS cohort which
21	is a cohort of women, 871 HIV-positive and 439 HIV-negative
22	women.
23		They have been followed for over six years or up
24	to six years with six-month sampling.  They have extensive
25	sexual behavior and drug-use history.  They have also had a

			189 1	variety of laboratory studies conducted.
	2		[Slide.]
	3		The important new data with respect to parenteral
	4	transmission is in this population of women who are
	5	obviously not at risk for male-male sex transmission where
	6	there is a major driver for transmission of HHV-8.  In these
	7	women, there is a highly significant correlation between

	8	drug use, parenteral exposure, and HHV-8 seropositivity,
	9	with 35 percent of women who share drugs regularly being
10	HHV-8 seropositive as opposed to 12 percent of those who
11	deny drug use so about a four-fold increased relative risk
12	associated with high-level drug use, no significant

13	association with a variety of other parameters such as crack
14	cocaine use and other characteristics.
15		[Slide.]
16		In addition, when they looked at these samples
17	from these women and correlated the HHV-8 status with other
18	markers of either blood-borne or sexually transmitted

19	infections, it turns out that there were significantly
20	higher rates of HHV-8 reactivity in persons who were
21	anticore-positive, HCV-positive, in particular.
22		And these are blood-borne viruses.  So this

23	laboratory association supports that there may be, in this
24	population at low risk for male-male sex transmission, there
25	seems to be a hint of a parenteral association, that you can

			190 1	potentially transmit this virus through use of drugs and it
	2	is correlating predominantly with blood-borne viral
	3	infections, not with HSV-2, which is an STD, so suggesting

	4	that, in this population, a blood-borne transmission may be
	5	important.
	6		Most important, if the analysis was restricted to
	7	women who denied any commercial sex, any prostitution, and
	8	who were negative for these other STD markers and said they
	9	had very few lifetime sex partners, so sort of the lowest-
10	risk group with respect to any sexual transmission, the

11	association with drug use held up.  So they continued to see
12	a significant increasing prevalence of HHV-8 with increased
13	use of drugs.
14		So this is a disturbing finding supporting an
15	association of HHV-8 with parenteral risk exposures.
16		[Slide.]
17		So the summary of Phil's work is that both
18	laboratory and self-reported risk data support an
19	association of HHV-8 with I.V. drug use in populations that
20	have low risk of sexual transmission.  This does not appear
21	to be an artifact of confounding and is also observed in
22	this lowest sexual risk population.
23		So this is somewhat disturbing and has led to

24	additional interest in expanding the studies about HHV-8
25	association with blood transfusion.  Perhaps, that will be

			191 1	discussed later.
	2		[Slide.]
	3		So we remain concerned, albeit that the data does
	4	not, at this point, demonstrate there has never been a
	5	documented case of HHV-8 transmission by blood transfusion. 
	6	So that is the story with respect to risk in terms of the

	7	blood supply and HHV-8.  Again, I was asked a few days ago
	8	to add one last bit of data so I have just a handful of
	9	slides from my colleagues, Sandy Schwartz and Willie
10	McFarland in San Francisco.  They are at the Public Health
11	Department.
12		Over the last six months or so, there has been
13	increasing concern about what might be called relapse in
14	high-risk behavior in the gay community.  This has led to
15	some very public meetings and press interest in the
16	potential relapse of infection.
17		[Slide.]
18		I just wanted to share that this is--this is

19	actually a curve that should peak up here and come down
20	here.  This is the estimated number of new HIV infections

21	per year in San Francisco.  It shows that in the late '70's,
22	early '80's, the percent of at-risk people infected per year
23	went up dramatically.  Over 8,000 people per year were
24	becoming infected in the early '80's.
25		This dropped dramatically.  This curve shows that,

			192 1	in the mid-'90's, the frequency of new transmissions further
	2	declined from 1,000 to 500.  But the figure actually sort of
	3	dovetails out at the end here because we are not sure, and
	4	there is some suggestive evidence, that there is an
	5	increasing transmission going on.
	6		I will summarize data from AIDS surveillance
	7	cases, risk studies and, most important, incidence data that
	8	supports a concern that there has been some increasing--so
	9	you can see that you have got these potential modeled
10	estimates of incidence.
11		[Slide.]
12		So this is their surveillance data.  Overall, AIDS
13	cases have dropped in the last few years as a reflection of
14	HAART and the rate of death due to AIDS has also dropped. 
15	This is attributable in great part to the introduction of

16	highly active antiretroviral therapies.
17		But one of the down sides of highly active
18	retroviral therapies, if you will, is it has resulted in a
19	plateau, an increase in a plateau of infected people in the
20	population.  There is a concern that some of these people,
21	because they are on HAART and healthy and often virus-
22	negative by viral-load test, that they may be engaging in
23	increased high-risk behavior and there may be increased

24	transmission of the virus.
25		[Slide.]

			193 1		This has been documented in a series of studies

	2	looking at STD frequency in various clinics.  You can see
	3	that, in the last few years, there has been a significant
	4	increase in the rate of STD diagnoses in clinic settings.
	5		[Slide.]
	6		Rectal gonorrhea rates have gone up again in the
	7	last three or four years fairly consistently, so we are
	8	seeing increasing rates of both general STD and gonorrhea,
	9	particularly.
10		In some street-outreach analyses, again, of gay
11	men, the rate of condom use has begun to drop and the rate

12	of frequent multiple anal-risk exposures has begun to creep
13	up through survey studies.
14		[Slide.]
15		Then data coming from several populations; the
16	Young Men's Study has formally documented risk behavior and,
17	again, rates of increased high-risk behavior have gone up in
18	these studies, both unprotected anal sex and multiple

19	partner unprotected anal sex, a small trend upwards.
20		[Slide.]
21		And then, from several studies, I will show
22	incidence rates that, again, have documented dramatic
23	declines in incidence, either measured formally through
24	prospective studies or using what is called the detuned

25	assay, or the less sensitive HIV incidence projection model.

			194 1		[Slide.]
	2		A series of studies from San Francisco have shown
	3	this same phenomenon--I will just bounce through them--that, 
	4	over the last three or four years, the curve has begun to
	5	come up.  So there is evidence that there is increased
	6	incidence occurring in these cohorts.
	7		[Slide.]
	8		This is overkill.  Why don't we stop here.  This
	9	is just a summary.  Basically, there are a variety of

10	sources of data that are of concern but I think, as Andy
11	will play out, these are very, very sort of small, barely
12	statistically detectable trends toward increased incidence
13	and that, in the blood supply, there is such a small
14	fraction.
15		Of course, we are talking incidence.  So we are
16	talking about people coming in, potentially, during the

17	window period which we have got all these tests now and we
18	are not talking about eliminating deferral for recent
19	behavior.  The consideration is a much more lengthy, five-
20	year or one-year deferral period.
21		Thank you.
22		DR. HOLLINGER:  Thank you, Mike.  Any questions of
23	Mike before Andy continues?
24		DR. CHAMBERLAND:  Mike, I may have missed this

25	because it went by pretty fast, but when you were talking

			195 1	about your findings of these pre-ramp-up viremic blips, were
	2	those consistently detected by minipool or single-donation
	3	NAT testing methodologies?
	4		DR. BUSCH:  Yes; again, these are fairly recently
	5	uncovered as we have tested back on these very early bleeds
	6	that are now being identified.  As a result of NAT
	7	screening, we have these early bleeds available.  We have
	8	done a series of studies where, after initially seeing these
	9	samples, we recoded samples and sent them to two or three--
10	or processed them through two or three different NAT systems
11	including the TMA assay, PCR assays, Andy Conrad's high-
12	input.
13		They have been confirmed, so they are observed

14	consistency and they are very low titer.  So, although we
15	have not done a lot of formal pooled study on them, they

16	tend to have copy numbers in the less-than-100 to 200 genome
17	equivalents per ml.
18		They were initially missed, actually, by the
19	routine pool screening as done in the plasma industry.  So
20	our expectation is that these low-level viremic-phase
21	observations are only detectable by single-donation nucleic-
22	acid testing.
23		However, even if you factor them in and assume
24	that they are infectious, they are really a very, very small
25	source of risk because they are very transient and they only

			196 1	are observed over the several weeks prior to ramp-up
	2	viremia.
	3		DR. PELLETT:  Phil Pellett, Chief of the Herpes
	4	Virus Section at Centers for Disease Control.  First, I want
	5	to thank Mike for a nice summary of the data.  It was just a
	6	very nice overview.  I think if I ever get invited to give a
	7	seminar on the study that he described, I can just defer it
	8	to Mike because he actually covered our data quite nicely.
	9		I need to credit someone named Michael Cannon,
10	part of our group, who actually did the analyses on the HERS
11	study.  I have a couple of minor points and then I have a
12	couple of points that I would like to raise relating to the
13	deferral issue.
14		One minor point is the name of the virus.  In some
15	rooms I am in, the language is human herpes virus 8.  In
16	other rooms I am in, the language is predominantly Kaposi's-
17	sarcoma-associated-herpes virus, or KSHV.  I have become
18	bilingual on it, but my native tongue is HHV-8.
19		Mike talked about the presence of the virus in
20	bodily fluids.  I think it is important to make clear that
21	the bodily fluids that the virus has been found in have come
22	predominantly from individuals who are HIV-positive, not
23	just people who have healthy immune systems and are
24	seropositive.  You very rarely find the virus.
25		So I had four questions I wanted to raise relating

			197 1	to the MSM deferral that I think maybe relate to some of
	2	this.  One question is, is the virus in the MSM population. 
	3	Mike showed clearly yes, 15 to 30 percent of the population
	4	does have the virus.
	5		Then, importantly, is the virus concentrated in
	6	this population.  The answer there is clearly yes, relative
	7	to the U.S. blood donors, 2 to 4 percent positive.  The 15
	8	to 30 percent really is a different number.
	9		Other than MSM in the United States, the
10	injection-drug users who are high-frequency intravenous drug
11	users are the other easily identified group.  I think it
12	might be a smaller group.  There are other places around the
13	world that have relatively elevated levels of the virus;

14	Mediterranean Europe, some portions, as well as some parts
15	in Africa.  So there is a very significant concentration of
16	the virus in MSM in the United States.
17		I think a big question is is the epidemiology of
18	virus distinct from that of HIV; that is, would HIV
19	screening eliminate the virus from the pool.  The reality
20	is, yes.  As Mike showed, the prevalence of the virus was

21	high before the HIV epidemic and in a substantial proportion
22	of men who have sex with men, the virus is actually present.
23		So elimination of people based on HIV status would
24	not actually eliminate the virus.  Then we get to the

25	important question of is there a risk for transfusion

			198 1	transmission.  I think, obviously, the answer is we are
	2	uncertain on that right now.  The CD19-positive cell
	3	presence, the study of Blackbourne who actually, and I think
	4	I will disagree with Mike a little here--I think in 7 out of
	5	11 occurrences over a year and a half period, that person
	6	was culture-positive for the virus, which it makes it hard
	7	to ascribe to contamination.
	8		There is our injection drug-use data.  Mike talked
	9	about zero for 30 of individuals who have gotten blood from
10	HHV-8-positive donors have become positive, so it is clearly
11	a relatively low risk for transmission, and the fact that in
12	the U.S. blood donors, of those who were seropositive, none
13	of them were PCR-positive argues, again, on the side of low
14	probability of transmission.  But, at this point, overall,
15	it remains uncertain.
16		So thank you.
17		DR. HOLLINGER:  Thank you.
18		Questions of Mike for right now?  Dr. Simon?
19		DR. SIMON:  What about the associated issue if you
20	do transfuse it, does that mean you transmit disease.  If
21	you transmit the virus, does it also mean that the virus
22	will cause disease in the recipient?
23		DR. BUSCH:  One issue is, in terms of transfusion,
24	even if you were PCR-positive, what we know is, as with CMV
25	and HTLV, these cell-associated viruses, the cells probably

			199 1	have to be viable to actually proliferate and transmit.  So,
	2	with blood that is stored, the transmission rates for CMV
	3	and HTLV plummet over the first week of storage.
	4		So, even though the virus is in the blood, it may
	5	not transmit by a stored blood component.  But, if it does,
	6	the issue is really you need to have HHV-8 probably plus
	7	some immunosuppression to manifest disease.
	8		So that is why KS and these lymphomas are
	9	virtually seen, at least in the United States, in HIV-
10	infected, highly immunosuppressed or moderately
11	immunosuppressed patients.  So the disease, it seems to me,
12	in addition to the virus, needs to be associated with some
13	type of immunosuppression.
14		DR. SIMON:  So it is a story much like the CMV
15	story.
16		DR. BUSCH:  Right.
17		DR. NELSON:  Lisa Jacobson, from the MAC study,
18	has done some very interesting studies looking at the timing
19	of the infection with KS related to the immunosuppression. 
20	The data that she has suggests that if the HHV-8 preceded
21	immunosuppression, there is often no clinical--the error
22	rate of clinical, but of patients who are severely
23	immunosuppressed and then receive HHV-8 and become infected,
24	the likelihood of progression to KS or some clinical
25	manifestation is much greater.

			200 1		That may be relevant to a transfused population
	2	who might be suppressed for one or another reason when they
	3	got a blood transfusion, I suspect.
	4		DR. HOLLINGER:  Thank you, Mike.
	5		Dr. Dayton?
	6	    Risk Assessment Model and Proposed Policy Questions

	7		DR. DAYTON:  Thank you, Mike, for an excellent
	8	presentation.
	9		[Slide.]
10		What I am going to do is take a lot of the data
11	Mike has presented and data that other people have

12	communicated to me or that we have gleaned from the
13	workshop, et cetera, and try to put this into an analysis of
14	the predicted effects of changes in the policy that we may
15	be considering.
16		[Slide.]
17		To go back to a piece of the original diagram that
18	I gave you, we were concerned, largely, with infectious
19	units and potential donors getting through the test by these
20	various mechanisms and getting into the blood supply.  The
21	question is going to be how can we quantitate this.
22		As I mentioned, this occurs because of various
23	problems.  As I said before, there are prevalence issues and
24	incidence issues to approach these quantitatively.  We have
25	undetectable strains so if there is a prevalent undetectable

			201 1	strain, it can get through.  For the most part, we are not
	2	taking this into consideration for lack of data that these
	3	are a predictable problem at the moment for HIV.
	4		Blood banks errors is where most of the discussion
	5	is going to be today.  Primary-test failure; this is
	6	essentially zero.  Then the incidence issues, the window
	7	period.  When we calculate these, we think in terms of
	8	frequency of these, so there will be an error frequency,
	9	times the prevalence--when we are calculating this out, we
10	think in terms of an error frequency times a prevalence
11	frequency times the change in the population.
12		This brings us back to this equation.
13		[Slide.]
14		Again, the change in errors is going to be equal
15	to the change in population so that the new infectious units
16	that could slip through the system appearing because of a
17	new donor population are merely the summation of what I
18	showed you on the last slide, the prevalence issues plus the
19	incidence issues.  This is just a correction factor for the
20	length of the window period that we use.
21		[Slide.]
22		FDA is considering changing donor-suitability

23	criteria to defer for MSM behavior within the last five
24	years prior to donation, so we would allow people to donate
25	if they hadn't had any MSM activity in the last five years

			202 1	prior to donation.
	2		We are going to calculate how many new individuals
	3	will join the set of donors who are not deferred by the

	4	questionnaire and, thus, have their units enter into the
	5	blood banks for testing.  So we will start out by, we need
	6	to know the size of the MSM population that has abstained
	7	from MSM behavior for five years or more, and then we will

	8	multiply that by the frequency at which they can be expected
	9	to donate.  That should give us the number of new MSM
10	donors.
11		[Slide.]
12		What is the size of the MSM population that has

13	abstained from MSM behavior for five years or more?  Lynda
14	Doll, in 1997, went to a great deal of effort to give us
15	some very useful numbers.  She came up with a population
16	size of approximately 1.4 million MSM in USA at five years
17	of abstention.

18		At what frequency can they be expected to donate?
19		[Slide.]
20		We expect them, for lack of any better evidence,
21	to donate at a rate equivalent to the general population,
22	namely about 5 percent.  So, given an MSM population, so I
23	thought with five-year abstention, a population size of
24	1.4 million, and assuming a donation rate of 5 percent, we
25	would get a total of 70,000 new MSMs who had come to the

			203 1	blood centers and have their blood drawn and have that blood
	2	sitting in the center awaiting testing.
	3		However, some of these will already have been
	4	donating.  I have a calculation here--again, we have
	5	presented this to the committee in the past--of how we
	6	calculated how many are donating.
	7		[Slide.]
	8		I am going to tell you a answer before I tell you
	9	how I got it so that you will know where we are going.  We
10	calculate that 0.55 percent of the newly eligible MSMs have
11	already been donating which comes out to 0.55 percent of
12	70,000 which is 7,700.
13		What that means is 7,700 of this 70,000 that are
14	newly eligible have already been donating so that changing
15	the deferral to a five-year deferral for MSM behavior would
16	result in approximately 62,300 new MSM presenting to donate
17	blood.  So that is the delta population that I have been
18	talking about.  That is the new MSMs who haven't been
19	appearing before.
20		How did we get this number of 0.55 percent?
21		[Slide.]
22		What that number is is the frequency at which MSM
23	with deferrable risk will donate.  We assume that that is

24	equal to the current frequency at which deferrable MSM
25	donate.  Of course, you could simply go out and ask 100,000

			204 1	MSMs whether or not they donate, and you could generate that
	2	number from that kind of survey.
	3		We don't have that, but we do have another way of
	4	calculating it.  I believe Alan Williams was the first one

	5	who actually suggested this.  We can simply take the number
	6	of MSM currently showing up to donate, which we can
	7	calculate from REDS by a frequency number from REDS and
	8	divide it by the size of MSM population.
	9		We know from the REDS study that 0.57 percent of
10	men who present to donate have deferrable MSM history.  And
11	we know that 4.5 million donors are male.  So the number of
12	MSM who currently donate will be 0.57 percent times that
13	4.5 million number.
14		The MSM population with deferrable risk is
15	4.7 million.  It is only an accident that these two numbers
16	are so close.  So the current donation frequency of MSM
17	having deferrable risk equals the number showing up to
18	donate divided by the number of MSM in the relevant
19	population which is this number divided by this number. 
20	That is how we get the 0.55 percent number.
21		[Slide.]
22		So, to reiterate, the critical take-home here is
23	that 62,300 new MSM would present to donate blood that have
24	not been presenting before with a five-year deferral.
25		[Slide.]

			205 1		Let's look at the prevalence and incidence issues
	2	separately to see how they contribute to the possible errors
	3	that might occur in transmitting infected units into the
	4	blood supply.  I just calculated the change in population
	5	number.  Now, I am going to go through the prevalence
	6	issues.
	7		First, let's focus on what we calculate prevalence
	8	to be.  HIV prevalence in MSM varies widely according to the
	9	geography of the United States.  It varies from 6 percent to
10	36 percent.  The average U.S. prevalence is approximately

11	8 percent.  However, about three-quarters of these already
12	know their seropositivity status and are expected to self-
13	defer.
14		So the effective average prevalence rate

15	nationally would be about 2 percent.  As I mentioned
16	earlier, undetectable strains, which is this term here--we
17	just discussed the prevalence term; now we are going to
18	discuss these three terms--undetectable strains are ignored
19	for lack of evidence.  They represent predictable threat for
20	HIV, again, in a population size of 62,000 or so, you are
21	safer making that assumption.
22		Blood-bank errors will be a major focus today. 
23	Blood-bank error rates involving release of HIV-positive
24	units have been poorly reported but I am going to go through
25	some data in which we can estimate what they are like.  I

						206
	1	will get into that in a minute.
	2		Pipetting errors or technician errors occur at the
	3	rate of 0.5 to 1.3 times 10	                
					-3.  This was the data that Mike
	4	Busch summarized in his task and it comes from a paper that
	5	he has published and also from data that Sue Stramer has
	6	very generously provided from the American Red Cross.
	7		Finally, primary-test failure.  Essentially, that
	8	is equal to zero.

	9		[Slide.]
10		Let's go on to the test-error issues here.  If we
11	calculate out this term here, the prevalence basically times
12	the error, since this and this are equal to zero, it is

13	2 percent from the prevalence times 1.3 times 10	                
		-3 which is
14	the error rate and times the change in population, the new
15	population which is this.
16		With just a single test, we could predict that--

17	and, again, these numbers are pretty iffy.  I am sure you
18	are all aware of that.  Blaine contacted me and, very
19	correctly, asked for confidence intervals and I contacted
20	him and said I don't have any.  The problem is that a lot of
21	these numbers are 1 for 3 incidence that you are picking up. 
22	So the confidence intervals are going to be very large in

23	some of these.  But it is the best we have.  It is all we
24	have to go with.
25		Anyway, using this approach, it is possible that

			207 1	as many as 1.6 units, HIV-infected units, could slip through
	2	the system.  However, the NAT test provides a minimum of
	3	twenty-fold of redundancy.  What I mean by that is anything
	4	that is EIA-positive is also going to be positive on NAT. 
	5	When I say twenty-fold, I am just using a loose number
	6	saying that if something is EIA-positive, at least
	7	95 percent of those and probably a good deal more are going
	8	to be NAT-positive.
	9		Since those are separate tests, they provide
10	redundancy for one another.  When you take that into
11	account, the NAT reduces this introduced prevalence rate at
12	least by twenty-fold, so we could use the number of
13	0.081 units, infected units, getting into the blood supply
14	for a year.  That is a worst-case scenario.
15		That is not a bad number.
16		[Slide.]
17		Furthermore, this number would decrease as HIV
18	tests eliminate the effective prevalence among repeat donors
19	from this category.  All that means is, as this group newly
20	donates, the positives will be picked up, the effective
21	prevalence rate will, essentially, go down in that group
22	amongst repeat donors.
23		The big caveat here is that this estimate was made
24	assuming errors only came from performing tests or
25	technician error or pipetting errors is an easy one to

			208 1	visualize.  Unfortunately, double-testing, for instance the
	2	ELISA and NAT, confers no protection against release errors.
	3		Release errors have been difficult to quantify but
	4	I was very fortunate in contacting Jeanne Linden who
	5	provided me with some data from New York State.  It turns
	6	out to be very interesting data and suggests that the

	7	erroneous release rate may be a bigger problem for us.
	8		[Slide.]
	9		This is a selection of some of the data that Dr.
10	Linden sent to me.  Over the recent time period from 1999
11	and 2000, out of about 700,000 donations in New York State,
12	there were four inappropriate release of anti-HBC-core-

13	positives from hospitals.  There was one inappropriate
14	anticore-positive release from blood centers and there was
15	one inappropriate HCV-positive release from hospitals.
16		I have broken this out into hospitals and blood
17	centers, again at Jeanne's suggestion.  It is very
18	interesting that hospitals which, in New York State, acquire
19	about 10 percent of the blood have over 80 percent of the
20	overall errors.  They are producing errors which are
21	disproportionate to their number.
22		The reason is that hospitals, being generally
23	small, don't have automated blood-handling systems whereas
24	blood centers do and that is a major factor in reducing
25	inappropriate release.

			209 1		Dr. Linden did not have one of the key numbers we
	2	needed from the New York data.  What we want to do is we
	3	want to take these numbers and say, "Well, we got four
	4	inappropriate releases of anticore, but how many anticore-
	5	positives were there?"  So we had to estimate that for the
	6	New York data.
	7		So I used data that Alan Williams supplied from
	8	the Red Cross and was collected by ARCNET.  From a period of
	9	1-98 through 6-30-99, which is reasonably close to the New
10	York time period, nationally, out of about 5.9 million

11	donations, there were collected about 5,000 anti-HCV
12	positives and about 26,000 or 27,000 anticore positives.
13		So, by using the ratios or the percent of units,
14	or the percent of this 5.9 million which were either core-
15	positive or HCV-positive, and assuming that the prevalence
16	in New York was the same as the percent prevalence
17	nationally, I was able to calculate how many HCV positives
18	were in this 70,000 donations from hospitals, how many
19	anticore positives were present in this.

20		Also, I could do the same thing for the numbers in
21	the blood centers.  Then I just used those as denominators

22	and these as numerators to calculate the release-error rate. 
23	Those numbers are summarized at the end of this table.
24		I want to focus on the anticore data.  The reason
25	I want to focus first on the anticore data is because there

			210 1	were four events measured there.  When you do this
		2	calculation for these four events in hospitals, you end up
		3	with a very surprisingly high release rate of about
		4	1.3 percent.  I think we were all very surprised that it was
		5	that high.
		6		Granted, it is a small sample and there is going
		7	to be a large confidence interval around it, but, in spite
		8	of all, even for the HCV data which had only one event, the
		9	HCV data calculates to about 1.7 percent.  So it is a number
	10	consistent with the anticore data.
	11		For the blood centers, there was only one event

	12	and that calculates out to about 3.5 times 10		   
						-4 as the
	13	release error rate.

	14		[Slide.]
	15		So, if you apply that to what we would expect for
	16	MSMs donating nationally, nationally, about 8 percent of the
	17	donations are in hospitals and about 92 percent are in blood
	18	centers, so it is not that different from New York State.

	19		If you had the 63,300 appearing, how many units
	20	would get through?  If you just use the simple incidence
	21	times the proportion of the population which would be in
	22	hospitals and the simple incidence times the proportion of
	23	the population which would be in blood centers, these are

	24	the numbers of units of HIV-positive material that would be
	25	in the blood bank.

				211 1		If you multiply that times the error rate, you
	2	come up with small, non-automated blood collection systems

	3	would contribute possibly as many as 1.3 HIV-infected units
	4	into the blood supply per year if this error rate is
	5	correct.
	6		The highly automated blood centers, on the other
	7	hand, would be calculated to contribute about 0.4 units per
	8	year, making these assumptions, for a total of about 1.7. 
	9	So, to the extent that we believe the numbers I have

10	calculated for release error rates--and, of course, there is
11	a certain "if" associated with that, and you have seen the
12	actual numbers.  Changing the policy to a five-year deferral
13	for MSMs could conceivably result in a total of	1.7
14	infectious units getting through that would not otherwise
15	get through.
16		[Slide.]
17		What I have discussed previously are prevalence
18	issues.  If you remember, then, the other category of issues
19	is incidence issues.  That is what I am going to discuss

20	now.  Essentially, incidence issues will turn out to be a
21	minor problem with the five-year deferral.  I can tell you
22	that is the answer.
23		So, using an average incidence in the MSM in the

24	U.S. is an incidence about 3 times 10		                
				-2 per person years. 
25	Although the typical window period is 11 to 16 days,

			212 1	roughly, depending upon the technology, following about
	2	51 needle-stick accidents, it was discovered that about
	3	5 percent--maybe not quite that--seroconvert after the first
	4	six months.
	5		So, almost all of the window periods seem to be 11
	6	to 16 days, but there is a reasonable number that are very,
	7	very long.  We don't really know anything about those window
	8	periods.  Presumably, these window periods were at least six
	9	months long.
10		We assume that they were infectious for the entire
11	six months but we don't know that.  There is also no reason
12	to assume that all of them seroconvert in the second six
13	months.  So I have made some assumptions here and given you
14	some ideas of what the answers would look like.
15		What I have done here is I have essentially
16	assumed a 95 percent decay rate every six months.  What does
17	that mean?  That means that 95 percent of all the people who
18	have been infected, 95 percent will seroconvert every six
19	months or another way of looking at that would be 95 percent
20	of what is left seroconvert.
21		Or another way of looking at it would be, of all
22	of the ones that have not seroconverted, 5 percent will fail
23	to seroconvert, will still fail to seroconvert, in the next
24	six months.  This is a very loose number, but I have said,
25	"Well, what if we are wrong?  What if it were 75 percent? 

			213 1	What if 75 percent converted every six months," which would
		2	mean that 25 percent had not converted every six months?
		3		That is a worst-case scenario and I really don't
		4	think the data could ever be construed as permitting that. 
		5	But if you take these possible scenarios and assume a decay,
		6	with a five-year deferral rate, you would end up with less

		7	than 3 times 10	             -5
units if it were the 5 percent number.
		8		If even if were the obviously not correct 25
		9	percent number, you would still only be introducing 0.42

	10	units per year.  So we think that the incident issues give
	11	you a tremendous margin of safety with a five-year deferral
	12	for the obvious reason that there are almost no window-
	13	period conversions going out into five years.
	14		[Slide.]
	15		I should say that I have given myself a little bit
	16	of leeway in these calculations in that I took into account
	17	the possibility of donor confusion or poor memory by
	18	assuming that a five-year query was entirely ineffective

	19	except for the behavior within the last three years, which
	20	is a pretty conservative assumption.  We know, certainly,
	21	that people are going to forget; "Did I do that three years
	22	ago?  Was it five years ago?"  And you are in the middle of
	23	an 85-question questionnaire.
	24		But what I actually assumed was that essentially
	25	people would always remember behavior within the last three

			214 1	years and defer themselves on the basis of that question. 
	2	So I have been somewhat conservative in that respect.
	3		[Slide.]
	4		What about a one-year deferral?  A one-year
	5	deferral would result in approximately 112,000 new MSM
	6	donors rather than the 62,300, or about 1.8 times as many as
	7	a five-year deferral policy.  This would result in about
	8	0.15 new seropositive units escaping interdiction per year
	9	from errors in performing tests and possibly as many as
10	three units from errors in unit release.
11		I will give you a table shortly to summarize all
12	of these numbers.  Also, a one-year deferral policy poses
13	window-period problems.  Again, if there is only 95 percent
14	seroconversion every six months post-HIV exposure, then
15	0.25 percent would seroconvert after the first year.
16		Using this formula to calculate how many infected
17	units you would get appearing into the blood supply, you
18	could get 3.1 from this mechanism.
19		[Slide.]
20		So, let me summarize how the story looks for HIV. 
21	Again, with tremendous caveats because you understand that a
22	lot of this data is based on one to four incidents of
23	something being measured.  So it is hard to come up with
24	good statistics on them.  But with a five-year deferral, we
25	would expect zero window-period errors to be introduced into

			215 1	the population by adding 62,000 or so donors.
	2		Release errors could conceivably contribute
	3	1.7 infectious units per year from that size population and
	4	technical errors, such as pipetting errors, would introduce
	5	far less than 1.0--maybe 0.08 or less.  With a one-year
	6	deferral, it is conceivable we could have as many as three
	7	window-period units newly introduced into the blood supply. 
	8	Again, you realize that we just really don't know what those
	9	long-term window periods look like, so there is a big
10	question mark associated with that number.
11		Release errors would conceivably contribute as
12	many as three new units per year and technical errors would
13	still be down well below 0.2 per year.  Again, all of these
14	numbers should decrease with time with repeat donors being
15	weeded out for seropositivity and, thus, reducing the
16	prevalence error.
17		The other take-home from my talk is that
18	inappropriate release, primarily due to non-automated blood
19	handling systems remains the biggest risk factor.  I should
20	say "problem.  "

21		[Slide.]
22		HCV I am not going to go into nearly as detailed
23	analysis as I did for HIV.  The reason is that the
24	prevalence of HCV in non IVDU-MSM, about 4 percent, is only
25	about twice that of the general population, 1.8 percent. 

			216 1	Given the high sensitivity of the HCV ELISA and the
	2	redundancy of HCV NAT, together with the similar prevalence
	3	rates in the two populations, deferral of MSM would be only
	4	marginally effective in preventing HCV transmission.
	5		[Slide.]
	6		Similarly, for HBV, I don't think it is necessary
	7	to go into as detailed an analysis as we did for HIV but, to
	8	summarize it, as with HIV, essentially all of the infectees
	9	who are going to seroconvert will have done so well before
10	three to five years.  Therefore, incidence issues are of
11	minor concern.
12		The real danger is chronically infected donors,
13	long-term HBsAg-positives.  In MSMs, the prevalence of HBsAg
14	positivity is about 1 percent.  This would result in about
15	623 new positive units presenting to the blood supply. 
16	Again, that would reduce to small numbers of HBsAg getting
17	through.
18		Also, the anti-HBV core provides redundancy, as
19	NAT does for HIV.

20		[Slide.]
21		To look at how many HBsAg-positive units could be
22	inappropriately released, again a bigger problem, by
23	changing to a five-year MSM deferral policy, I have come up
24	with this analysis.  It is the same one you saw for HIV.  I
25	won't go through the details.  I will take you right to the

			217 1	end of the story.
	2		Making the same assumptions, small non-automated

	3	blood systems, could conceivably contribute as much as 0.64
	4	new units per year with a five-year deferral and automated
	5	blood centers could conceivably come up with 0.2 units per
	6	year.

	7		Of course, I don't need to remind you that HBV has
	8	a much lower morbidity than HIV.  So changing to a five-year
	9	MSM deferral would introduce minimal risk of HBV morbidity
10	from blood transmission.
11		[Slide.]
12		You have seen this slide before.  I will just show
13	you one thing.  This is data that Mike presented earlier. 
14	This is pre-NAT and post-NAT residual risk broken out by

15	error.  I just wanted to show to you that the error numbers
16	for HIV and HCV pre-NAT go down to zero post-NAT so the
17	redundance is a real phenomenon.
18		[Slide.]
19		Again, this is similar to, a subset of the data
20	that Mike presented on the increasing incidence of HIV and

21	STDs in general in the MSM population.  This was provided by
22	Dr. Hansfield from Seattle.  In 1997, the incidence of HIV
23	in MSM goes from a unit of 1 to 1.7 in non-IVDU-MSMs.  So

24	that is a worrisome number.
25		[Slide.]

			218 1		These are in your notes.  These are just the
	2	contributors to Dr. Hansfield.
	3		[Slide.]
	4		He asked that we display them.
	5		[Slide.]
	6		To bring my talk to a conclusion, we have
	7	quantitatively analyzed the risks to the blood supply of

	8	changing the deferral of MSM from "since 1977" to "within
	9	the last five years."  This analysis has taken into account
10	prevalence and incidence issues, testing errors and release
11	errors.
12		This analysis has not summarized projected
13	improvements in blood banking from improved automation but
14	does demonstrate that inappropriate release remains a
15	significant risk.

16		[Slide.]
17		The final conclusion is that there is some
18	scientific data to support relaxation of the current MSM
19	deferral policy which defers men donors who have had sex
20	with another male even one time since 1977.  Also, a five-

21	year MSM deferral policy for blood donation would harmonize
22	with the five-year deferral policy for tissue donation.
23		[Slide.]
24		One of the true privileges of working in the FDA
25	on an analysis such is this is the tremendous amount of

				219 1	support and help I have had from many people, both inside
	2	the FDA and outside the FDA.  The truth is, they did all the
	3	real work and I am very grateful to them.
	4		[Slide.]
	5		Finally, the question, as we proposed it, is, "Do
	6	the available scientific data support the concept that men
	7	who have sex with other men can be deferred from donating
	8	blood for a period of five years following MSM activity
	9	rather than being deferred for any MSM behavior since 1977?"
10		Thank you.
11		DR. HOLLINGER:  Thank you.
12		Any questions of Andy at this point?  Dr. Boyle?
13		DR. BOYLE:  Just one question for clarification. 
14	All of the equation that you have up there is based upon
15	what is effectively changing a test.  The test is the
16	question in the screening--
17		DR. DAYTON:  Changing the question; yes.
18		DR. BOYLE:  But the question is the equivalent of
19	the test.
20		DR. DAYTON:  Yes.
21		DR. BOYLE:  Basically, all of that is based upon
22	an assumption about what that change will do, whether or not
23	it is 100 percent specific or, in your case, reducing it to
24	three years rather than five years.  It is all an
25	assumption.  There is no evidence; right--what the effect

			220 1	would be?
	2		DR. DAYTON:  Well, no; it is not all an
	3	assumption.  It depends on what number you are talking about
	4	because if it is the population number, the change in
	5	population, how many new MSMs would present--that is not an
	6	assumption.  That was calculated.
	7		DR. BOYLE:  No, no; the question is that if you
	8	change a question, how a person will respond to it, is based
	9	upon--
10		DR. DAYTON:  You are getting into an entirely
11	different--and, actually, I am very glad you brought that up
12	because would did consider this.  You get into this whole
13	area of test-seeking behavior and reliability.
14		When we first started this particular analysis,
15	one of the take-homes that came out of it very early on in
16	1997 was we were very worried, well, how do you account for
17	people who are doing test-seeking behavior?  How do they fit
18	into the equation and how do you take that into these
19	numbers of new MSMs presenting to donate.
20		To a first order approximation, people who are
21	already doing test-seeking behavior are going to continue
22	doing it.  So that number does not change.
23		You are shaking your head and I think I know where
24	you are going in that and I certainly agree with you.  Maybe
25	people will say, oh, now you are only deferred for five

			221 1	years, and maybe they will be more likely to engage in test-
	2	seeking behavior.  We simply can't calculate that number. 
	3	But I think that is where you were going.
	4		DR. BOYLE:  Just one follow up.  As I understand
	5	it, there is a task force that is going to be looking at the
	6	whole questionnaire and trying to put together some evidence
	7	about what works and what doesn't.  My question is why is

	8	this issue presented now rather than a year from now when,
	9	presumably, the task force is looking at the questionnaire
10	across the board and maybe you have some evidence.
11		DR. DAYTON:  You may have some input into that
12	decision.  Actually, you will have some input into that

13	decision.  As I said, the real reason we thought it was a
14	great time to look at it now is because of the redundancy
15	that exists with the concurrent NAT and ELISA tests.
16		Also, we have learned more about blood-banking
17	errors which are two previous concerns.  So we are a mile
18	further than we were last year.
19		DR. HOLLINGER:  Dr. Nelson?
20		DR. NELSON:  As a follow up, I think the real
21	issue--you presented one side of the equation.  But the

22	other is the questionnaire and the validity of the answers
23	to a different question.  We already have some data on
24	validity of answers to the previous question since 1977.  In
25	other words, how many men who actually had sex with men

			222 1	during that period were then found to have a viral marker
	2	and then, on subsequent testing after they were found to be
	3	positive really didn't answer, or forget, or for whatever

	4	reason, didn't give a valid answer to the 1977 question.
	5		We don't really know what effect the change will
	6	be.  I think that is the big part of the equation rather
	7	than what happens to the tests in these long window periods. 
	8	I think, with the current redundant test, that is probably

	9	pretty insignificant.  But the real issue is how will the
10	change in the question affect the validity of the answers
11	that one will get with the population.
12		Do you agree with that?
13		DR. DAYTON:  Yes; I agree with it very much.  I
14	think we can give you a partial answer, and part of it is
15	the answer I just gave and part of it isn't.  We feel--we
16	don't have data to prove it, but we feel that a five-year

17	deferral will be perceived as a much fairer mode of deferral
18	than, basically, forever.  I think that that will actually
19	engender more compliance.
20		Granted, it might be harder to remember was it
21	five years ago or three years ago as opposed to in the last
22	twenty years.  But, as I say in the calculations, we gave a
23	slack to that in asking for five years expecting to get
24	three years effective deferral.  So we think that is going
25	to be okay.

				223 1		Finally, the point I made to Dr. Boyle deserves
	2	reiteration that the people who are consciously engaging in
	3	test-seeking behavior will continue to do that.  They are
	4	not going to represent a change.  They are not going to come
	5	into the change that results from this policy.
	6		But, unquestionably, designing a good
	7	questionnaire and getting it to work is a major, major
	8	problem.  It is just that it is not a delta that is
	9	associated with this policy.  We definitely need to put a
10	lot of homework into that questionnaire.
11		DR. NELSON:  Dr. Schmidt?
12		DR. SCHMIDT:  Another aspect of this, following up
13	on these two comments, is a question of memory.  I only had
14	one surgical insult in my life.  That was my gall bladder. 
15	I found out, as I took physicals after this, year after
16	year, I couldn't remember how long it had been.  I can tell
17	you what the room looked like and how many pounds I lost
18	before I had it, but it is not a human type of framework, I
19	think, to know that with the exactitude.
20		You really came down to it at the end--you are
21	now, when you are telling us five years is really three
22	years.  So I am not talking about test seeking or anything. 
23	I am talking about answering questions.
24		I almost think, and what we are talking about,

25	calls for a change in your question to the committee which

			224 1	doesn't say that they didn't have sex in five years, but, as
	2	far as they remember, they didn't have sex in five years. 
	3	That is really the issue.
	4		DR. DAYTON:  I think that is fair.
	5		DR. HOLLINGER:  Dr. Simon?
	6		DR. SIMON:  Perhaps I missed it, but I also
	7	thought that one of the reasons for concern to change at
	8	this time is harmonization with the tissue provisions
	9	because we have just had that conference and I believe we
10	are going through with--you all are going through with a
11	rewrite of those.
12		That was, I thought, one reason.
13		DR. DAYTON:  Yes; I didn't dwell on it, but I did
14	have it there on a slide.  It is a good point.  The
15	harmonization makes for less confusion and a more coherent
16	questionnaire and a less confusing policy.  So that is a

17	benefit.
18		DR. SIMON:  I guess one of the questions that
19	comes to mind, and it may be that you have already hit on

20	the answer in some of your other questions, is the agency's
21	thought about going to five years with the permanent

22	deferrals--that is, IV drug abuse and sex for money or
23	drugs.  Is that something that you are putting off to the
24	whole look at the questionnaire or are you thinking about
25	that?

				225 1		DR. DAYTON:  We periodically reexamine all of
	2	those issues.  They are all so complicated.  We certainly
	3	didn't want to wrap them into one discussion.  So we keep an
	4	eye on those and, when we feel that the data supports
	5	reexamining those issues, we will very rapidly reexamine
	6	them or bring it before here, actually.
	7		DR. MACIK:  In the numbers that you have for men
	8	who continue to donate, is there any feeling for how many of
	9	those may have gone out and had themselves tested?  The
10	people who, say, had one relationship or one event and then
11	were worried about it and went out and had their doctor do
12	all the tests on them.  In their mind, they are negative and
13	they are going to come in and donate.
14		Was there any feeling to how often that would
15	happen?
16		DR. DAYTON:  We do have a number for what
17	frequency of men who donate have a history of deferrable MSM
18	behavior.  We do have that number, but I am not quite sure
19	what you are looking for beyond that.
20		DR. MACIK:  That they went to their doctor and
21	said, I want you to test me for AIDS and I want you to test
22	me for hepatitis C.  And so their doctor sent all the tests
23	and the tests come back negative.  Then that man shows up at
24	the blood donation and--
25		DR. DAYTON:  Oh; I see.  So you would want to take

			226 1	that number and adjust the number that I did present.
	2		DR. MACIK:  I just wonder if you have any idea of
	3	how often that would happen.
	4		DR. DAYTON:  I don't.  Alan, do you know anything
	5	from the REDS study on that?
	6		DR. KLEINMAN:  I would have to say that, at this

	7	point, the data are not available in the 1998 survey.  We
	8	did start to probe a little bit on donors who did proceed
	9	with those donations despite deferrable risk and get some

10	basic rational as to why they did that.  But it doesn't get
11	as detailed as you are suggesting.
12		DR. HOLLINGER:  A question to the committee and
13	then there looks like there is a group forming at the back
14	to do something to us.  Steve, why don't you go ahead.
15		DR. KLEINMAN:  Dr. Steve Kleinman.  Comment for

16	Dr. Boyle.  As a member of that donor task force, one of the
17	things that we wanted to avoid doing was spending a lot of
18	time on questions that there was no intention to have
19	changed by the FDA.  I think when you asked why is this
20	brought to the committee, if the committee says don't change
21	this, the FDA says don't change this, there is no point in
22	having a task force look at it and come up with a
23	recommendation to change it.
24		So the concept is we are looking for a direction
25	and want to spend our time just on those things that are

			227 1	really potentially changeable because it is a lot of work to
	2	review the whole questionnaire.
	3		A couple of other comments, on two parts of the
	4	model.  One is the prevalence rates for HIV antibody in MSMs
	5	which you said range from 6 to 30 percent and you took a
	6	number of 8 percent.  I think that is probably quite valid
	7	except the kinds of persons that might come in and now be
	8	eligible to donate would seem to me to be two kinds of
	9	people.  One would be a person who was actively engaged in
10	male-to-male sex and stopped five years ago.
11		But the other type of person which I think is more
12	common would be somebody who might have experimented and had
13	one or two experiences back ten or fifteen years ago.  I
14	would submit that it is unlikely that the rates are going to
15	be 8 percent in that group of people.
16		So I think that we might be kind of overestimating
17	the HIV risk in the people who would come back in and be
18	eligible to donate.  I wonder if you could comment on that.
19		DR. DAYTON:  That is a perfectly fair question. 
20	What you are getting into is the whole issue of what defines
21	MSM behavior.  That, in and of itself, is a complicated
22	field.  It is very hard to decide which of those two
23	categories--if both of those two categories are handled
24	equivalently.
25		We didn't have data to distinguish between the two

			228 1	so we lumped them together.  But I think that where it comes
	2	out in the wash is that the really important data is the
	3	overall prevalence data and the blood-banking release
	4	errors.  I would assume that the overall numbers include
	5	both those types of people that you have just described, for
	6	lack of an effective way to really factor it out.
	7		Maybe Alan can correct me on that.  He is shaking
	8	his head no.  So we just don't have the information to do
	9	that.
10		Also, you are quite right that all of these

11	numbers here, if I had a chance to choose reasonably a
12	conservative number, basically conservative meaning which
13	would bias against relaxing the policy, I generally did

14	that.  I felt, since we didn't have confidence intervals, I
15	felt an obligation to do that basically to be in compliance
16	with the publicly mandated and Congressionally mandated
17	policy of zero error tolerance in this matter.
18		DR. KLEINMAN:  I think that my last comment is
19	that probably applies to your numbers for release errors as
20	well because in the era where we are--obviously, the release
21	errors were from the hospitals, but I want to remind the
22	committee that, in the level of redundancy, there is not NAT
23	testing taking place in hospitals so all the NAT testing is
24	taking place with automated systems in blood centers so

25	that, since the HIV-positive person would presumably be

			229 1	positive both by antibody and by NAT, then the release error
	2	rate would apply to the NAT-tested blood centers.
	3		So most of those units would never get to a
	4	hospital even if the hospital collected it.  I guess the
	5	unit would be at the hospital, but the testing information

	6	would get back to the hospital.  I guess they could still
	7	make a release error, though, even with correctly supplied
	8	information.
	9		DR. DAYTON:  Where that would come into play in
10	the hospitals where you only have the one test and no
11	redundancy, you would go back to the testing error number. 
12	And that would become significant.  It would rise to about
13	1.6 nationally if all of the tests were done that way.  But
14	only 8 percent of them are under that, so you would only
15	have 8 percent of that 1.6 percent getting through.
16		So you would still have a very small number, and
17	your biggest worry would still be the inappropriate release
18	number with the standard prevalence rates.
19		DR. HOLLINGER:  Jeanne, would you respond to some
20	of that, please?
21		DR. LINDEN:  I would just like to add to that

22	because I really disagree with something that Steve said,
23	and there may be a misunderstanding of what the errors were
24	that were presented in my data.
25		We are talking about blood collected by a hospital

			230 1	where the testing may be done either at the hospital in the
	2	microbiology department, immunology, something like that, or
	3	it may actually be done by a blood center or reference lab. 
	4	The results come back but they don't come back
	5	electronically.  They come back by paper or, worse yet, by
	6	fax.  Those can be disworded or difficult to read.
	7		The problem is, even when you get those results,
	8	then they may not be read properly.  The fact that it is
	9	positive may be overlooked.  The fact that the test is
10	pending, which means actually it was reactive and not
11	reported, is overlooked.  That is really what those problems
12	primarily were.
13		Even if the NAT testing is done, it can still be
14	misinterpreted when it goes back to the hospital.  That is
15	why the hospitals had a much higher error rate than the

16	blood centers because of the way the testing is set up.
17		DR. HOLLINGER:  Thank you, Jeanne.
18		DR. DAYTON:  Can I ask a question of Dr. Linden? 
19	How difficult would it be for hospitals to change their
20	procedures to deal with this and reduce that rate? 
21	Obviously, they are seeking to do that, but how major a
22	hurdle is that?
23		Even you seemed surprised at the rather high
24	release rate.  If this is a real surprise, what can
25	hospitals do to address it?

			231 1		DR. LINDEN:  It has been a problem that I have
	2	been concerned with for many, many years.  My personal bias
	3	is that units collected by hospitals are much more dangerous
	4	than units collected by blood centers for a variety of
	5	reasons.
	6		I cannot, personally, speak for the feasibility of
	7	hospitals changing their systems.  I don't know if anybody
	8	here can.  But, certainly, we have seen that, as the blood
	9	centers have improved their automated systems, the hospitals
10	have not been able to do so.  In fact, it has, actually, in
11	a way, gotten worse because the old system of paper, you
12	could mark things in red and make things more obvious.
13		Now, the way things are coming, they are actually,
14	in my opinion, more error-prone, not less error-prone.  So,
15	short of having hospitals not collect, I am not sure.
16		DR. HOLLINGER:  Dr. McCurdy?
17		DR. McCURDY:  I think that one very important part
18	of this equation, as far as hospitals are concerned, is to
19	ask the question why is a hospital collecting a unit of
20	blood.  If I were in a hospital, the liability that I would
21	assume by collecting a donor would seem to far outweigh the
22	value of that unit of blood.
23		I suspect that part of it is the difficulties in
24	getting autologous units collected and provided at a blood
25	center.  It really has to go off-line, in effect, and is a

			232 1	pain in the neck.
	2		The other thing is the question of whether
	3	intermittent shortages of blood from the blood center, or
	4	perceived shortages, push the hospital to collect "to help
	5	out their local blood supply."  But I think it is important
	6	to ask why is the hospital collecting the unit of blood.  If
	7	you can find out why, and it is something that is
	8	potentially correctable, that may be a better approach than
	9	trying to change how they do it.
10		DR. LINDEN:  In my experience, most of the
11	hospitals collect for one of two reasons.  The primary one
12	is cost.  I know that it not something that this committee

13	is supposed to deal with, but I think that is the rationale. 
14	That is not going to be easy to fix.
15		The other is a perceived either shortage or lack

16	of availability from their supplier, that they feel they
17	need to be able to collect their own blood to supplement
18	what they get from a blood center.

19		DR. KATZ:  I have a couple of questions, and some
20	of it may be that I was out of the room for a minute.  You
21	cited a 2 percent prevalence rate in men having sex with men
22	with HIV seropositivity and used that, I believe, in your

23	calculations.  That is not discounted for that number, I
24	presume, for those that already know their serostatus and
25	would be excluded by a different question.

					233 1		DR. DAYTON:  I couldn't totally hear the question,
	2	but the average effective prevalence in MSM is 8 percent. 

	3	About 75 percent of them know their seropositive status and
	4	self-defer.
	5		DR. KATZ:  Okay.
	6		DR. DAYTON:  So the 2 percent has that taken into
	7	account.
	8		DR. KATZ:  The other question is probably for--
	9	well, I don't know, Dr. Dayton.  You may know.  It is my
10	presumption that underlying this entire discussion is that
11	any consideration of relaxation would not take effect until
12	there were licensed NAT assays.  I mean, that seems to run
13	through all the discussions of redundancy.
14		DR. DAYTON:  I didn't specifically address the
15	issue, but I think it is a good idea.

16		DR. HOLLINGER:  Dr. Epstein?
17		DR. EPSTEIN:  That would be our intent, would be
18	to wait for licensed NAT.  Since I have the mike, let me
19	just comment that there are a couple of drivers why we are
20	bringing the issue.  As has been stated, we have had a

21	general program of updating the donor suitability standards
22	which ultimately will be reflected in revised regulations. 
23	So we are trying to deal scientifically with each of the
24	issues, and there are a large number of them which have been
25	reflected in discussions at the advisory committee and

			234 1	scientific workshops.
	2		Secondly, it is very much in our thinking to
	3	determine the extent to which we can and should harmonize

	4	the standards for donor suitability as they apply to blood
	5	donation and as they apply to tissue donation and cell-

	6	derived product donation, which is an active area of PHS
	7	guidance and also is soon to emerge as FDA regulation.
	8		Above and beyond that, the agency is also
	9	responding to the fact that, over the years that we have had
10	this deferral in place, there has been a great deal of

11	criticism of the agency, particularly by gay and lesbian
12	activist groups and persons concerned in their behalf

13	including, for example, college students who have had
14	demonstrations on campuses that the current restriction
15	appears discriminatory and even if not discriminatory,
16	appears to be unduly strict.

17		The arguments that have been made are that, first
18	of all, a post-'77 history, for a person born post-'77, is
19	really a lifetime exclusion for even a single MSM
20	experience, and that why aren't we taking advantage of the
21	fact that screening test technology has improved remarkably
22	and can we not trade off some of the exclusion based on risk
23	history against better testing.
24		Then the third argument that has been made is that
25	we are kidding ourselves asking about remote risks.  We

			235 1	should be focussing on recent risks.  One way of doing that
	2	is to deal with a moving deferral interval rather than one

	3	reckoned from some remote time in the past.
	4		So these have been all the drivers why the issue
	5	comes to the fore now, although I accept the comments that
	6	have been made by several around the table, that the true
	7	impact won't be known unless we understand what a revised
	8	question might do.

	9		But I think what we are saying here is okay, let's
10	say we revise the question and it works perfectly.  On those
11	grounds, is it scientifically sound based on the modeling of
12	the risk, because, certainly, that is the best-case
13	scenario.  If we reject it in the best-case scenario then,
14	as also has been said, there is not a lot of point pursuing
15	a question which might, in fact, not work as well.
16		DR. DAYTON:  One just modification of what Jay
17	said.  Actually, we are not expecting the new question to
18	work perfectly.  We are assuming it will work as well as the
19	old one did.
20		DR. HOLLINGER:  Dr. Bianco?
21		DR. BIANCO:  Celso Bianco, America's Blood
22	Centers.  Dr. Dayton, thank you.  You have created a model
23	that tries to include every one of the major factors that
24	would contribute to that.  That is fun, actually, because we
25	can try to plug different numbers and see what is the impact

			236 1	there.
	2		I would like just to make a couple of observations
	3	about your assumptions.  Your assumption of 5 percent of
	4	individuals donating blood and that this would also apply to
	5	the gay community; one, I think that the gay community is
	6	very aware and they have, over the years, from our
	7	experience, particularly in New York, stayed away from
	8	donating blood.
	9		But the second thing is, even in New York, only
10	1.5 percent of the population donates blood, so that
11	reduces, by a factor of 3, the level of risk that you would
12	see.  The other point that I think would be very important
13	is that there is a dataset with the Centers for Disease
14	Control that I feel should have been part of that estimation
15	because it is very good, the data obtained with the HIV-
16	positive panel study.
17		From the beginning, or for many years, CDC has
18	been collecting data, very serious interviews.  And this was
19	presented at a workshop on panel suitability in '98 by

20	Kenneth Clark--actually, a copy of his slides with me--
21	showing very nicely the changing risks of donors that are
22	found to be positive after they donate blood.
23		The objective of the study was exactly that, of

24	identifying why did people go through the screening and were
25	able to donate.  There are a couple of figures that are very

			237 1	important there.  One is that today, this was '97 and I
	2	believe that today this is actually more true, only half of
	3	the HIV-positive donors are males, the ones that donate
	4	successfully and we detect them as positive.
	5		The second thing is that, among those that are
	6	males, only about 30 to 40 percent are the ones that reveal
	7	that they had risk behavior, sex with another male, in the
	8	past.  Of those, 90 percent of them had had risk behavior in
	9	the past year.
10		So I would love to see your model include some of
11	that data and revised estimates because I believe, just in
12	my mind, trying to divide the numbers, that we would not see
13	a real difference between the five years and the one year.
14		Thank you.
15		DR. HOLLINGER:  Thank you.
16		Dr. Linden?
17		DR. LINDEN:  One other question, thinking about

18	your calculations and your model, you are suggesting there
19	are 62,000 MSMs out there who would really like to donate
20	blood and are not able to right now.  So January 1, we say,
21	okay you can donate.

22		You are looking at calculating the number of units
23	that could get into the system per year, but if we suddenly
24	made a change, this is basically a one-time thing, assuming
25	they would all come out of the woodwork and say, oh, yes;

			238 1	here I am.
	2		In, say, 2001, they would come get tested and
	3	then, after that, presumably, a second test is going to take
	4	care of the problem with the errors because, basically, you
	5	would cull out those who are really positive and were
	6	somehow missed.
	7		So, on an ongoing basis, do you think the number
	8	might be less and that this is really worst-case scenario of
	9	the first year you make the change?  Can you just comment on
10	that issue?
11		DR. DAYTON:  Absolutely.  I did mention that

12	although I am not sure how to best quantify it.  But,
13	basically, as people come in and get tested and they get
14	weeded out for prevalence, the effect of prevalence does go
15	down, let's say, after the first year, just as you
16	described.
17		But I find it is a hard number to calculate. 

18	Also, opposed to that is every year you now have another
19	20 percent of that population coming in.  But it is a
20	totally correct consideration.
21		DR. HOLLINGER:  Question for Andy?
22		DR. BOYLE:  Yes.  One thing I am a little confused
23	on after hearing this.  Are you trying to establish a policy
24	of a five-year deferral regardless of what the question is,
25	or are you trying to establish a three-year deferral with a

			239 1	five-year question?
	2		In other words, let me phrase it differently.  If
	3	you are trying to establish a five-year deferral policy,
	4	would that mean that we would be developing questions that
	5	would accurately capture that even if we had to say seven
	6	years, or ten years?
	7		DR. DAYTON:  There are a couple of things implied 
	8	by your question.  One is what we are asking for and two is
	9	what will happen if we do something.  My analysis addressed
10	what would happen if we did something.  So the analysis I
11	gave you said what would happen if we did the five-year
12	deferral policy.
13		The question we are proposing to the committee is
14	do you think that the data supports this new policy or
15	suggests this new policy.  At that point, you need to take
16	into consideration the other elements you have brought in on
17	how well the questionnaire works.
18		This really comes back to what Jay mentioned and
19	what I added to, is that we expect the new question to work
20	as well as the old one does, relatively, for what it tries
21	to do.  I think that answers your question.  If not, pin me
22	down more.
23		DR. HOLLINGER:  Dr. Mitchell?
24		DR. MITCHELL:  I am still trying to get clear the
25	current number of people who test positive.  Is that around

			240 1	the 12 to 14 people per year?
	2		DR. DAYTON:  Do you mean the number of units that
	3	appear at the blood bank and get tested and are HIV-
	4	positive.
	5		DR. MITCHELL:  Yes.
	6		DR. DAYTON:  That number has been dwindling over
	7	the years.  It is typically around 1,000.  I think it is
	8	down to 800 or 900 now in the last couple of years.  Then, a
	9	few years before, it was up around 1,200.  That would be per
10	the entire whole-blood industry, the 13 million or 14

11	million donations per year, not including the plasma
12	industry.
13		DR. MITCHELL:  I think your analysis is very good. 
14	It is very, very conservative, but I think that it is very
15	good to have that kind of analysis.  Thank you.
16		DR. HOLLINGER:  Dr. McGee?
17		DR. McGEE:  I am a little bit confused about what
18	the final issue is.  In this multiplicative model,
19	everything has errors.  None of them are taken into account. 
20	We end up with a number of roughly 2 out of 60,000.
21		Let me just ask you; suppose you are off by a
22	magnitude of 5, which is not unreasonable.  I could give you
23	some scenarios.  Then, would you still make the same
24	recommendation, if you had come up with ten cases instead of
25	two?

				241 1		DR. DAYTON:  I am truly not avoiding the question,
	2	but whatever we take into account, I am not in the position
	3	of making a recommendation, and we are seeking a
	4	recommendation from the committee.  The reason I am doing
	5	that is because it is a very tough question to answer and I
	6	don't have an answer.
	7		DR. McGEE:  I thought you had kind of told me that
	8	things were safe as long as it was 2.  Your number was 1.7-
	9	something.
10		DR. DAYTON:  When we first started analyzing, and
11	this is kind of historical, we didn't realize the release-
12	error rate was going to be such a problem.  If it weren't a
13	problem, if you just looked at test condition errors, for

14	instance, then the errors are very, very low and probably
15	pretty safe.
16		DR. McGEE:  The question from the floor, one of
17	your estimates, he thought, was off by a factor of 3.
18		DR. DAYTON:  I absolutely agree.  We don't have
19	any better estimates.  I have tried to make that point very
20	clear and I am glad you brought it up because I don't think
21	it was clear.  These are very "iffy" numbers and,
22	unfortunately, it is all we have to go with.

23		DR. HOLLINGER:  Dr. Chamberland?
24		DR. CHAMBERLAND:  I have a question for the at
25	least two statisticians that I know are on the committee. 

			242 1	Is there a way to work with this model building into it some
	2	range of errors for each of these variables so that you can
	3	come out with I would assume a range?  You are not going to
	4	come out with a point estimate--or a point estimate with
	5	some sort of a range.  I think the point you raise is a good
	6	one because even though it may not be a FDA's intent to do
	7	this with coming forward with a very low number that would
	8	seem reassuring but there are no confidence intervals, there
	9	is no error range around these estimates.
10		Is it possible that work that into it?
11		DR. McGEE:  You start with 1.4 million.  It is

12	probably done on a small survey, who knows what 95--the
13	error is to that, but these multiplicative things, you can
14	derive the standard errors as you go.
15		DR. DAYTON:  One of the reasons we have not
16	dedicated ourselves to actually pinning down all those
17	numbers, because you could do a statistical analysis--the
18	errors associated with many assumptions are probably going
19	to be even greater than what the statistics tell us.  It
20	would be helpful to know the statistical numbers and what
21	confidence intervals they represent.
22		But I can almost guarantee you that many of our
23	assumptions are going to introduce even bigger errors such
24	as how well is the questionnaire going to work, how well

25	does the questionnaire currently work, what is the behavior,

			243 1	how do you define MSM behavior?
	2		It is a daunting task, but you are quite right
	3	that, in theory, it is doable.  But it is a heroic
	4	undertaking.
	5		DR. STUVER:  I think beyond just the statistical
	6	error that might exist, so you get a 95 percent confidence
	7	interval based on that, you can do some kind of sensitivity
	8	analysis where you change your estimates given what variable
	9	numbers there might exist from different sources of data
10	just to get a range, a sensitivity range, as opposed to
11	purely statistically related to that error.
12		DR. McGEE:  Some of the numbers in here are pure
13	guesses.
14		DR. STUVER:  Exactly.
15		DR. CHAMBERLAND:  This very well may, and should,
16	come up in the committee's larger discussion, but I think
17	why we are more or less stuck with this is that this is the
18	approach FDA has chosen to present this question to the
19	committee.  It is largely through a mathematical
20	presentation.
21		There have been supporting epidemiologic data and
22	this NAT testing data, all of which I think is very relevant
23	and germane and we need to discuss, but this has primarily
24	been funneled to the committee, at least in the FDA's
25	approach, through this mathematical model which I think, at

			244 1	best, we could say might be incomplete or could be
	2	amplified.
	3		DR. DAYTON:  When we began to reexamine this in
	4	1997, we began to assemble a lot of data about behavior, MSM
	5	behavior, risk behavior, prevalence, incidence, et cetera,

	6	et cetera.  It soon became clear to me that at least I felt
	7	the only way I could bring kind of a structure to the
	8	decision-making process is to actually say, "All right; we
	9	are going to change the policy.  What changes is that going
10	to introduce?"
11		And that necessarily leads into this kind of
12	analysis.  I think all of the weaknesses of that analysis
13	that have been pointed out are truly weaknesses.  Again, as
14	is so often the case in this situation, we need to make
15	tough decisions, science-based decisions, and our decisions
16	are often necessarily running ahead of where the data is
17	ready to take us with a lot of assuredness.
18		DR. HOLLINGER:  We have two final questions and
19	then we are going to take a break.  Dr. Simon and then Dr.
20	Kleinman.
21		DR. SIMON:  I am certainly not capable of
22	discussing the statistical issues but it seemed to me that
23	Dr. Dayton's analysis was framed so that it would sort of a
24	worst-case scenario, in which case, hopefully, it has been
25	biased--you say that is not the case.

				245 1		DR. McGEE:  That is not the case at all.
	2		DR. SIMON:  Because that is the way I interpret

	3	it, as being biased as sort of the worst thing that could
	4	happen, what would that give you?
	5		DR. DAYTON:  I see a lot of nodding heads here. 
	6	That was our intention, but the only way we could approach
	7	that is, given a choice of two numbers, we chose the worst-
	8	case scenario number.  But, again, that is not the same as
	9	doing a good statistical analysis.

10		DR. McGEE:  You did what you said.  You picked one
11	of two numbers.  But the second number also had error
12	involved in it so there was a worst-worst case, then, if you
13	will.  So this is what they thought among a bunch of point
14	estimates.  Each period gave them the biggest answer.  But
15	that is not the same at all as a sensitivity analysis or as
16	looking at the pure error in the model.

17		DR. HOLLINGER:  Dr. Kleinman?
18		DR. KLEINMAN:  I just wanted to comment, though. 
19	Someone suggested a sensitivity analysis which I think is a
20	good idea, but on a very cursory level, it seems like the

21	model is most sensitive to the release-error information.  I
22	think that release-error information--again, it was driven
23	strongly by the hospital-based release and we really don't
24	have a lot of data.
25		We have data from one year from New York State.  I

			246 1	really do think that is high and I really think you would
	2	have to have a release error now on two tests.  Even if that
	3	hospital was sending its testing out, it would now get an

	4	HIV antibody test result back and it would get a NAT test
	5	result back, and it would have to take the opportunity to
	6	misinterpret both of them for that unit to get out.
	7		So I don't think the release error adequately

	8	accounts for redundancy.  I think, clearly, at least in your
	9	analysis today, it was most sensitive to the release error,
10	and that is what jacked the numbers up.  So I really think
11	it might be nice to have an overall standard-error
12	statistical analysis, I bet if you do that, the range is
13	going to be somewhere from zero units a year to 10,000 units
14	a year, or some huge number that won't help you in decision-
15	making.
16		So I think we have to work, just as we do with

17	lots of blood-safety decisions, with the best data that we
18	have and, if there are large errors, then we have to use

19	common sense and we have to use the impressions of informed
20	individuals.
21		So I don't think we can go beyond that.  Again, I
22	think that you have taken the most conservative numbers and
23	you are even taking a five-year deferral which, I think,
24	goes well beyond what the scientific data indicates would be
25	necessary.

			247 1		DR. HOLLINGER:  We are going to take a twenty-
	2	minute break and meet back here again at 4:25, and we will

	3	have the open public presentation at that time and then go
	4	into discussion.
	5		[Break.]
	6		DR. HOLLINGER:  We are going to have the open
	7	public presentations.  There are four of them that I know
	8	of.  The first is Dr. Katz for the AABB.

	9		          Open Public Hearing
10		              Presentation
11		DR. KATZ:  I wanted to take a brief opportunity to
12	add my kudos to Dr. Hollinger for his performance as
13	chairman of the committee, most particularly the almost
14	metaphysical ability to change questions, an activity I
15	tried to engage in during my tenure and was never successful
16	at, and to note to the committee that I am very aware of the
17	difficulty of the issue that you are being forced to deal

18	with and just to say that I am glad it is you and not me.
19		The American Association of Blood Banks is the

20	professional society for over 9,000 individuals involved in
21	blood banking and transfusion medicine and represents
22	roughly 2,200 institutional members including independent
23	and Red Cross blood collection centers, hospital-based blood
24	banks and transfusion services as they collect, process,
25	distribute and transfuse blood and components and

			248 1	hemopoietic stem cells.
	2		Our members are responsible for virtually all the
	3	blood collected and more than 80 percent of the blood
	4	transfused in this country.  For over 50 years, the AABB's
	5	highest priority has been to maintain and enhance the safety
	6	and availability of the nation's blood supply.
	7		Since 1977, the AABB has advocated that the
	8	deferral period for male-to-male sex be changed to twelve
	9	months.  Modifying the deferral time period for male-to-male
10	sexual contact to twelve months will make that deferral
11	period consistent with the deferral period for other
12	potentially high-risk sexual exposures and will improve the
13	clarity and consistency of the donor questions.
14		The potential donor will be directed to focus on
15	recent rather than remote risk behaviors and should have

16	better recall for answers to the screening questions. 
17	Retention of a specific deferral for males who have had sex
18	with other males is based upon extensive scientific data
19	that document a significantly higher prevalence and

20	incidence of HIV and hepatitis B in this population.
21		The 1977 time frame for questions concerning male-
22	to-male sex was implemented at a time when the data

23	regarding HIV transmission were more limited and HIV
24	serologic tests were less sensitive than the current assays. 
25	It is now possible to use a large body of scientific

			249 1	evidence concerning the natural history of HIV infection and
	2	serologic testing to reexamine the appropriate time
	3	intervals for such a deferral.
	4		Studies by many investigators--much of that you
	5	have heard today--demonstrate that FDA-licensed and required
	6	HIV laboratory screening has reduced the HIV seronegative
	7	infectious window to an average of 16 days.  In clinically,
	8	asymptomatic individuals, HIV infection will result in the
	9	development of HIV antibody for p24 antigen in less than one
10	year in all cases.
11		In healthcare workers exposed to HIV-infected
12	blood by needle-stick injury, the interval from exposure to
13	seroconversion was less than six months in 95 percent of
14	cases.  In two cases, the intervals were 213 days and
15	between eight and nine-and-a-half months and,
16	parenthetically, some of that analysis was done with assays
17	less sensitive than those currently used in blood-collection
18	facilities in the Year 2000.
19		HIV NAT performed in minipools under IND has

20	further reduced the seronegative infectious window to
21	approximately twelve days and, as we have heard from FDA
22	today, any change in the donor deferral policy in this area
23	awaits licensure of NAT.
24		Accordingly, with regards to Dr. Dayton's
25	presentation, we have just a few comments that were not in

			250 1	our written statement but that do not alter our bottom line. 
	2	First of all, the number of gay donors entering the blood
	3	supply was estimated to represent 5 percent of that
	4	population, approximately, and we believe this represents at
	5	least a three-fold high estimate based on donation histories
	6	in the general population.
	7		As Dr. Bianco told you in New York, approximate
	8	1.5 percent of age-eligible donors actually donate.  We have
	9	heard no data to suggest that gay men would donate more

10	frequently.  Current incidence and prevalence data on HIV
11	seropositive blood donors demonstrate that less than half of
12	those donors in the HIV donor study are, in fact, male and
13	approximately half or less of those admit to MSM behavior.
14		Finally, the seroconversion outlyers that are
15	referred to in the healthcare worker studies, once again, in
16	part and in general, rely on earlier generation testing.
17		Accordingly, the AABB respectfully encourages the
18	committee to recommend to FDA a twelve-month deferral in
19	lieu of dating questions back to 1977.  We believe this
20	modification should have no measurable detrimental effect on
21	the risk of transmitting HIV through transfusion or the
22	safety of the blood supply.
23		Thank you for your attention.
24		DR. HOLLINGER:  Thank you, Louis.  Any questions
25	of Dr. Katz?  Dr. Dayton?

			251 1		DR. DAYTON:  Not a question, but just a response. 
	2	I appreciate you pointing out that the rate of donations by
	3	MSMs, as measured, is three-fold lower than the number we
	4	were using.  That may, in fact, be the case.
	5		However, there is also the consideration that it
	6	is known very widely that MSMs are strongly discouraged to
	7	donate for any MSM behavior since 1977 which means,
	8	basically, any MSM at this point.  That probably results in
	9	a lot of self-deferral.  One presumes that word will get
10	out. If we change a policy to a five-year deferral, one
11	presumes that the word would get out and that the donation
12	rates would increase.
13		So I think what you pointed out is very valid and,
14	again, we used conservative estimates.  But even if you
15	accept your numbers, there is an error in the other
16	direction that we have to worry about as well.
17		DR. HOLLINGER:  Thank you.
18		The next presentation is by Dr. Adrienne Smith of
19	the Gay and Lesbian Medical Association.
20		              Presentation
21		DR. SMITH:  Thank you.  I am a little hoarse today
22	but thank you very much for allowing me to speak.  I really
23	have enjoyed this afternoon's scientific discussion.  It is
24	very interesting.
25		I just want to make a brief statement.  On behalf

			252 1	of the Human Rights Campaign, the Lambda Legal Defense
	2	Education Fund and the Gay and Lesbian Medical Association,
	3	we urge that you carefully consider advising the FDA to
	4	alter the guidelines excluding male donors who have had sex
	5	with another man even once since 1977 as has been discussed
	6	a number of times.
	7		First and foremost, we stand united in our belief
	8	that the integrity and safety of the nation's blood supply
	9	must be preserved and maintained.  Any change in the
10	guidelines governing the donor deferral must be based upon
11	current medical expertise and up-to-date testing technology,
12	just as licensed NAT would provide.
13		We are not supportive of any change that would
14	meaningfully increase the risk exposure to recipients of
15	blood and blood products.  At the same time, the committee's
16	action should be guided by a fundamental public-health

17	principle that would ensure a simultaneous commitment to
18	both safety and fairness.
19		That principle is like risks should be treated
20	alike, which is just what Dr. Katz was, I think, alluding
21	to.  This maxim exposes the central flaw in the current

22	donor deferral policy which tolerates a wide range of risks
23	associated with heterosexual sex while imposing a zero

24	tolerance attitude towards MSMs regardless of the risk
25	associated with individual behavior.

			253 1		For example, under the current policy, a man who
	2	engaged in one act of oral or anal sex with another man in
	3	1978 and had been celibate ever since then would
	4	automatically be deferred while a woman who has had
	5	unprotected anal sex with multiple partners over the past
	6	year with no knowledge of the personal histories remains in
	7	the donor pool.
	8		Similarly, a man who had oral sex with another man
	9	in 1979 would be excluded whereas a woman who had
10	unprotected anal sex with the same man thirteen months ago
11	would be allowed in the donor pool.  A more rational policy
12	would address donors who engage in risky heterosexual

13	behavior with partners whose histories are unknown and
14	consider the status of MSMs whose behavioral histories do
15	not present any meaning risk to the blood supply.
16		By focusing on the source of the risk rather than
17	the size of the risk, the current policy stigmatizes gay

18	men.  The donation of blood as well as other life-saving
19	products such as organs is viewed by many as a civic duty
20	and a responsibility.
21		At a time when the demand for blood and blood
22	products is outpacing the availability, healthy gay and

23	bisexual men are repeatedly turned away from donating blood
24	despite messages from mass-media campaigns appealing for
25	donations.

			254 1		In addition, many gay men are shocked to learn

	2	that they are automatically deferred when eligible blood
	3	donors are typically described as being healthy, at least
	4	seventeen and weighing at least 110 pounds.
	5		Gay men often first find out that they are

	6	eliminated automatically as donors when they are turned away
	7	at a blood drive which is frequently at the place of
	8	employment, a local community center or at a church.  Our
	9	organizations have heard from many men who have encountered
10	stigmatization by being singled out because of their
11	sexuality despite the fact that they consistently practice
12	safe sex or are in a long-term monogamous relationship.
13		Rather than reaffirming the current blunt-
14	instrument--namely the questionnaire--we ask the committee
15	to consider a revised panel questionnaire that focuses on

16	more refined and specific behavioral criteria like recent
17	sexual histories that include unprotected anal sex or a

18	significant number of sexual partners over the prior year. 
19	Such an approach would allow blood banks to have reasonable
20	distinctions within the MSM donor pool and would weed out
21	heterosexuals whose behavioral histories would create a
22	meaningful risk for HIV and other blood-borne pathogens.
23		We also urge the committee to encourage the
24	development of pilot projects to test the effectiveness of
25	different types of donor questionnaires.  Furthermore, this

			255 1	committee's decision would reflect development in testing

	2	technology that has dramatically reduced the risk of both
	3	window-period donations and prevalence-related infections
	4	due to test error.
	5		Given these developments, the committee should

	6	consider moving the current lifetime deferral ban on MSMs to
	7	a time period that reflects the impact of these developments
	8	in medical technology on blood safety.  Moreover, the
	9	introduction of NAT testing will reduce the risk of
10	infections due to test error by adding another round of
11	testing to the collection process.
12		Finally, while we understand that the Blood
13	Product Advisory Committee deals solely with the regulation
14	of blood and blood products, we hope that any decision made
15	by this body will not have an adverse impact on decisions

16	made elsewhere within the FDA on the donation of other
17	biological products, namely reproductive tissue.
18		Given the availability of quarantine and retest
19	procedures, the relative risks associated with reproductive
20	tissues are separate and distinct from the issues before
21	this committee today.
22		I wish to thank you for your time and
23	consideration.
24		DR. HOLLINGER:  Thank you, Dr. Smith.
25		Any questions of Dr. Smith?  If not, the next

			256 1	speaker is Dr. Haley from the American Red Cross.
	2		              Presentation
	3		DR. HALEY:  Thank you, Mr. Chairman and members of
	4	the committee.  I am pleased to be here today to discuss
	5	donor-deferral policies relating to males who have had sex
	6	with males even once since 1977.  My name is Dr. Rebecca
	7	Haley and I am the chief medical officer of the American Red
	8	Cross.
	9		Red Cross Blood Services is the nation's largest
10	supplier of components serving more than 3,000 hospitals

11	nationwide.  Last year, we collected more than 6 million
12	units of whole blood through the generous donations of
13	approximately 4.5 million healthy donors.

14		Each day, 22,000 donors visit one of the 400 Red
15	Cross blood-donation sites.  Approximately 1 million liters
16	of plasma are also recovered each year from our volunteer
17	blood donors and are processed into life-saving plasma
18	derivatives that are distributed to hospitals, hemophilia
19	treatment centers and other providers.
20		For more than 50 years, the Red Cross has been an

21	innovator and a leader in transfusion medicine and research. 
22	It is within this context that I am here to comment on the

23	MSM deferral period.  The purpose of the MSM question on the
24	blood-donor record form was and remains to identify risk
25	behaviors that pose a threat to the blood supply.

			257 1		Advances over the last fifteen years in viral
	2	testing methods have dramatically decreased the risks of
	3	transfusion-transmitted disease and extensive research has
	4	provided much more information about the early phases of HIV
	5	infection.
	6		Nucleic-acid test, better known as NAT, is now
	7	being implemented at the Red Cross under investigational new
	8	drug status and will further reduce the HIV and HCV window
	9	period.  There are two fundamental factors regarding this
10	national public health resource, the blood supply, which
11	must always be considered.
12		First, the safety of the blood supply and the
13	patients we ultimately serve much be our number-one policy. 
14	Second, it is a public-health issue not a social-policy
15	issues.  Their worst-case estimates of the impact of
16	modifying the MSM deferral criterion to a five-year period. 
17	At a previous workshop, the CDC suggested, and Dr. Dayton

18	reiterated here today, that approximately 60,000 previously
19	deferred individuals might donate blood annually.
20		From that particular pool, about 1,200 units HIV-
21	positive blood would enter the system for testing each year
22	on a CDC-based estimate of HIV prevalence of 2 percent,

23	which we just went over, in this population.  We cannot
24	change our procedures in a way that would result in
25	increased numbers of infectious donations in our blood

			258 1	supply.
	2		The FDA, the AABB and America's Blood Centers and
	3	the American Red Cross have, together, invested hundreds of
	4	millions of dollars and immense effort in reducing the risk
	5	to the nation's blood supply.  We have created one of the
	6	safest blood supplies in the world.  Introducing,
	7	theoretically, over 1,000 HIV-positive units into the system
	8	prior to testing would be expected to raise risk even
	9	considering our layers of safety from the blood-donor-record
10	questions to the current tests that screen HIV-positive
11	units out of the blood supply.
12		Modifying the MSM deferral criterion to five years
13	would result in a small, but measurable, increase in the
14	possibility that infectious blood might be released.  If the
15	Public Health Service could assure us that introducing
16	previously deferred donors into the pool could be
17	accommodated with out increasing the risk, the American Red
18	Cross would support appropriate action to do so.
19		The worst-case scenarios that were presented here
20	by Dr. Dayton would give back the realized gains by NAT in
21	the last year.  The American Red Cross supports the current
22	FDA and AABB comprehensive donor-questionnaire review. 

23	There are no current comprehensive studies related to
24	modifying these questions.
25		We believe that each of the 37 questions that

			259 1	relate to donor deferral should be systematically addressed
	2	regarding timeliness, relevance and, in relation to the
	3	current science and whether these questions properly
	4	complement each other based on our current biobehavioral
	5	research.
	6		We urge the Blood Products Advisory Committee to
	7	advance the behavioral, medical and technical research to
	8	appropriately evaluate all the questions asked of potential
	9	blood donors.  We urge the FDA to fully license NAT testing
10	as another means to reduce risk to our patients.
11		Until data are available to show that changing the
12	MSM deferral criterion will not elevate the risk to the
13	nation's blood supply, we cannot support this change.
14		Thank you for the opportunity to provide the views
15	of the American Red Cross on this public-health issue.
16		DR. HOLLINGER:  Thank you.

17		Any questions of Dr. Haley?
18		DR. SMITH:  My question to the American Red Cross
19	is, in terms of the questionnaire, would you expand the

20	questionnaire to include other risk behaviors that are
21	outside the MSM or the gay community, which is what our

22	point is?  Like risks should be treated alike, and, at this
23	time, they are not.
24		DR. HALEY:  Our questions for deferral are based
25	on data that were presented to the FDA by the CDC.  The

			260 1	practices that you are talking about and the population

	2	studies have not come up with an increased risk to the
	3	extent that this risk behavior does.
	4		So if the CDC were to come to the FDA and say, "I
	5	have a new practice and it is obvious that this is a high-

	6	risk practice, we need a question," we would be the first to
	7	accept that.
	8		DR. HOLLINGER:  Dr. Epstein?
	9		DR. EPSTEIN:  I appreciate being recognized.  I
10	just wanted to respond to Dr. Smith.  The FDA is certainly
11	willing and interested in improving the safety of the blood
12	supply by expanding deferrals as applicable for heterosexual
13	risk.  We simply think that it is two different issues.  If
14	we can make progress with respect to MSM risk, we will.  And
15	if we can make progress with respect to non-MSM risk, we
16	will.  So that is point one.
17		Second, on point two, treating comparable risks
18	comparably, I certainly agree with that.  However, there may
19	be a subtle misunderstanding that comparable behaviors
20	always connote comparable risks.  For example, we know very
21	well that the multiple-partner risk among heterosexuals is
22	quite different than the multiple-partner risk among gay men
23	for the very simple reason that gay men are at a much, much
24	higher HIV prevalence.
25		So, whereas I agree with the principle, we have to

			261 1	be a little bit careful not to equate the concept of
	2	comparable risk with comparable behavior.
	3		DR. HOLLINGER:  Thank you.
	4		Dr. Nelson?
	5		DR. NELSON:  I think that the one figure you cited
	6	would disturb me, too, if there were an additional 1,200
	7	HIV-positive prevalent cases introduced.  But I think that
	8	figure was a derivative--I am not sure that estimate is
	9	correct or even near correct.
10		Basically, I think, and Dr. Dayton can correct me,
11	it was based upon the 8 percent prevalence of men who have
12	sex with men 75 percent of whom know their status, 25
13	percent of whom don't.  But it wasn't based upon a man who
14	has not had sex with a man in the last five years, but prior
15	to that, as to what their prevalence would be.
16		I think that figure is not known.  I think it is
17	likely that it is much less than the overall prevalence,
18	maybe far less.  Am I misinterpreting Dr. Dayton's model?
19		DR. HALEY:  Our concern is we don't know that.  I
20	think if you figured this back over time, and Dr. Dayton can
21	comment on this, you would find the place where the risk

22	went to baseline that we have in every donor.  At that
23	point, we are ready.
24		DR. DAYTON:  You are correct in how we came up
25	with that number.  We didn't find data on prevalence rates

				262 1	on five-year abstention MSMs so we just used the best data
	2	we could find.  So you are absolutely right.
	3		DR. HALEY:  The other thing is we do have a
	4	penetrance of 5 percent in a lot of our communities that are
	5	giving blood.  I know we are not New York City but we have
	6	some other places that do, actually, have that high a
	7	penetrance of donors.
	8		DR. NELSON:  Prevalence?
	9		DR. HOLLINGER:  Could you respond again to that?
10		DR. HALEY:  I said the penetrance of donors into
11	the available population, not prevalence.  I am saying we

12	have 5 percent of some communities who give blood. 
13	Penetrance is what we call that--of blood donation into the
14	community of available donors.  I'm sorry.  I introduced a
15	new term.
16		DR. HOLLINGER:  Dr. Busch?
17		DR. BUSCH:  I think it was useful that you
18	summarized the numbers because I think I, personally, got
19	lost in the earlier presentation in terms of how we end up
20	with that incremental risk of potentially 1 to 2 additional
21	infections.  It does factor, from the 60,000 potential new
22	donors who will be eligible who had remote male-male sex
23	times the 2 percent which gives you that potential 1,200
24	incremental HIV-positive donations.
25		Then that gets multiplied by this potential error

			263 1	rate, particularly driven from hospital exposure which,
	2	theoretically, according to the analysis, results in one to
	3	two additional releasable units that would add to what we
	4	are saying, or only about ten currently per year, our
	5	current risk.
	6		So this worst-case scenario, again from one
	7	perspective, could argue that we would increase risk by 10
	8	or 20 percent.  I would agree that is almost comparable to
	9	what we have achieved through adding HIV NAT.  But I really,
10	personally, do not believe that we will see anything close
11	to a more than doubling of our HIV-positive rate were we to
12	relax this criterion.
13		I think these estimates are very conservative and,
14	applying a 2 percent rate to the people who will become
15	eligible, I think, 60,000 additional eligible people is an
16	over estimate, et cetera.
17		But your proposal that says wait until we have the
18	data, how do we get the data until we can do studies in the
19	context of revised questionnaires?  A proposal that says
20	wait until there is data to address these things is
21	basically saying don't address changing them ever because,
22	until we have a mechanism to implement studies--the
23	measurement is right there.
24		We implement it and if we don't see a significant
25	increment in HIV prevalence rate in our donors, then it says

			264 1	that there 1,200 estimate was just completely off the wall.
	2		DR. NELSON:  I would suggest that if--and I am not
	3	sure whether the committee will vote to change it, but if
	4	there are any changes in the donor questionnaire, that there
	5	really be a very active effort to look at the prevalence. 

	6	If there is a significant increase, that could be detected
	7	in probably a couple of months, that level of change.
	8		I suspect that there won't be, but that is just
	9	kind of a phase IV--it could almost be clinical trial,

10	although you can't do a clinical trial to find a negative
11	result.  So we would have to change and see what happens, I
12	suspect.  Ethically, it would be tough to sell this.
13		DR. HOLLINGER:  Dr. Dayton?
14		DR. DAYTON:  In theory, we could, if somebody had
15	the money, came up with the funding.  You could support a
16	population survey to actually survey MSMs and determine

17	their MSM behavior, which is no small feat.  The numbers we
18	are dealing with, you probably could get some numbers, and
19	whether that 2 percent, or 8 percent reduced to 2 percent,
20	is realistic or not.
21		So I think that actually is an addressable
22	problem, not today, obviously.  But, given the daunting
23	nature of a lot of the problems we face, I think that is one
24	of the easier problems to solve if there were funding.
25		DR. HOLLINGER:  Thank you, Dr. Haley.

			265 1		The next speaker is Dave Cavanaugh with the
	2	Committee of 10,000.
	3		              Presentation
	4		MR. CAVANAUGH:  If it okay with you, Mr. Chairman,
	5	I will just stay here.  I only have a few points, and that
	6	was a tough exchange to follow.  We are kind of in a tough
	7	position, too.  We are an AIDS organization.  We work a lot
	8	with groups representing the MSM population and plenty of
	9	others.  We know their desire to contribute to the health of
10	their peers.
11		We also don't want anything in the blood that
12	would come near the holocaust that we have already
13	experienced or anything like it.  So we are very interested
14	in the committee's deliberations on this issue.  We heard
15	the presentation that was given three years ago by Mr.
16	Dayton on this issue.  We had presented at that meeting and
17	felt that absolutely no change should be made without
18	serious study.
19		We were very surprised at some of the assumptions
20	that were made then and some of them have not been changed. 
21	We are pointing out, as others have this afternoon, that
22	assumptions regarding the size of the MSM population itself,
23	estimated at 4 million, some might say 11, the number who

24	have abstained for five years, which was fairly loosely
25	derived, the number who would be expected to come forward

			266 1	after not being able to help their peers for so many years
	2	being estimated at only the background rate for the general
	3	population, just to name a few, would be a considerable
	4	problem.
	5		And there are those who would give blood
	6	regardless of what the questionnaire asks them.  There is
	7	deliberate response to the questions wrongly by lots of
	8	populations, but those infected, in many ways.  We find that
	9	tagging and presenting data on those who turn out to have an
10	MSM background who are caught only by virtue of an HIV-
11	positive test underestimates the percentage of people who do
12	that because of all the HIV-negative ones that got through.
13		So, pointing to response to the questionnaire in
14	one case but not clearly looking at some of the data on
15	questionnaire responses, even now that we have got the U.K.
16	deferral question, now that we have the other questions
17	dealing with long-term abstention, seems to be a missing and
18	necessary part of this review.
19		We are very pleased to see the GLMA here to
20	present some of the perspective from a scientific standpoint
21	from the experience of the community and we wish there was
22	more of the questionnaire research community presented here,
23	too.  We are also kind of stunned by the lack of confidence
24	intervals, even though multiplying them does greatly
25	increase the variability of the estimates.  That has to be

			267 1	done anyway.
	2		As I said, tossing out the number 11 million and
	3	saying maybe--let's just say that the percent coming forward
	4	is the same, the percent abstaining for five years is the
	5	same, but what about the number coming forward not being
	6	62,000 but 162,000.  The HIV rates therein could be all over
	7	the map.
	8		Now, we are concerned about identifying the group,
	9	not the behavior.  Anyone, male or female, engaged in risk
10	behavior should be deferred appropriately.  We would refer
11	you to Ms. Smith's suggestions as to how to do that.  A
12	sexual history is really what you want rather than, "Do you
13	self-identify with a certain behavior?"
14		Anybody who has worked with Hispanics knows that
15	identification of MSM behavior is very difficult.  Other
16	methods are needed rather than just tagging with a label.
17		Supply; to back up a little bit, the point of this
18	exercise is to increase the supply.  Supply can be increased
19	in many other ways and much further than by admitting
20	potentially high-risk groups.  High-risk donors may carry
21	other risks not yet identified.  We need data on cumulative
22	exposure to pathogens.  We have concerns about what was
23	presented this afternoon about HHV-8.
24		In general, we would encourage the committee to
25	proceed very carefully with this.  We note that the question

				268 1	is worded, "Should the FDA consider."  We have no quarrel

	2	with that.  Consideration is actually what this needs, a
	3	much brighter spotlight on the question.
	4		Thank you.
	5		DR. HOLLINGER:  Thank you.  Any questions to Mr.
	6	Cavanaugh?  Celso?  I didn't have you on here, but that is
	7	all right.  You can get up and speak if you want.  You
	8	should have been on here.  I just didn't have it before me

	9	here.  Sorry about that.  Dr. Bianco for the America's Blood
10	Centers.
11			            Presentation
12		DR. BIANCO:  I exist.  America's Blood Centers, or
13	ABC, is an association of 75 not-for-profit community-based
14	blood centers that collect nearly half of the U.S. blood
15	supply from volunteer blood donors.  We thank FDA, CBER, for
16	the opportunity to make public comments before the Blood
17	Products Advisory Committee.
18		ABC members urge FDA to modify the current
19	lifetime deferral of men who have sex with men since 1977

20	from donating blood.  We believe science supports limiting
21	deferral to a year to make it consistent with other
22	deferrals related to risk behavior; for example, sexual
23	contact with a prostitute.
24		ABC members have expressed this position before
25	BPAC and at FDA-sponsored workshops.  The lifetime MSM was

			269 1	introduced in the early '80's when little was known about

	2	the epidemiology of HIV and the screening assays required
	3	further refinement.  ABC members are comfortable with this
	4	recommendation because the last 17 years of donor health
	5	history and fifteen years of laboratory screening have seen
	6	major changes.
	7		Donors receive clear and unambiguous information

	8	about risk behavior, HIV transmission and why they would not
	9	donate to obtain an HIV test results.  Individuals with one
10	HIV-positive test in their lifetimes are permanently
11	deferred.  Medical history became more rigorous with direct
12	questions about risk behaviors, venereal diseases, contact
13	with individuals with infectious diseases, use of I.V.
14	drugs, and so on.
15		More important, significant technological
16	developments led to a reduction of the window period for HIV
17	assays from an average of 56 days at the beginning of HIV

18	testing to an average of eleven days with the introduction
19	of NAT.  There is evidence from animal models that this

20	window is even shorter, and we heard this from Dr. Busch
21	today.
22		ABC members are concerned about the unintended
23	consequences of the current deferral criteria for MSM,
24	lifetime deferral for a man who had sex with another man

25	once, even once, since 1977.  The question focuses attention

			270 1	on events that took place more than twenty years ago instead
	2	of events that occurred within the currently known window
	3	period of days or weeks.
	4		Donors may repress or deny these old events.  The
	5	question is inconsistent with similar risk behaviors that
	6	are deferred for one year.  The logic of the current
	7	deferral is difficult to justify because risk of exposure to
	8	HIV and other infectious diseases is associated with
	9	behavior, not sexual preference.
10		Individuals who respond affirmatively to risk-
11	behavior questions use confidential unit exclusion, use
12	post-donation callback, and they do not present additional
13	risk to the blood supply because they are deferred,
14	permanently or temporarily.  I didn't put in the statement,
15	those who do not reveal risk during medical history and have
16	risk will not change regardless of the changes that we make
17	in questionnaires or in what we do.
18		Obviously, individuals who indicate that they had
19	a positive HIV test in the past are deferred permanently. 
20	Actually, this assumption that has been discussed and the
21	1,200 HIV-positive individuals that could potentially donate
22	is an assumption that is made assuming that 100 percent of
23	those individuals will come and they will pass through
24	medical history, they will pass through the entire screening
25	system, which many of them do not pass today.

			271 1		So I, again, do not believe that this number--I
	2	believe that the number is at least an order of magnitude
	3	smaller than that.  Medical history can be improved in order
	4	to become more effective.  We are happy to note that an AABB
	5	task force with participation of ABC, FDA, ARC and other
	6	organizations is addressing this issue.
	7		In our opinion, the change in deferral will not
	8	increase risk.  Thus, we request that FDA modify the current
	9	lifetime deferral of males who have had sex with males since
10	1977 from donating blood to a one-year deferral.
11		Thank you.
12		DR. HOLLINGER:  Thank you, Celso.  Any questions
13	for Dr. Bianco?
14		We have one final person who asked to speak.  It
15	is not specifically this topic, but it was earlier today and
16	he was promised that he would be given a position.  So we

17	are going to do that.  Derrick Robertson for the Hemophilia
18	Treatment Center.
19		              Presentation
20		MR. ROBERTSON:  Good afternoon, Mr. Chairman and
21	members of the committee.  Thank you very much for allowing
22	me this time to present to you.  I am especially
23	appreciative since this is somewhat off the topic which is
24	under consideration currently.
25		My name is Derrick Robertson and I represent

			272 1	fifteen hemophilia treatment centers across the country.  We
	2	are particularly concerned about the current supply
	3	situation or recombinant Factor VIII products.  This
	4	situation is reaching critical levels as we speak with
	5	centers not being able to get product as they would normally
	6	be able to.
	7		We have centers that are down to four vials for

	8	recombinant product and they are having to take steps to
	9	switch patients from recombinant product back to plasma-
10	derived products.  We have centers that are changing
11	treatment protocols and this is very concerning.

12		There are a number of events that have taken place
13	over the past few months which we feel has contributed to
14	this situation.  Genetics Institute, who recently got a
15	product licensed, Refracto, by the FDA has decided that they
16	will not be able to bring that product to the U.S. market
17	until sometime in 2001.  Baxter Hyland Immuno has had
18	difficulties in getting a new suite license and that has
19	limited their supply.
20		Bayer has decided to launch its newly approved
21	product through a direct marketing program and we are not
22	sure exactly what the availability of the Aventis product is
23	going to be in the coming weeks.
24		We are particularly concerned with the Bayer
25	direct program which is going to be launched because we feel

			273 1	that that will exacerbate the supply situation in two major
	2	ways.  The program, as it has been outlined, intends to
	3	allocate to specific patients specific amounts of product to
	4	the exclusion of those that are not able to enroll due to
	5	the limited availability that Bayer may have.
	6		This we feel might create a situation where
	7	product is allocated to one particular patient where there
	8	is another patient who would need product but is not able to
	9	get it.  The second way we feel this will adversely affect
10	supply relates to the inpatient market.  Bayer direct, as

11	proposed, does not intend to sell to hospitals and we feel
12	that that is going to put an added burden on the other

13	manufacturers to make sure that large hospitals have a
14	supply of clotting factor.
15		As you are aware, in the treatment of hemophilia,
16	it is extremely important to treat the bleeds as quickly as
17	possible.  We do not want to have a situation where patients
18	end up in an emergency room or in a hospital and are not

19	able to get immediate treatment because they do not have
20	product.
21		While it might seem that the hospitals may have
22	other alternatives to go to, over the years, the market for
23	recombinant product has always fluctuated.  One thing that

24	has become clear is that we need all the manufacturers to be
25	participating in the marketplace so that there is some

			274 1	amount of product available for everybody.
	2		We are concerned that if one manufacturer is not
	3	doing its part to be a part of the supply, that that will
	4	adversely affect the situation.  We are concerned about what
	5	will happen if this does continue in this way.  We are
	6	concerned that patients will be forced to go back to plasma-
	7	derived products which will go against a 1995 recommendation
	8	by the National Hemophilia Foundation's Medical and
	9	Scientific Advisory Council which recommended recombinant
10	treatment, a recommendation which was endorsed by the Public
11	Health Safety Blood Safety and Availability Committee.

12		We are asking that this committee look at this
13	issue to make sure that if, indeed, there is a shortage,
14	that this is a real shortage and that there is not product

15	out there in the distribution channels that are somehow not
16	getting to the patients or, if the product is tied up with
17	the manufacturers, that the FDA work with these
18	manufacturers to expedite this product getting into the
19	marketplace.
20		I think another critical thing for the FDA to look
21	at and understand is the decision-making process that goes
22	into deciding how much product is coming into the U.S.
23	market vis-a-vis the international marketplace. 
24	Understanding that will probably give a better determination
25	and an understanding of how much product will be available

			275 1	and when it is available.
	2		We do not want to go back to a situation--even

	3	though the plasma-derived products have had an excellent
	4	record over the past many years, I think it is of concern,
	5	especially to the new patients, not to have to go back to a
	6	plasma-derived product.
	7		Again, I thank you for your time and I am
	8	extremely appreciative for giving me this opportunity to
	9	present our position.  Thank you very much.
10		DR. HOLLINGER:  Thank you, Derrick.
11		We are going to move back to the topic at hand. 
12	Before we close the open public hearing, is there someone
13	else that would like to say a word?  Yes?  Please give your
14	name.
15		              Presentation

16		DR. JACKMAN:  My name is Dennis Jackman.  I am the
17	Executive Director for the Plasma Protein Therapeutics
18	Association for North America.  I wanted to take a moment

19	here to address the questions about recombinant supply,
20	Factor VIII supply.
21		First, I would like to state that the industry is
22	working diligently to meet the needs of consumers and

23	medical professionals recombinant factor VIII.  We are
24	concerned about making sure there is adequate supply to meet
25	those needs.

			276 1		We want to state that, over the longer-term
	2	period, supply has remained relatively steady or, in some
	3	cases, improved in certain months with periodic variation. 
	4	We do recognize there is some variation right now during
	5	this period and we also recognize that demand is increasing. 
	6	I actually have a chart that could be shown on an overhead,

	7	if we had a moment, that would show the supply for the last
	8	eighteen months.  But, in any case, it shows a relatively
	9	steady situation and we know that, right now, we have a
10	tightening situation as well.
11		But investments have resulted in recent increased
12	capacity and new formulations.  First of all, Baxter's
13	Thousand Oaks facility was approved earlier.  That increased
14	their capacity by up to 40 percent.  That helped the supply
15	situation.  Bayer's new formulation was approved as well--
16	that is Cogenate FS.  That has increased the overall supply
17	of factor in the U.S. market as well.
18		Baxter is working diligently to try to get
19	approval of a new suite which will also increase the supply
20	of recombinant factor VIII.  All those things combined
21	ultimately will have a result of improving the supply
22	situation and ameliorating the situation over the long term.
23		We also cannot forget that we do have high-quality
24	plasma-derived products available as well for those patients
25	who want to utilize them.

				277 1		Thank you very much.
	2		DR. HOLLINGER:  Thank you.
	3		If there are no other comments on the MSM topic,
	4	then we are going to close the open public hearings for
	5	right now and open this up to the committee discussion.
	6		Committee Discussion and Recommendations
	7		DR. HOLLINGER:  Who would like to start out?  Dr.
	8	Linden?
	9		DR. LINDEN:  A couple of things.  One is that in
10	the model that Dr. Dayton presented, it seemed like the vast
11	majority of the risk was attributed to post-analytical or

12	release errors.  One way to potentially get around that
13	would be if people could basically get pre-screened before
14	the donation so you would have two tests rather than one.
15		I was wondering if Drs. Bianco, Haley and Katz
16	could, perhaps, comment on the idea of pre-screening and
17	whether that is anything that could be feasible.
18		DR. HOLLINGER:  Yes; I think these are important
19	questions.  The issue would be of asking a question to

20	individuals, have you ever had sex with another male ever---
21	one of the "ever" questions--and then go on from there about
22	some timing if you want, but the question is, if they have,
23	and they fit into that time span, if there is a time span

24	that is chosen, then one issue would be to screen them and
25	then have them come back at another time if they are

			278 1	negative for donation, similar to what, perhaps, is done in
	2	the plasma industry and other things.
	3		So would somebody like to take on this issue
	4	because it could be an important issue.
	5		DR. KATZ:  We could talk about this for hours. 
	6	The source-plasma industry has done this as part of their
	7	quality plasma program in a certain sense with a 60-day hold
	8	to make sure that people come back, a high percentage then
	9	been retested before anything is released.
10		Whole-blood collection these days is done in some
11	fixed sites but lots and lots on mobiles, at corporations
12	and elsewhere.  So the logistics of a separate visit to give
13	us a sample, be tested and then, at subsequent visits, at

14	whatever intervals, which may be as long as six months or a
15	year, have always been considered daunting and it has not
16	met with great favor.
17		To say it is impossible I think would be wrong,
18	but I do not think it would positively impact the adequacy
19	of the blood supply to essentially not draw donors at their
20	first presentation.
21		DR. HOLLINGER:  Dr. Haley?
22		DR. HALEY:  I think this has both merit and
23	difficulty attached.  This might be the form of the study
24	that we keep talking about.  When we keep batting back and
25	forth, well, is this the rate, isn't this the rate, that

			279 1	would certainly answer the question.
	2		The other objection to singling out and
	3	identifying these donors as labeled or different might,
	4	certainly, be valid if we had a group of donors that we drew
	5	and a group of donors that we took a tube on in a mobile
	6	unit.
	7		Again, with the right kind of situation, we might
	8	be able to overcome that.  I think that our electronic
	9	control of donor records may be sufficient that we could
10	probably handle, with some planning and some timing, being
11	able to test a sample and then be able to mark a record as
12	"MSM tested, okay."
13		It is certainly an interesting thought.
14		DR. BOYLE:  Dr. Linden, I think that concept has
15	been raised on a couple of occasions but I just want to
16	remind you that approximately 85 percent of the blood donors
17	are repeat donors so they are in that process.  They have
18	been screened before.  They come back.  Actually, one of the
19	efforts that we have in medical history is not to torture

20	them again with all these sets of questions in the same way
21	that we do today every time they come back.
22		The second thing is, in terms of logistics, those
23	donors donate approximately 1.5 to 2 times a year, on
24	average, so that makes it a logistic problem.  So we have
25	about 15 percent of the donors that are first-time donors

				280 1	that we try to attract into the donor base with the intent
	2	of replacing the donors in the pipeline that will get old,
	3	sick or will abandon the idea of donating.
	4		So, essentially, the vast majority of the blood
	5	donors are repeat donors.  They are continuously screened. 
	6	I think that is the essence of the safety.  Actually, Dr.
	7	Dayton, maybe we could divide these by 6 again because only
	8	15 percent of what is added every year are first-time
	9	donors.
10		DR. NELSON:  But, Celso, isn't it true that if you
11	change the criteria for people who didn't meet the criteria
12	before, they will all be first-time donors the first time

13	they donate.
14		DR. BIANCO:  Yes, but the number of first-time
15	donors will increase from 15 to 17 percent or 18 percent. 
16	But, overall, the change in the donor base is going to be
17	small.

18		DR. NELSON:  No; but I think it is this population
19	that we are concerned about; right?  The 60,000 are the ones
20	we are concerned about.
21		DR. BIANCO:  No; it is the 1,200.
22		DR. NELSON:  Yes; it is the proportion of the--

23		DR. BIANCO:  That is correct.  That would come in
24	the first year.  That would be part of the first-time
25	donors.  But they would be diluted again in the overall.

				281 1		DR. HOLLINGER:  Dr. Smith, would you like to

	2	respond to that, about how you think the gay or lesbian
	3	community would--is she here still?  I guess she is not
	4	here.
	5		Dr. Linden?

	6		DR. LINDEN:  On a different issue, the issue that
	7	Dr. Nelson raised about the prevalence in the people, men

	8	who haven't had sex with another man in five years versus
	9	the overall population, could somebody from FDA or CDC
10	comment?  My recollection is that, at the CDC meeting a few
11	months ago, there were data presented on remote risks and my
12	recollection is it was still quite high.
13		Was that consistent with the figures that you
14	used, Dr. Dayton, in your model or am I completely
15	misremembering that meeting?
16		DR. DAYTON:  Maybe somebody else went to that
17	meeting because I was not there.  Anybody else from FDA?
18		DR. LINDEN:  Dr. McCurdy agrees with my
19	recollection.
20		DR. SIMON:  I don't have the exact numbers, but I
21	think they were pushed, the CDC speakers were pushed, if
22	there was a group with remote risk that had lower
23	prevalence.  I think the issue was they didn't have such a
24	group, they had no group in their studies of MSMs that had
25	the kind of extremely low prevalence, but they didn't have a

			282 1	sizeable group, as I recall, that was remote enough, I
	2	think, to answer this question.
	3		DR. NELSON:  I think this group with the remote--
	4	sex with another man--can be very heterogeneous.  Two sort
	5	of outlyers, if you will, were, a), an adolescent or young
	6	adult who is experimenting and does not continue having sex
	7	with me.  Another type of population would be one--a person
	8	who is in prison or is an all male situation where sex
	9	occurs.  I would suspect that the risk would be different in
10	those two.
11		DR. HOLLINGER:  Dr. Epstein?
12		DR. EPSTEIN:  I can't recall specifically those

13	data from the Atlanta meeting, but we do know that persons
14	with remote risk of intravenous-drug abuse have a markedly
15	higher prevalence of certain markers including hepatitis C
16	than persons negative for that history.
17		So there is every reason to believe that, for

18	chronic blood-borne infections, remote risks do matter.
19		DR. NELSON:  But I am not sure about the

20	adolescent.  I think that is a different situation.
21		DR. HOLLINGER:  Dr. Chamberland?
22		DR. CHAMBERLAND:  Mine was more of an overarching
23	comment following Dr. Linden's query about trying to, I
24	guess, sort of evaluate certain parameters in the model that
25	FDA has developed.  Again, certainly with deference to the

			283 1	statistical consultants that sit on the committee, if FDA

	2	wants to continue using this model as a framework for the
	3	discussion, and I think that is a very valid thing to do--I
	4	am not being critical of using a modeling approach, but my
	5	sense is that what you can do in these sensitivity analyses

	6	that have been put forward is that you can actually use them
	7	to assist you in determining which factors in the model
	8	exert the most influence on outcome.
	9		If you could pull out of the model--I think, right
10	now, there is a lot of confusion--not confusion, but people
11	are bringing up a lot of questions about either the
12	derivation of these estimates, their reliability, et cetera. 
13	So if you could do a sensitivity analysis of each of these

14	factors in the model and maybe, as I said, it could point
15	you in the direction as to what is influencing this risk
16	estimate the most, maybe that at least could pare down

17	whatever studies or research that you might need to pursue
18	to get a better handle on it.
19		It has been presented as a large black box, but
20	maybe it is actually just a couple of parameters that are
21	really going to drive this.
22		I will, as I said, defer to the statisticians to
23	help me clarify that, perhaps, a little bit better.

24		DR. McGEE:  Personally, I think the whole analysis
25	is driven by two numbers, the 1.4 million--this is my

			284 1	intuition and you can disagree if you like--and the other is
	2	this assumption of prevalence and then the proportion who
	3	self-defer.  So they decreased from an 8 percent prevalence
	4	to a 2 percent who would actually go in and donate.
	5		You can see immediately that if it were really

	6	three-quarters who came in, you would multiply the risk
	7	estimates by 3.  So I think those two numbers need to be
	8	pinned down.
	9		DR. HOLLINGER:  Dr. Simon?
10		DR. SIMON:  I will just try to say a couple of

11	words to kind of bring together the industry point of view. 
12	I guess, as you have gathered, the blood bankers are divided
13	between the position brought to us by the American Red Cross
14	of not changing and sticking with a deferral of anyone since
15	1977 and the other group has suggested the one year which
16	gets to the like risk being treated like, and that is the
17	12-month period to cover all your various windows with the
18	testing.
19		I think the FDA has tried to come in between those
20	two, and I would actually speak for that approach, or at
21	least for the approach of the question, because Dr. Epstein,
22	I think eloquently, spoke to this issue at the CDC
23	conference about the differences between incidence risks and
24	prevalence risks and the concern about drawing from a high
25	prevalence population.

			285 1		So, from that point of view, one would want to go
	2	beyond the twelve months which we apply for the incidence 
	3	risks to something that would also pick up the prevalence. 
	4	I think the five years is a reasonably good compromise that
	5	I think, intuitively, should protect us safetywise.
	6		From the point of view of the plasma industry, I
	7	think there is less feeling that this is going to make a
	8	significant difference in our number of donors.  But I
	9	believe the plasma industry would go along with the change
10	to five years.  Of course, as has been pointed out with the
11	applicant donor program and the inventory hold, we have
12	dealt with almost all of the potential release problems, so
13	that issue doesn't figure in in terms of test error.  I
14	think one can be more reliant on the test results to pick up
15	any window case.
16		So I think if you put the whole thing together,

17	and I know there has been a lot of talk about Dr. Dayton's
18	model--I accept that it is flawed, but I think the problem
19	is it is hard to get much better in terms of numbers or in
20	terms of data that can support a position.  I think, given
21	all the data presented by Dr. Busch, I think the model,
22	taking some conservative estimates, the weight of all the
23	information that we have indicates that safety will not be
24	significantly impaired at all by going to the five year.
25		I would speak for that as I think a reasonable

			286 1	approach to the issue.  I think it would achieve the
	2	concordance between the tissue regs and the blood
	3	regulations which I think would be very useful, to have a
	4	single standard.
	5		I think that it preserves safety and moves us
	6	along in the right direction and, perhaps, some small number
	7	of individuals who do not present a risk would now be able
	8	to donate and contribute.
	9		DR. HOLLINGER:  I would like, for just a minute,
10	if I could, get a feeling from the committee at this stage
11	so I see sort of where we are a little bit.  I am not going
12	to shut off discussion but I would just like to know.  I
13	would like to know how many on the committee here, at least
14	at this point, are in favor of a change in the current--I am
15	not going to deal with five years, four years, three years,
16	two years, one year and so on or anything like this, but how
17	many people here on the committee so far feel that there
18	should be a change in the question from having sex even once
19	back through 1997.
20		I would like to see how many are in favor of at
21	least making a change in that question.  If you would just
22	give me a feel.
23		[Show of hands.]
24		DR. HOLLINGER:  Okay.  So a fair number.  It looks
25	like the majority are.  I wanted to start with that because,

			287 1	if so, then--I don't want us to get bogged down in maybe
	2	five years or three years or one year as the question.  The
	3	question states one thing, but it looks like the majority of
	4	the committee are certainly willing to have this question
	5	changed.
	6		Now I would like to sort of open it up either way,
	7	with comments for and against, but other things, too.  So I
	8	am going to start with Paul McCurdy and then come back here
	9	with John.
10		DR. McCURDY:  When this issue came before the

11	committee in 1997, I was in favor of making a change,
12	thinking that either two or five years might be quite
13	acceptable and would not result in an issue.

14		In the meantime, however, the HHV-8 situation has
15	come to the fore and it is my belief, at this point, that
16	the HIV question and all the modeling that has been done on
17	that is basically irrelevant, that the issue now is HHV-8. 
18	As Dr. Pellett said at the close of his presentation, we
19	just don't know about that.
20		There have been a couple of statements made, one

21	of which is that the absence of evidence is not evidence for
22	absence.  I think the data that do not indicate transmission
23	are really relatively few on which to base a decision.
24		I think that another situation, my recollection is
25	that the approach that he took to whether or not HHV-8 could

			288 1	be transmitted by blood carried about the same amount of
	2	evidence that rang very, very similar to what was presented
	3	in 1982 and 1983 about what turned out to be HIV infection
	4	and blood transfusion.
	5		Finally, I think HHV-8 poses the greatest risk for
	6	immunocompromised patients.  I think it is worthwhile
	7	considering that there is a rather small class of patients
	8	that are routinely immunocompromised and for whom an
	9	infection with HHV-8 could be devastating, and that is the
10	premature infant who receives, often, a number of donor
11	exposures as a result of various different testing
12	procedures and their immature hemopoietic system as well.
13		So I am opposed, at the present time, to any
14	change until we have settled, or at least gathered
15	considerably more evidence about what HHV-8, what the risk
16	and what the situation is with that.
17		DR. HOLLINGER:  Once again, along these same
18	lines, Paul, again, and perhaps, Mike, you could again help
19	me with this, the highest prevalence is in what groups,

20	again, so far--I know there is a lot of data that still
21	needs to be done, but, so far, where does the highest
22	prevalence seem to be located?

23		I know you talked about injection-drug users and
24	so on, but--
25		DR. BUSCH:  HHV-8 seroprevalence rates run around

			289 1	20 to 30 percent in most studies of gay men with much higher
	2	rates in HIV-infected gay men.  I think a couple of points;
	3	one is, as Phil pointed out, it is the HIV-infected gay men
	4	in whom people can detect viremia.  You need to have
	5	immunosuppression as well as HIV, HHV-8, infection not only
	6	to manifest disease but to have viremia.
	7		So, at least in the studies that have been done,
	8	you can't detect circulating virus in HHV-8 seropositive gay
	9	men who are not HIV infected.  I disagree with Paul.  I
10	think HHV-8 is a very--one, I think the evidence is pretty
11	compelling that it is not transfusion-transmitted from the
12	epidemiology that, at a time when there was high prevalence
13	not only of HIV but HHV-8 in the donor pool, there were high
14	rates of HIV transmission to hemophiliacs and to recipients,
15	and yet there is no KS.
16		There is no HHV-8 infection in these individuals
17	who acquired HIV from transfusion.  I think that broader

18	epidemiology is much more powerful than the limited number
19	of direct transmission cases that have been studies which
20	only number about 30.  So I think the epidemiology is, to
21	me, strongly against transfusion transmission of HHV-8.

22		In addition, the storage effect is a major impact
23	on non-transmission.  Again, the attributable risk of male-
24	male donor pool changes--if there is HHV-8 in the blood
25	supply and 1 percent of our donors are infected, we would be

				290 1	screening the blood supply for HHV-8.
	2		The contribution of male-male sex-donor prevalence
	3	is small because they represent a small fraction of the
	4	donor pool, if there is a problem which, personally, I don't
	5	think there is.
	6		DR. HOLLINGER:  Mike, you are saying that it
	7	appears to be mostly in the PBMCs or PBSs; is that correct?
	8		DR. BUSCH:  It is a b-lymphocyte-associated virus.
	9		DR. HOLLINGER:  Would leukoreduction make a
10	difference?
11		DR. BUSCH:  Yes; it certainly would.  If there is
12	a transmission effect, it would make a difference.  Again,
13	only a small fraction of HHV-8 seropositive people are
14	circulating virus and those tend to be immunosuppressed HIV-
15	infected people.
16		DR. McCURDY:  The only thing is that HIV is
17	transmitted by virtually any blood component and any of the
18	derivatives that was not virally inactivated whereas HHV-8
19	would probably be transmitted only by white-cell-bearing

20	components and those that are relatively fresh, primarily,
21	perhaps, platelets, for example, which are fairly fresh and
22	are not inactivated, or they do have white cells.
23		DR. HOLLINGER:  Do we know if there is any in
24	platelets?  I hadn't heard anything that says that HHV-8 is
25	found in platelets.

			291 1		DR. McCURDY:  It might be found in the peripheral
	2	blood mononuclear cells that are in platelets.  There are

	3	fewer in the current platelet concentrates, particularly
	4	those that are obtained by pheresis but, on the other hand,
	5	I think they are there.
	6		DR. HOLLINGER:  Dr. Boyle?
	7		DR. BOYLE:  Thank you.  Let me tell you what

	8	concerns me, and I have no objection to changes in the
	9	questionnaire that would make it better.  This morning, we
10	heard a presentation where we were presented a lot of
11	information which made a fairly easy choice about changes in
12	the safety system.  In that case, it was the testing
13	standards.
14		This afternoon, we are presented with another
15	change and another aspect of the safety system with donor--
16	in this case, it is donor screening--and, although there was
17	quantification of what could be quantified, the core
18	assumptions were just that; assumptions.  There was really
19	no evidence.
20		So I was a little disturbed about being asked to
21	choose between something that we could say with a fair bit
22	of assurity was between the size of a bread box and a barn. 
23	But that doesn't bother me as much as the two pieces which
24	is if we are starting to move down the road towards non-

25	evidence-based or differential-evidence-based decisions on

			292 1	things like donor screening, and I hear presentations that
	2	some people in the industry would like to move to a one-year
	3	standard and there is a lot of research literature that says
	4	past-year prevalence of risky behavior is way under
	5	reported, that I get very, very concerned that we will be
	6	deciding that issue down the line without the evidence put
	7	forward.
	8		Moreover, the statements that I hear that we don't
	9	have this information, we couldn't get this information--I'm
10	sorry; it is a lot cheaper and easier to test reliability
11	and validity of survey instruments than it is to do a lot of
12	these biological markers that you are dealing with.
13		I am just concerned where we are going.  So, in
14	the beginning, until we got to a certain point, I was
15	probably just going to abstain for lack of information. 
16	Because I don't think there is enough information to make a
17	decision at this point in time because what I am concerned
18	with as a direction, I will oppose this.

19		DR. HOLLINGER:  Thank you, John.
20		Dr. Chamberland?
21		DR. CHAMBERLAND:  A couple of things.  When you
22	asked us if we were open to considering changing the MSM
23	deferral question, I did indicate yes because I am open to
24	that.  However, just a couple of thoughts about the

25	information and what we know to push us in one direction or

			293 1	another that we have at the moment.
	2		I will reiterate that I think, because FDA has

	3	chosen to use a model-based approach for the committee to
	4	consider, that I, for one, would like to see the model
	5	expanded or amplified in some of the ways that the other
	6	committee members have spoken to and to see if there can be
	7	any more statistical rigor or robustness brought to the
	8	model, or at least point us in a direction, as I said, of

	9	what factors seem to be influencing it because I do think
10	that people are sort of responding to this, your bottom
11	line, which is this very, very low, one or less than one,
12	additional unit or donation that would enter the supply
13	annually.
14		So I think it would be actually a more fair

15	estimate if we had at least some range of what that might be
16	and the parameters around that.
17		Be that as it may, I think all of us that have
18	heard the data this morning about the nucleic-acid-testing
19	data I think have to have a lot of confidence that, with the
20	advances in testing that we have seen, that contributions to
21	safety have been tremendous in that my gut tells me that,
22	even if this deferral period was going to be changed in some
23	way, it would not really--the testing is that good that we
24	probably are going to cap the incidence-prevalence arguments
25	that have been put forward could probably be adequately

			294 1	addressed.
	2		An additional concern that I have, though, is one
	3	that Paul McCurdy started to articulate.  I use HHV-8 sort
	4	of as an example or a bookmark or a flag, whatever you want
	5	to call it.  My personal feeling is that it is uncertain if
	6	HHV-8 is transmitted in the blood supply based on what we
	7	know.
	8		I think it is possible.  I do, though, agree with
	9	Mike Busch that I can't believe that it is happening in any
10	large extent, that it is something that we would have picked
11	up by this time.  But that doesn't preclude that it may
12	happen occasionally, and I can't quantify that in any way.
13		But I think, clearly, there are more studies that
14	can be done.  I think HHV-8 is just kind of a reminder out
15	there that certain risk behaviors would not--changing the
16	deferral to a floating five-year exclusion would not
17	necessarily protect the supply, the blood supply, from other
18	infectious agents that we know about, don't know about.
19		Most of our discussion today is focussed on those
20	that we know about and have really good tests to detect.  It
21	is a bit of a gamble because you don't know which population
22	is going to be affected by the next emerging agent.  It
23	could be, as it was, pig farmers in Malaysia that
24	experienced significant morbidity and mortality or other
25	agents, so it is a bit of a crap shoot.

			295 1		In totally agree with the other comments.  It is
	2	very crude to say it is the MSM population.  We all know it
	3	is a subset of the MSM population as it is a subset of
	4	heterosexuals, et cetera.
	5		Unfortunately, the questionnaire that we have been
	6	using is just very crude at getting at that.  I do think it
	7	is amenable to study but I think, John, do not--I don't
	8	think that this task force that had been put together, which
	9	is very good--it doesn't have resources and tools to set up
10	the very careful studies that would be needed to be done if
11	you wanted to evaluate different ways to ask a question or
12	do population-based surveys of MSMs and find out additional
13	information.
14		I am open to changing the question, but I,
15	personally, don't have all the information at hand to do it.
16		DR. HOLLINGER:  Dr. McGee?
17		DR. McGEE:  I just wanted to say that my
18	indication that I wouldn't vote was not that I wasn't

19	interested in changing the question but that nobody has
20	offered me a set of criteria that I could use to judge how
21	to make that decision.
22		If I just accept the FDA, we get a 20 percent

23	increase in the risk.  I think somebody threw out that
24	number.  That is a sizeable increase in risk for a minor

25	increase in the donor pool.  At any rate, nobody has offered

			296 1	me yet what I would consider a criteria that I could base
	2	judgement on.
	3		DR. HOLLINGER:  Dr. Mitchell?
	4		DR. MITCHELL:  I think I approach this from, well,
	5	several points of view.  But the main thing is that the
	6	current criteria of having MSM contact since 1977, on its
	7	face, seems very discriminatory and it seems very arbitrary. 
	8	And so I feel very strongly that it needs to be changed.
	9		Now, the question is what does it need to be
10	changed to?  I think that a lot of the things that we were

11	presented today were, again, very, very conservative, very,
12	very high estimates of risk.  Again, we know that in the

13	overall blood-donation population, that the risk is much
14	lower than the overall population for a number of different
15	conditions.
16		I would expect that it would also be the same for
17	the MSM population.  We know that, again, if somebody is not
18	practicing male sex on a regular basis, or in five years, or
19	have been abstinent--anybody who has been abstinent for a
20	number of years is going to have lower risk than the general
21	population of sexually active people.
22		So I think that, even using the 2 percent estimate
23	is much, much too great.  But the question is what should

24	the number be, and I certainly don't have that number.  I
25	think it would be difficult to get that number.

			297 1		Part of what I am basing this on is also the 1997
	2	presentation and other presentations from the REDS study.  I
	3	wish that we had had more data on the population from the
	4	REDS study.  As I remember, the population that did donate,
	5	in fact, were people who did not consider themselves to be

	6	gay or bisexual.  Oftentimes, if they were men, they were
	7	married and there were a number of women.
	8		So I think that if you change this, you are not
	9	going to get the higher-risk population.  I think that a

10	one-year time period is a reasonable time period and I think
11	that that will turn out to be a reasonable time period.
12		I don't think that we have had the evidence to
13	support that--I don't know that it has been specific enough,
14	the things that were presented today, to make that
15	determination.  But I think that a two- to five-year--to me,
16	the weight of the evidence is clear enough that a two- to
17	five-year deferral would be reasonable.
18		DR. HOLLINGER:  Ms. Knowles?
19		MS. KNOWLES:  I support the change, but I think
20	this goes hand-in-hand with updating the panel questionnaire
21	and really focusing in on behavior irregardless of sexual

22	orientation because of exactly what you just said, Mark.  I
23	mean, there are people who are engaging in high-risk
24	behaviors who may not self-identify as being MSM.
25		DR. HOLLINGER:  I need to just take a moment. 

			298 1	Colonel Fitzpatrick also sent something, a comment, and he

	2	asked if we would read it into the record and I need to do
	3	that.  So if you will bear with me while I read his
	4	comments, I would appreciate it.
	5		This is on this issue here and I presume, if he
	6	were here, he would have said this very thing.  It says,

	7	"While the statistical data supports reduction, I am
	8	concerned about the logic for requesting it.  One of the
	9	reasons offered by the FDA is to bring deferrals for semen,
10	tissue and blood donors into agreement.  There are a number
11	of other deferrals for high-risk behavior.  I.V. drug use
12	even once; that is a permanent deferral.  Sharing needles
13	even once, such as for steroids, which is not a high-risk
14	population; permanent deferral.

15		"Yet we only ask about the following behaviors for
16	the past twelve months.  'In the past twelve months, have

17	you received blood, blood products or a tissue transplant
18	including any you may have donated for yourself?' like an
19	autologous.  'In the past twelve months, have you had a
20	tatoo, ear or skin piercing or acupuncture?' 'In the past
21	twelve months have you had an accidental needle stick or
22	come in contact with someone else's blood?'
23		"In the oral questions, we ask about sex with a
24	prostitute in the past twelve months, but also ask, 'Have

25	you ever taken money or drugs for sex?'  It seems to me that

			299 1	we have either deferred permanently or for one year for
	2	high-risk behavior.  MSM is a known high-risk behavior and,
	3	while there those donors who have changed their lifestyle,
	4	they are relative few and the REDS data confirms these
	5	donors are not always truthful and some still donate to get
	6	tested.
	7		"Will the next step be accepting a male in a
	8	monogamous relationship for the past five years with another
	9	HIV-negative male?  Changing the deferral to five years,
10	based on the statistical model provided, may seem like a
11	reasonable risk but, to me, it says we should change all the
12	other deferrals from one year to five years.
13		"I would like to see the same model run on each

14	high-risk behavior so that we can determine the relative
15	risk of each high-risk behavior before making a
16	recommendation.  The FDA has used theoretical models to
17	eliminate donors who spend six months or more in the U.K.
18	when there has never yet been a recorded transmission of
19	mvCJD through human transfusion.
20		"This seemed to be a political and scientific
21	response to an unknown problem that could not be easily

22	quantified.  Reducing the MSM deferral to five years has a
23	real increase in risk, albeit small.  These two policies
24	seem contradictory.  We are to accept a theoretical model
25	which indicates the real risk of accepting one additional

			300 1	HIV-positive unit if the deferral is changed to five years.
	2		We know HIV is transmitted by transfusion and yet
	3	this risk is acceptable because individuals choosing an
	4	alternate lifestyle are being discriminated against.  At the
	5	same time, we are spending millions of dollars to perform a
	6	NAT test for HIV to detect three to five HIV-positive units
	7	a year.
	8		"These two FDA guidances seem to be at cross

	9	purposes.  Continuing to defer MSM donors permanently
10	enhances the safety of the blood supply much more cost
11	effectively than NAT.  There is no additional cost to

12	continuing to keep that one HIV-positive unit out of the
13	blood supply.  We will continue to spend millions to keep
14	the other few out with NAT.
15		"I would recommend that the committee continue

16	current deferral policies even in the face of possible cries
17	of discrimination.  There are less risky methods of

18	increasing the donor pool than reinstating previously
19	permanently deferred donors.  If present, I would be voting
20	against dropping the deferral to five years."
21		I just wanted to read that into the record from
22	Colonel Fitzpatrick.
23		Yes?
24		DR. NELSON:  I think this is a pretty tricky and
25	delicate issue and difficult, but it isn't as difficult as

			301 1	the CJD because we have to wait quite a while to get an

	2	answer on it.  One of the things that occurs to me is I
	3	think the sort of bottom line is if we change the deferral
	4	criteria to five years, and I would think that if it would

	5	be changed at least initially that should be the change, not
	6	one year, until we have more data.
	7		But if we change it to five years, we would have
	8	information on the prevalence in the additional population,
	9	whether it was 62,000, 160,000 or 10,000.  We could get
10	prevalence data on that population.  If the prevalence
11	significantly increased, then, even if it is one, or however
12	small number, that might, for one reason or another, escape
13	all the testing with NAT an antibody, et cetera, the policy
14	could be reevaluated.
15		But if it turned out that there was no increase,
16	then the benefit would be however many additional donors
17	that yielded.  The estimate was that the CJD policy
18	decreased the donor pool by 2.5 percent, maybe more, of some
19	units.  This, it wouldn't increase it by 2.5 percent but
20	maybe 1 percent.  So it is not completely insignificant.
21		That is my thinking.  I don't think that people,
22	necessarily, have a right to be a blood donor.  I can
23	understand all the issues and that there are issues, but it
24	isn't quite the same as a right to insurance or a right to a
25	job or a right to many other things.

			302 1		I think the instruments that we use in a busy
	2	blood bank, et cetera, will have to be sort of blunt and not
	3	totally personalized.  So, therefore, I think we need a
	4	single question or two.
	5		But I think we could change it to a five-year and
	6	before the risk of a unit slipping through, we would have
	7	data as to whether the risk has been increased.
	8		DR. HOLLINGER:  Thank you.
	9		Dr. Schmidt?
10		DR. SCHMIDT:  I don't think we are going to get
11	any data asking people do they remember when; is it three
12	years, four years, five years, et cetera.  We are setting up
13	an artificial situation where we are going to accept what we
14	think they said.  We wouldn't accept another test based on
15	such--the terrible certainty of what the test would result. 
16	And this really is a test.  So I am against making any
17	changes until we do them all and do them right.
18		DR. HOLLINGER:  Dr. Epstein?
19		DR. EPSTEIN:  I just want to make a few points
20	that I hope are clarifying.  A lot has been said about the
21	inconsistency of criteria that lead to twelve-month deferral
22	versus lifetime deferral.  The concept that emerged in
23	putting forward these different deferral periods was that,
24	in some cases, we were trying to address risks that
25	presented themselves as discrete or one-time exposures where

			303 1	the real issue was to wait for something in excess of a
	2	window period before permitting the blood collection on the
	3	notion that you would then have positive tests and could
	4	exclude use of the unit.
	5		However, there was independently the notion that
	6	there were, in fact, some risk histories that connoted
	7	lifestyle choices that imply ongoing risk and where one
	8	could not be confident that simply waiting one window period
	9	from a discrete exposure was meaningful.
10		Those lifetime deferrals, as has been stated, were
11	for history of intravenous drug use, sale of sex for money

12	or drugs, or male sex with males since 1977 in the AIDS era. 
13	I think that it needs to be understood that two concepts

14	were driving FDA thinking, that these relate to the whole
15	notion of layers of safety; in other words, a series of
16	overlapping safeguards to protect the blood supply.

17		The idea was that first you educate people so that
18	they don't present as donors if they have known risk, that
19	you then ask them questions to try to exclude them from

20	donating if they might be a person at high risk either
21	because of incidence or because of prevalence.
22		This is a very key point, that we have, forever
23	and a day, tried to keep from collecting persons likely to
24	have a positive collection because it would go into the
25	quarantine inventory but there is finite risk that it would

			304 1	come out in error.  We have always done this.
	2		Then, of course, the third layer of protection is
	3	testing deferral registries, quarantine management, et
	4	cetera.  So, again, the deferral criteria have always been

	5	organized to try to capture both persons at high incidence
	6	but also persons identifiable as being in groups with high
	7	prevalence to prevent infectious units from entering the
	8	inventory at the blood center.
	9		I would also like to address what I think is a
10	misunderstanding whether FDA criteria are based on
11	identification of self-identification of a group as opposed
12	to behavior.  The question that we ask of persons who may

13	have had sex with males as males is not do you self-identify
14	as gay or bisexual.  We ask, "Have you, as a male, since
15	1977, even one time had sex with another male?"
16		I would contend that that is behavior.  We also
17	can look at it as lifestyle choice, identification, personal
18	identity, whatever else.  But the bottom line is we are not
19	asking people to self-identify.  We are asking whether they
20	have engaged in a certain behavior.
21		I think that the current FDA policy has been very
22	much misrepresented on this point.  It is, indeed, behavior
23	that we ask about.  There is no question, in general, that
24	the behavior, that history, is associated with known high

25	prevalence and known high incidence of, at a minimum, HIV

			305 1	and hepatitis B and, marginally, for HCV, as has been said
	2	twofold for HCV, but at least tenfold for hepatitis B and
	3	even higher than that for HIV.
	4		So the real challenge, as I see it, is whether
	5	knowing that MSM, persons who have that behavior, in
	6	general, are at known high prevalence and high incidence, is
	7	there any way to identify a safe subset.  That is the real
	8	question.
	9		One attempt to do that has been to look at persons
10	who deny that behavior within the last five years.  I would
11	suggest that issue is not merely whether we have captured
12	window period.  Of course, we capture window period in five
13	years.  The issue with moving to one year is whether we have
14	really captured a safe cohort that are not engaged in
15	ongoing risk behavior.
16		I think that is a fundamental difference between a
17	one-year exclusion and a five-year exclusion.  The point was
18	brought up earlier, and I am sorry that Dr. Smith has left,
19	but we have looked at, alternatively, the question of
20	whether a person states that they are in a monogamous or
21	mutually monogamous gay relationship as well as the question
22	of whether they state that they practice only safe sex.

23		But, to our knowledge, based on data that have
24	been made available to us by the CDC and actually are
25	published in, I think, the paper from Valroe was put in the

			306 1	packet, none of those criteria has yet been established to
	2	correlate with low risk.
	3		In other words, in the face of stated monogamy, in
	4	the face of stated safe sex, persons who engage as males in
	5	sex with males still have indistinguishable risk from those
	6	who do not state monogamy and safe sex.
	7		We can have a long discussion about why that is
	8	so, but the fundamental point here is that we still wish to
	9	try to identify safe donors before we put a needle in the
10	arm.  We want individuals at low prevalence and low
11	incidence before we put a needle in the arm.
12		The question is have we gotten far enough in that
13	direction with a floating five-year exclusion as opposed to
14	a floating post-'77 exclusion, a lifetime exclusion.  We all
15	understand that it is somewhat nonspecific and undoubtedly
16	captures uninfected individuals whose lifestyles may not put
17	them at increased risk.
18		We understand this.  It is nonspecific.  It is
19	overinclusive.  But it works.  It works because it captures
20	the high-risk subset.  The question is whether it is also
21	safe to relax it in the way that has been described.  That
22	is really what the debate should be about.
23		So I hope I have clarified the distinction between
24	a one-year deferral, a five-year deferral and a life-time
25	deferral and what I think is the pivotal question.

			307 1		DR. NELSON:  Do you think monitoring the
	2	prevalence, if a change was made, and stating some sort of
	3	criteria is useful?
	4		DR. EPSTEIN:  I think it is a useful concept.  We
	5	have never actually done it by implementing the change in
	6	the blood supply.  In other words, when we contemplated this
	7	kind of change, we have usually moved towards studies,
	8	epidemiologic studies, that would predict for us what would
	9	happen if we made that change in the blood supply.
10		What is being suggested is that, if we think it is
11	safe enough and, at some point, I assume there will be a

12	vote, that the way to go about it is make the change but
13	monitor it closely, hopefully on the notion that we could

14	catch it quickly enough if it appeared that prevalence among
15	donors was rising or incidence among donors was rising
16	where, and I would hope not, but transmission rates were
17	rising.
18		So that is a different model for how to go about
19	change.  I don't reject it up front but I think there has to
20	be some notion that we would only apply that strategy for
21	changes where we were fairly well convinced that it wouldn't
22	cause decreased safety and we were just monitoring to make
23	sure that we were right.
24		DR. SCHMIDT:  Jay, your logical progression down
25	the line omits something that we didn't discuss today at

			308 1	all, and that was the concept of giving people the
	2	opportunity, after they had told us something, to say,
	3	"Oops; I lied," or, "I forgot," and, after they donated the
	4	blood, let us know to throw the blood away.
	5		If we were doing that, then to say we are going to
	6	believe them now or that it was logical without that, it
	7	doesn't fit at all.
	8		DR. HOLLINGER:  Paul, I would like to go back to

	9	something you said earlier.  While I might favor a one-year
10	deferral, I think the reason for going to a five-year or
11	something might be because of the question you just entered
12	into, that it is maybe sometimes to know, or difficult to
13	remember, what that last time was, so to speak and,
14	therefore, that gives you an element of safety.

15		The other issue is that it is my intuition, if you
16	will, that people who have not engaged in sex with another
17	male for five years are probably not somebody who maybe
18	engaged in sex previously, extensively.  I may be wrong on
19	that, but I think--that is just my feeling without any data,
20	but we haven't had any data today, anyway.
21		Are there any other burning issues here before we
22	bring this to a vote?  Dr. Macik?
23		DR. MACIK:  There are a couple of things that keep
24	going through--I am really trying to decide where I stand on
25	this.  On the one hand, I am always opposed to a limitation

			309 1	that brands all people for a possible risk in a subset of
	2	that group, which is basically what you are doing if you say
	3	everybody is excluded back to '77.
	4		What ways do we have of finding, as Dr. Epstein
	5	said, the safe subgroup within the group.  There are
	6	possibilities.  Do these people get tested and come back? 
	7	It was brought up earlier, what is the likelihood they are
	8	actually going to come back?
	9		Well, if they want to be a blood donor, if that is
10	really an issue for them, they will come back.  If they were
11	showing up just because it was part of the office procedure,
12	then they won't come back.  But it gives an option to a
13	subset of people who maybe have not had sex in five years,
14	maybe had a single encounter, who really want to donate, to
15	give them an entry into it without branding them because of
16	a single incidence or lifestyle that they have left behind
17	or something.
18		We, ultimately, have to rely on our science test
19	over our behavior test anyway because there are going to be
20	so many liars, both intentional and unintentional people
21	saying, "Well, I didn't do that," "I only did it once; that
22	is not really going to matter.  I am just going to answer

23	'no' to this question."
24		That is true whether we are dealing with men who
25	have sex with men or whether we are dealing with

			310 1	heterosexual groups that are at high risk or an I.V. drug
	2	user who is at high risk.  Some assumption by this

	3	questionnaire is that people always tell the truth.
	4		We, of course, know that that is not necessarily
	5	true.  So I think some of the issues--I am leaning towards
	6	lifting the current restriction but, perhaps, looking a
	7	little bit more until we maybe get some more data.  Is the
	8	prevalence really less in people who had sex one time or

	9	haven't had sex with a man in five years, if we can get that
10	information in some way.
11		What better way to get that information if we
12	offer them the ability to test and, if they test negative,
13	to donate.  If they don't, they we actually have some
14	information, some data, to go into our prevalence file.  So
15	I think there are a lot of things that we need to address
16	here.
17		I just hate to exclude an entire group without
18	giving some options for how to get them back.
19		DR. HOLLINGER:  Clearly, if know if we really want
20	to get subsets, we could really get a clear subset.  Young
21	males who have sex with a male who is black who has had an
22	STD.  You could really focus in on it, but I think you have
23	to paint with a broader brush than that, unfortunately,
24	because, while that might grab the majority, there is still
25	a fairly large number outside that who you might not pick

			311 1	up.
	2		I think those are important with any question you
	3	have.
	4		DR. MACIK:  But going broadly by saying have you
	5	not had sex in five years--that is the broad subset.
	6		DR. HOLLINGER:  If there are no other burning
	7	questions, Andy, could you have the question put up please,
	8	or would somebody please put the question.
	9		For the record, I will read the question for the
10	committee.  "Do the available scientific data support the

11	concept that men who have sex with other men, MSM, can be
12	deferred from donating blood for a period of five years
13	following MSM activity rather than being deferred for any
14	MSM behavior since 1977?"
15		All of those who are in favor of that question,
16	please raise your hand.
17		[Show of hands.]

18		All those opposed?
19		[Show of hands.]
20		Abstaining?
21		[No response.]

22		The consumer representative?
23		MS. KNOWLES:  Yes.
24		DR. HOLLINGER:  The industry representative?
25		DR. SIMON:  Yes.

				312 1		DR. SMALLWOOD:  The results of voting on the

	2	question as read, there are six "yes" votes, seven "no"
	3	votes, no abstentions.  Both the consumer and industry
	4	representatives agree with the "yes" vote.
	5		Dr. Epstein?

	6		DR. EPSTEIN:  For the record, you had a straw poll
	7	and I wonder if we could record that voting because I think
	8	it was a pertinent question.  You had asked how many of the
	9	committee favored some change in the donor question.  You

10	only asked those in favor to vote, of whom there were eight. 
11	By implication, had there been no abstentions, there would
12	have been five votes against.
13		I think that is also useful information to the
14	FDA, especially given the closely divided vote.
15		DR. SMALLWOOD:  I'm sorry; I didn't record the
16	straw vote because it wasn't the question that we had before
17	us.  Sorry.
18		DR. HOLLINGER:  Are there any other comments from
19	the committee?  This has been a very difficult issue.  Dr.

20	Linden?
21		DR. LINDEN:  I don't know if I can speak for the
22	other people who voted no, but I felt that the data that we
23	have been presented, particularly today, did not allow me to
24	vote yes for this.  But I very much endorse the concept of
25	trying to change this, trying to identify subgroups, looking

			313 1	at this as a reentry mechanism.
	2		So, even with my no voting, I would encourage FDA
	3	to continue to pursue this issue, to look at possible

	4	options where this could be changed in a safe fashion.
	5		DR. HOLLINGER:  What would we look for as
	6	additional data that would help you make that decision. 
	7	What kind of data would you want?
	8		DR. LINDEN:  I think additional data on the
	9	prevalence in this or other subpopulations would be helpful. 
10	That was missing from what we had today.  The assumption was
11	that the prevalence and MSMs as a whole are the case for

12	this population.  I am not sure that that is the case.  It
13	would useful to look at that particular issue as well as
14	generally, perhaps, looking more thoroughly at the issue.
15		Dr. Dayton did a wonderful job with this, but I
16	know it was put together very quickly and I am sure that,

17	given more time, there are, perhaps, other things that could
18	be looked at.
19		DR. HOLLINGER:  Thank you, Jeanne.
20		Dr. Nelson?
21		DR. NELSON:  There are two key pieces of
22	information that are missing.  One is the left side of that
23	equation.  If you change the questionnaire, what would
24	happen and how many people would you get and how many would
25	respond adequately and how many would the ratio remain the

			314 1	same.  That is completely unclear.
	2		The other issue is what is the prevalence.  What
	3	is the size of the population under five--we were presented
	4	some data on that--we were presented data on the size of the
	5	population which may or may not be correct, but we have no

	6	idea how many of those would be blood donors if there was a
	7	change, and we have not the vaguest idea as to whether the
	8	prevalence in that population is the same as the prevalence
	9	in all MSM.
10		My guess is that it is probably far lower if you
11	exclude all the other risk behaviors that are currently

12	excluded, drug use, et cetera.  But some of those data could
13	be obtained, I think, like the prevalence in that particular
14	population would be very useful.
15		If it turns out it is 8 percent or 30 percent,

16	then I would say that we probably shouldn't change the
17	criteria.  But if it turns out it is closer to the 
18	heterosexually active population, then it is not really
19	changing the risk at all.  I think that is key.
20		And maybe some surveys could define that.  The
21	only way we would know who would donate blood would be
22	changing the criteria and see what happens, I think.

23		DR. HOLLINGER:  Dr. Stuver?
24		DR. STUVER:  It would seem to me that a mechanism
25	for trying to evaluate how some of these changes in

			315 1	questions would have an effect would be within the context

	2	of this task force.  I would think there would need to be
	3	some specific evaluation of, well, if you change the
	4	question, this is what is going to happen.  These people
	5	will respond differently if is this way or that way.  These
	6	are the kinds of people that respond in the affirmative or
	7	not.
	8		It seems logical that would be a place to try to
	9	get at some of this exact information, for not just this

10	risk factor but for some of the other permanent deferral
11	risk factors.
12		DR. HOLLINGER:  Thank you, Sherri.
13		Anybody else have a comment?  I appreciate the
14	committee's staying.  It was a long day today.  Tomorrow, we
15	will start at 8 o'clock and the plans are to go until 4:00.
16		Thank you very much.
17		[Whereupon, at 6:10 p.m., the proceedings were

18	recessed, to be resumed on Friday, September 15, 2000 at
19	8 o'clock a.m.]
20