1 DEPARTMENT OF HEALTH AND HUMAN SERVICES 

FOOD AND DRUG ADMINISTRATION 
CENTER FOR DRUG EVALUATION AND RESEARCH
BLOOD PRODUCTS ADVISORY COMMITTEE SIXTY-SIXTH MEETING
							VOLUME I
			Thursday, June 15, 2000 

						8:00 a.m.
	Holiday Inn 8777 Georgia Avenue 

			Silver Spring, Maryland 

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

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

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

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

			3 C O N T E N T S 

Conflict of Interest Statement, Linda Smallwood, Ph.D.			5 
Committee Updates: 
Summary of PHS Advisory Committee on Blood Safety and Availability, Stephen Nightingale, M.D.			8 
	Summary of Workshop on Plasticizers: Scientific 
Issues in Blood Collection, Storage and Transfusion, 
	Jaroslav Vostal, M.D., Ph.D.		18 
	Report on Blood Supply Monitoring, Paul McCurdy, M.D.  26 
Summary of Transmissible Spongiform Encephalopathies Advisory Committee Meeting, David Asher, M.D.		36 
Plasma Pool Screening by Nucleic Acid Tests: 
	Introduction and Background, Robin Biswas, M.D.		46 
	Regulatory Options for HAV NAT, Sheryl Kochman		57 
Review of History of Hepatitis A Transmitted by Transfusion, Mahmood Farshid, Ph.D.		70 
Hepatitis A Virus: Epidemiology/Clinical Implications/Prophylaxis, Stephen Feinstone, M.D.		83 
	HAV Transmission by Factor VIII Concentrates, 
	Dr. Michael Chudy		102 
Open Public Hearing: 
Louis Katz, M.D., American Association of Blood Banks 108 Susan Stramer, Ph.D., American Red Cross	111 
Open Committee Discussion: 
	FDA Perspective and Questions	127 
Open Public Hearing: 
	Afzal Chowdhury, Ph.D., 
	Guardian Scientific, Inc.	153 

		4 C O N T E N T S(Continued) 
Development of Rapid HIV Tests: 
	Background and Introduction, 
	Kimber Lee Poffenberger, Ph.D.	158 
	Presentation by Robert S. Janssen, M.D., 
	Division HIV/AIDS	171 
	Presentation by Lt. Hassan S. Zahwa, DOD	180 
	Presentation by Nancy A. Wade, M.D., M.P.H., 
	NYS Department of Health	198 
	Presentation by Robert S. Janssen, M.D., 
	Division HIV/AIDS	210 
Open Public Hearing (Continued): 
	Bill Murray, Abbott Laboratories	237 
	Scott Dennis, Bio-Rad Laboratories	241 
	Hermes Chan, MedMira	247 
	Raymond Smith, National Alliance of State and 
	Territorial AIDS Directors	252 
Open Committee Discussion and 
	Questions for the Committee	257 

			5 1		         P R O C E E D I N G S
	2		          Conflict of Interest 
	3		DR. SMALLWOOD:  The following announcement is made 
	4	a part of the public record to preclude the appearance of a 
	5	conflict of interest at this meeting.  Pursuant to the 
	6	authority granted under the Committee Charter, the Director
	7	of the FDA's Center for Biologics Evaluation and Research 
	8	has appointed Dr. Kenrad Nelson as a temporary voting 
	9	member, and the Senior Associate Commissioner for the Food 
10	and Drug Administration has appointed Dr. Carmelita Tuazon 
11	as a temporary voting member for the discussions on the
12	development of rapid HIV tests. 
13		To determine if any conflicts of interest existed, 
14	the agency reviewed the submitted agenda and all relevant 
15	financial interests reported by the meeting participants.  
16	In the event that the discussions involve other products or
17	firms not already on the agenda for which FDA's participants 
18	have a financial interest, the participants are aware of the 
19	need to exclude themselves from such involvement and their 
20	exclusion will be noted for the public record. 
21		With respect to all other meeting participants we
22	ask in the interest of fairness that you state your name, 
23	affiliation and address any current or previous financial 
24	involvement with any firm whose products you wish to comment 
25	upon.  If there are any declarations to be made at this 

			6 1	time, we will accept those.  If not, then I will move

	2	forward with making a few announcements at this time. 
	3		First, I would like to introduce the members of 
	4	the Blood Products Advisory Committee.  When I call your 

	5	name, members, would you please raise your hand?  First we 
	6	will begin with Dr. Blaine Hollinger who is the Chairperson,
	7	Dr. John Boyle, Dr. Jeanne Linden, Dr. Ohene-Frempong, Dr. 
	8	Gail Macik, Dr. Paul Schmidt, Dr. Michael Fitzpatrick, Miss 
	9	Kathy Knowles, Dr. Toby Simon, Dr. Mary Chamberland, Mr. 

10	Terry Rice, Dr. Marion Koerper, Dr. Richard Kagan, Dr. Paul 
11	McCurdy.
12		Absent from this meeting are Dr. Norig Ellison, 
13	Dr. Daniel McGee, Dr. David Stroncek and Dr. Sherri Stuver.  
14	We will have with us for this meeting, as temporary voting 
15	members, Dr. Carmelita Tuazon and Dr. Kenrad Nelson, and we 
16	will also have as a guest of the committee Dr. Raymond Koff.
17		I would just like to announce that out on the 
18	table there is information regarding a workshop on 
19	recruiting blood donors.  It will occur July 6th and 7th.  
20	You may pick up that information at the table outside. 
21		So that our proceedings will move smoothly, we are
22	asking that cell phones preferably be turned off, however, 
23	if you must have them, that they be turned down low so that 
24	the ringing will not interfere with the proceedings.  Also, 
25	if you would be mindful that we have a full agenda today so 

			7 1	that all speakers will be prepared to speak when called upon
	2	and that you will adhere to the time frames that we have 
	3	allotted. 
	4		At this time I would like to turn over the 
	5	proceedings of the meeting to the Chairperson, Dr. Blaine 
	6	Hollinger.
	7		DR. HOLLINGER:  Thank you, Dr. Smallwood.  
	8	Welcome, everybody.  We have a very busy day and a half.  
	9	The last meeting I attended was a few weeks ago, where Paul 
10	Brown was chairing the meeting.  I noticed that he had a 
11	gavel and I told Linda that I needed a gavel up here.
12		[Laughter] 
13		We do have a busy  meeting today.  We are going to 
14	have several updates, both to start off this morning as well 
15	as tomorrow morning.  The two major topics today -- one is 
16	going to be on the potential for plasma pool screen by
17	nucleic acid testing for HAV.  There will be some questions 
18	about that, and potential recommendations from the 
19	committee.  This afternoon will be pretty much devoted to 
20	HIV rapid testing, again with some recommendations and 
21	discussions from the committee.  Then, tomorrow there will

22	be a session on leukoreduction, again with the same format. 
23		Since we do have a big morning, we are going to 
24	start off with the committee updates, and the first 
25	committee update will be a summary of the PHS Advisory 

			8 1	Committee on Blood Safety and Availability meeting which was
	2	held April 25th and 26th, and Dr. Nightingale is going to 
	3	give us an update. 
	4		           Committee Updates 
	5	    Advisory Committee on Blood Safety and Availability 
	6		DR. NIGHTINGALE:  Good morning and thank you.  Dr.
	7	Hollinger, I don't think that you will need to use that 
	8	gavel for me because as soon as my presentation is completed 
	9	my vacation begins. 
10		[Laughter] 
11		The advisory committee did meet on April 24th and
12	25th, and it made five recommendations.  When I spoke to you 
13	in March I indicated that our deliberations on error and 

14	accident management in transfusion medicine were continuing.  
15	The first of the five recommendations made by the advisory 

16	committee is lengthy but uncommonly literate for advisory
17	committee recommendations.  I will, nevertheless, refrain 
18	from reading it to you in its entirety but the meat of the 
19	issue is as follows: 
20		The advisory committee recommended that error 
21	management systems should acknowledge the rights of patients

22	to know of any risk or harm suffered as a consequence of any 
23	error or accident related to blood products received.  At 

24	the same time, there should be statutory protection from 
25	disclosure for voluntarily reported information and quality 

			9 1	assurance activities that are not associated with potential

	2	or actual harm, provided that the information is also not 
	3	associated with reckless or intentionally harmful acts. 
	4		These error management systems should complement 
	5	and not replace current regulatory activities, notably but 
	6	not exclusively, in the area of product safety.  All
	7	analyses of collected data should be made available in a 
	8	timely manner to regulatory agencies, national transfusion 
	9	medicine surveyance programs and other participants in 
10	reporting systems. 
11		While I think the god or the devil is in the
12	details, the feeling within the advisory committee is that 

13	its immediate charge was accomplished to lay a framework for 
14	ways to support the implementation of more effective error 
15	management programs. 
16		In a brief paragraph of this recommendation, the
17	advisory committee recommended that Congress should 
18	appropriate sufficient funds to develop these systems and 
19	for infrastructure sufficient to support and maintain them.  
20	In the Fiscal Year 2001 budget, Congress should stipulate 
21	that these funds should not be reallocated for other
22	purposes and that no other funding should be reduced because 
23	of the availability of these funds.  Funds necessary to 

24	maintain these systems should be appropriated annually. 
25		I know that Dr. Hollinger receives a copy of all 

			10 1	the mailings of the advisory committee, and I believe that
	2	they are, or certainly can be, distributed to the other BPAC 
	3	members.  For the public, these are available on our web 
	4	site, which is www.dhhs.gov/bloodsafety.  The web site is 
	5	slightly less clunky than its predecessor. 
	6		The advisory committee made four other
	7	recommendations, and the second and third are also directed 
	8	at Congress.  Although I believe the advisory committee was 
	9	aware that it is the Secretary of Health and Human Services 
10	and not Congress that it advises, nevertheless, the Congress 
11	is interested in the deliberations and these have been
12	communicated to the Congress. 
13		The second of these recommendations was that there 
14	is a small but non-zero risk associated with the use of 
15	blood products or plasma derivatives that cannot be 
16	eliminated with current technology.  The advisory committee,
17	therefore, supports the prior recommendation of the 
18	Institute of Medicine and of others that a prospective 

19	national system to compensate recipients for injuries or 
20	death caused by blood products or plasma derivatives, and 
21	not associated with reckless or intentionally harmful acts,
22	should be enacted and funded by Congress. 

23		This is clearly a complex issue.  The Institute of 
24	Medicine and others have previously recommended it.  Of 
25	course, the details here that the advisory committee did not 

		11 1	address are how to identify who should be compensated and
	2	what is just compensation.  So, I don't anticipate immediate 
	3	reaction to it but this is clearly, like the first issue, an 
	4	issue that goes beyond the scope of either the advisory 
	5	committee itself or, for that matter, we believe the 
	6	Department.  So, this at the moment was directed to Congress
	7	for further action and we will see, in an election year and 
	8	afterwards, what becomes of it. 
	9	          The third of the five recommendations is of 
10	substantial interest to the blood community.  To summarize, 
11	there is a "whereas" at the beginning -- safety and
12	availability is dedicated to ensuring patient access -- it 
13	goes on though -- the advisory committee, consistent with 

14	prior recommendations, recommends that the Secretary and 
15	Congress support legislation to ensure fair and accurate 
16	reimbursement for inpatient blood-related products and

17	services.  Such legislation should provide sufficient 
18	funding to account for increased blood-related costs, 

19	including those associated with new blood safety measures, 
20	and require that these costs be reflected in annual updates 
21	of inpatient diagnosis related groups.
22	          Again, this is a complex recommendation.  I think 
23	the advisory committee has stated its position and from this 
24	point on it is for the Congress and the Executive Branch to 
25	take further action. 

			12 1		The fourth of the five recommendations, the
	2	advisory committee recommended that HCFA promptly distribute 
	3	guidelines for coding and billing for its outpatient 
	4	prospective payment system.  I believe that you will have 

	5	seen in the papers that the implementation of that system 
	6	has been delayed for 30 days so that recommendations, such

	7	as this one for appropriate implementation, can be effected 
	8	before the outpatient PPD is implemented. 
	9		The final recommendation of the advisory committee 
10	in April was that, recognizing the significant economic 
11	issues currently affecting the blood system, the advisory
12	committee seeks to review the role of various considerations 
13	and decision-making related to new and existing blood safety 
14	measures.  Underneath that somewhat opaque language is a 

15	further discussion of the realities of the transfusion 
16	business -- using that word intentionally -- and what the
17	government can do to provide relief not only for the 

18	business but for the people for whom that business is 
19	intended to help.  We will meet for a single day on August 
20	24th.  I would be glad to answer any questions. 
21		DR. HOLLINGER:  Steve, there was a lot of
22	discussion at this meeting on compensation of people who 
23	perhaps may develop some diseases from blood products and so 
24	on, as well as reimbursement for these very expensive items 
25	which we discuss frequently.  In terms of the one about 

			13 1	compensation, was there any discussion about similar ideas
	2	as to what is done with vaccines where so much of a vaccine 
	3	product goes into a pool to pay for that so that, for 
	4	example, any blood product that is given a certain portion 
	5	would go to make up some money available for problems that 
	6	develop?
	7		Secondly, how does this work?  I mean, I know this 
	8	goes to the Secretary of Health but what committee does this 
	9	go to in terms of reimbursement and how does this finally 
10	get into the Congress where it perhaps can be acted upon? 
11		DR. NIGHTINGALE:  In response to the first
12	question, the discussion about no fault was really lead by 
13	Mr. Justice Krever's presentation to the committee.  When I  
14	spoke to you in March I noted that there would be a jurist.  
15	I didn't have in writing Horace Krever's acceptance and I 

16	just did not feel at liberty to say there is a 99 percent
17	chance that Mr. Krever, now retired, would be there.  So, I 
18	wasn't holding back from the committee; I just didn't have 
19	it on paper at the time. 
20		The committee and those in attendance were very 
21	taken up by Mr. Justice Krever's presentation, in particular
22	taken with his very clear demarcation of the line between 
23	what tort can accomplish and what tort cannot accomplish.  
24	Mr. Justice Krever was very clear and articulate in his 
25	views of the limitation of tort systems in his home country 

		14 1	to deal with the tragedies that can ensue in the course of
	2	attempts to make people better, and it was on the basis of 
	3	the limitations of the tort system that he strongly 
	4	advocated a no-fault system.  He did note, however, that in 
	5	his own country that had not by any means been completely 
	6	implemented.
	7	          The second recommendation, which was for such a 
	8	system in the States, can be seen in the transcripts to come 
	9	fairly directly from the persuasiveness, at least to the 
10	committee, of his recommendations, but there are clearly 
11	political and real-world details to be worked out.
12	          The answer to the second question as to where do 
13	these things go, our charter is fairly clear.  We advise the 
14	senior management of the Department of Health and Human 
15	Services -- we, being the Advisory Committee on Blood Safety 
16	and Availability.  In practice, both of these
17	recommendations come to the blood safety director who takes 
18	that advice and makes his own recommendations to the 
19	secretary.  That is what is on paper.  In the real world, a 
20	lot of people are interested in blood safety.  For example, 
21	the agenda item on errors and accidents was driven to some

22	extent by interest in the House Commerce Committee in that 
23	issue, although we had separately been anticipating that 
24	issue for some time before the Commerce Committee or the 
25	Institute of Medicine got wind of it. 

			15 1		I think as a courtesy we distribute the
	2	transcripts and the summaries to anyone who is interested 
	3	directly.  We post them on the web.  The interest right now 
	4	is in the House Commerce Committee, the Subcommittee on 
	5	Oversight Investigations which is chaired by Mr. Fred Upton, 
	6	Republican, Michigan, is particularly interested in this

	7	issue.  In this election year, it is unclear whether the 
	8	presence of election will promote or slow down progress on 
	9	these issues. 
10		DR. HOLLINGER:  Yes, Dr. Simon? 
11		DR. SIMON:  Just a couple of comments on this
12	report.  First, in my previous life I was involved with the 
13	issue of no-fault compensation for transfusion-related 
14	injury, first on behalf of AABB and then subsequently on 
15	behalf of ABC.  And, in fact, all the blood banking 
16	organizations tried hard to get a model program in the State
17	of Arizona, when I was with Blood Systems out there, and I 
18	think it never did finally come into being.  But over the 
19	years this has been an issue that the blood banking 

20	organizations have been very interested in and have tried to 
21	push for progress.
22		From time to time the model of the vaccine injury 
23	program comes up, as you mentioned, and we bring this up on 
24	Capitol Hill.  The two comments that are made by 
25	congressional staff people to dissuade us from moving in 

		16 1	this direction are, number one, when this was put into
	2	effect people like Congressman Waxman and Senator Kennedy 

	3	made it very clear that this was a one-time exception to 
	4	tort law that they were willing to make and take on the 

	5	trial lawyers in this area, but it was clearly a one-time 
	6	exception.
	7	          Secondly, it was explained to me that the logic 
	8	behind the vaccine injury program and a special exception 

	9	for this is that the parents vaccinate their children not so 
10	much for the benefit of that child but for herd immunity to 
11	protect society as a whole.  So, it is reasonable for
12	society, through a tax measure, to assure the parents when 
13	they vaccinate their children that, should anything happen, 
14	society will take care of that.  But it wasn't felt that 
15	this same principle applies to transfusion where someone is 
16	being transfused for their own benefit, just like any other
17	medical form of therapy.  So, I just thought I would add 

18	that to this discussion. 
19	          The second point I just wanted to make on errors 
20	and accidents is that it seemed to me, in reviewing this, 
21	that that is kind of right down the middle of the plate for
22	this committee and FDA.  I think it is certainly an area 
23	where we would be interested in further progress and would 
24	hope that FDA, as they presumably evolve in their internal 
25	discussions on this, might at some point bring some 

			17 1	suggestions to the committee.
	2		DR. NIGHTINGALE:  Dr. Hollinger, could I make a 
	3	response to that? 
	4		DR. HOLLINGER:  Yes, please. 
	5		DR. NIGHTINGALE:  I am aware of those previous 
	6	discussions and, in fact, I have been in contact with Dr.
	7	Sherman, who is going to prepare for me a summary of those 
	8	deliberations, and I have also spoken to the AABB about this 
	9	and I anticipate that there will be further discussion of 
10	what the blood community had accomplished in the past and 
11	the question about what should be accomplished in the
12	future. 
13		One of the comments that has been made, and it is 
14	not a comment that I made and attribute to somebody else but 
15	is certainly one that I share, is that the legs of such an 
16	enterprise are vastly strengthened when they include active
17	participation either by those who will be directly affected 
18	by that or their representatives.  When you talked about 
19	errors and accidents being right down the plate of FDA, 
20	within FDA's current budget there is a proposal for funds to 
21	assist in the implementation of error and accident systems

22	and, honestly, we will have to see what happens on or about 
23	September 30th of this year. 
24		DR. HOLLINGER:  Yes, Dr. Schmidt? 
25		DR. SCHMIDT:  I think for those on this committee 

				18 1	who are not involved in or keep up with these things, it is
	2	worthwhile mentioning -- you had Justice Krever from Canada, 
	3	but the events over the last few years have forced the 

	4	Canadian Red Cross to declare bankruptcy for its entire 
	5	operation and a complete revision of the blood collection 
	6	and distribution system in Canada.  So, this is a mighty
	7	effect of this tort problem. 
	8		DR. HOLLINGER:  Thank you, Dr. Nightingale.  The 
	9	second update is a summary of a workshop that was held on 
10	plasticizers: scientific issues in blood collection, 
11	storage, and transfusion, held on October 18, 1999, and Dr.
12	Vostal will give us an update on that. 
13	 Summary of Worship on Plasticizers:  Scientific Issues in 
14	         Blood Collection, Storage and Transfusion 
15		DR. VOSTAL:  Good morning.  Thank you very much 
16	for giving me the opportunity to review our workshop.
17		[Slide] 
18		We had a workshop last October, and it was 
19	entitled Plasticizers: Scientific Issues in Blood 
20	Collection, Storage and Transfusion.  It was jointly 
21	sponsored by the Center for Biologics and the Center for
22	Devices. 
23		The objectives of the workshop were to provide an 
24	open forum for discussion of scientific data on the use of 

25	plasticizers in blood collection and storage, and to examine 

			19 1	the risks and benefits of currently used plasticizers and
	2	other available plasticizers and plastics for blood 
	3	collection and storage. 
	4		[Slide] 
	5		So as a little bit of a background, you are all 
	6	well aware that blood components are collected and stored in
	7	soft, pliable and gas permeable plastic bags.  Now, the 
	8	characteristics that are given to these bags are that the 

	9	plasticizers are actually dissolved in the plastics, the 
10	main plastic that the bags are made of.  Plasticizers are 
11	not covalently bound to plastics, and can leach out into the
12	stored blood and be transfused along with the blood 
13	components.  One of the main plasticizers that has been 
14	debated over the years has been di(2-ethylhexyl) phthalate 
15	or DEHP.  The problem with this plasticizer is that it has 
16	demonstrated toxicity in rodents.  It has been a 30-year

17	debate or longer than 30 years whether this type of toxicity 
18	can also be extended to humans. 
19		[Slide] 
20		DEHP does have some demonstrated benefits.  It 
21	actually incorporates into the red cell membrane as it

22	leaches out of the plastic bags and extends the storage 
23	dating of red cells from 21 days to 42 days.  This was 

24	actually demonstrated by Dr. Jim au Buchon at the NIH Blood 
25	Bank, in the early '80s. 

			20 1		However, these are some of the risks that have

	2	been demonstrated in animals.  In rodents DEHP leads to 
	3	carcinogenicity, and the mechanism of this is peroxisomal 
	4	proliferation.  There are also new data coming out showing 

	5	that DEHP has negative effects on reproduction, and this is 
	6	both in male and female adult rodents.  There is new
	7	evidence coming out that shows that there is testicular 
	8	toxicity in developing animals, and this was done in 
	9	rodents.  So, again, with these types of things the question 
10	is whether these effects could be taking place in human 
11	after they have been exposed to DEHP through transfusion.
12		[Slide] 
13		In the workshop there was a great deal of debate 
14	on alternatives to phthalate plasticizers.  For platelets, 
15	manufacturers have actually moved away from phthalate 
16	plasticizers and they now use citrated plasticizers with PVC
17	or polyolefin bags which don't require plasticizers.  So the 
18	amount of plasticizers reaching out into platelet products 
19	has been greatly decreased. 
20		For red cells, there has been a lot of research 
21	for plasticizers also and, actually, Baxter came out with
22	citrated plasticizers in PVC for storage of red cells.  That 
23	was cleared by the FDA and introduced to the market in the 
24	early '90s.  However, it was not well received by the 
25	transfusion community.  There were problems with labels not 

			21 1	sticking to the bags.  There were reports of an unpleasant
	2	odor to the bags, and there was also an increased cost.  So, 
	3	after about two years these bags were taken off the market 
	4	and we were back to using bags that have DEHP. 
	5		The major concern that was discussed in the 
	6	workshop is that any new type of plasticizer that is
	7	introduced has to have adequate toxicological evaluation, 
	8	and the recurring theme is are we switching from devil that 
	9	we know to the devil that we don't know in terms of DEHP and 
10	phthalate plasticizers? 
11		[Slide]
12		About the time we were having this workshop, we 
13	were fortunate that there were three separate risk 
14	assessments being conducted and published.  One was done by 
15	the American Council on Science and Health.  This was an 
16	expert panel that was chaired by Dr. Koop.  Their conclusion
17	was that benefits of DEHP outweigh the risks to humans. So, 
18	they felt that use of DEHP in medical devices was safe. 
19		Another group, Health Care Without Harm, 
20	commissioned the Lowell Center for Sustainable Production, 
21	University of Massachusetts, to look at the issue of DEHP

22	toxicity in medical devices, and this was a report authored 
23	by Joel Tichner.  Their conclusion was slightly different.  
24	They said that DEHP poses a potential risk that should not 
25	be ignored, and that alternatives should be sought. 

			22 1		There is also another risk assessment that is
	2	still going on, and this was done by the Center for 
	3	Evaluation of Risk to Human Reproduction, which is part of 
	4	the National Toxicology Program, headed by Michael Shelby.  
	5	They have an expert panel of toxicologists and they have met 
	6	twice to discuss DEHP toxicity in humans, and they haven't
	7	come to a conclusion yet.  They have one more meeting coming 
	8	up in July, 2000.  I think this is going to be a very good 

	9	report, based solely on science, and we are looking forward 
10	to that report coming out. 
11		[Slide]
12		At the end of the workshop we had a discussion 
13	panel, and this discussion panel was clinically oriented.  
14	We had transfusion experts, we had pediatricians, 
15	epidemiologists, and we were looking for a clinical debate 
16	on toxicity and use of DEHP in blood products.
17		These are some of the highlights that the panel 
18	was discussing:  One of the points that they brought up is 
19	that DEHP has an extensive clinical record, 30-40 years of 
20	transfusions with DEHP plastic bags, and there is no clear- 
21	cut toxicity to humans that has been demonstrated.

22		They pointed out that immediate withdrawal of DEHP 
23	is not warranted because it would significantly affect the 
24	blood supply and alternatives to DEHP are not well studied. 
25		An important point that they brought up is that 

			23 1	past studies of DEHP toxicity may not have looked at the
	2	appropriate endpoints.  Most of the studies done in the past 
	3	have looked at carcinogenicity and recent reports indicate 
	4	that carcinogenicity in rodents doesn't have the same 
	5	mechanism as would be found in humans.  The more appropriate 
	6	endpoints now would be reproductive toxicity.
	7		They also pointed out that there are 
	8	subpopulations of patients, such as pediatric patients, that 
	9	may be more sensitive to DEHP or other plasticizers because 
10	of undeveloped metabolic pathways and higher per kilogram 

11	exposure.  They suggested that new clinical trials should be
12	set up to evaluate levels of DEHP that patients are being 
13	exposed to currently and corresponding toxicity in humans. 
14		[Slide] 
15		Since the workshop, there have been a couple more 
16	interesting updates on the risk of DEHP.  The International
17	Agency for Research on Cancer has downgraded DEHP from what 
18	for many years was labeled as "possibly carcinogenic to 
19	humans," to "not classifiable as carcinogenic to humans."  
20	This is because it is now felt that the carcinogenicity in 
21	rodents is not applicable to humans.
22		The Center for Evaluation of Risk to Human 
23	Reproduction has had two out of the three meetings and they 

24	have released some preliminary conclusions.  It sounds as if 
25	they will conclude that doses that cause testicular effects 

			24 1	in rodents are only about 10-fold higher than what may be
	2	reached in some medical procedures, such as dialysis or 
	3	ECMO.  So, they are concerned about this type of toxicity 
	4	going on with the use of current medical devices. 
	5		[Slide] 
	6		From our perspective, this is what we got out of
	7	the workshop.  It again demonstrated that there are benefits 
	8	to DEHP in red cell storage, and that to remove DEHP from 
	9	use currently would significantly affect the supply of red 
10	cells. 
11		It was also pointed out that human dose and
12	toxicity from DEHP in blood products is not well defined but 
13	should be reinvestigated.  Some of the things that were 
14	suggested in the workshop were studies of multiply 
15	transfused individuals such as sickle cell and thalassemia 
16	patients, and special subpopulations of patients such as
17	infants exposed to extracorporeal membrane oxygenation.  
18	This is an interesting situation were there is IV 
19	application of DEHP exposure.  Most of the studies that have 
20	been done in the past with animals are oral exposure because 
21	it is very difficult to do IV exposure in small rodents. 
22	So, this is an interesting colleague situation where we can 
23	look at effects of DEHP through IV infusion in humans. 

24		The reproductive toxicity of DEHP should be an 
25	area of active research, and there are a couple of studies 

			25 1	ongoing right now that are international reproductive
	2	toxicity studies.  This will show whether offsprings of 
	3	treated animals do have any type of reproductive effects.  
	4	We would also encourage development of alternative 
	5	plasticizers to improve the efficacy in storage, as well as 
	6	improve the toxicity as compared to DEHP.  As with any other
	7	complicated issue, this may in the future become a Blood 

	8	Product Advisory Committee issue.  We will be looking for 
	9	your advice.  Thank  you very much. 
10		DR. HOLLINGER:  Any questions for Dr. Vostal?  
11	Yes, Dr. Simon?
12		DR. SIMON:  I guess the only comment is that, you 
13	know, this is such an old issue.  When I was with NIH in 
14	1972-74 there were several contracts let to look at 

15	toxicity, and the conclusion then was that it wasn't 
16	significant.  I guess it just keeps rearing its head and
17	people continue to be uncomfortable but it seems that with 
18	the passage of time it becomes sort of a non-issue. 
19		DR. HOLLINGER:  Yes, Dr. Mitchell? 
20		DR. MITCHELL:  I guess I am concerned about the 
21	reproductive health aspects of it.  Do you know of any

22	ongoing studies?  You talked about recommendations for 
23	looking at the exposure in humans.  Do you know if there are 
24	any studies looking at the exposure level in humans? 
25		DR. VOSTAL:  Right now, I am not aware of any 

			26 1	studies in humans that are looking at correlating DEHP
	2	exposure and reproductive function.  There are studies going 
	3	on in rodents.  However, there is always going to be a 
	4	problem with these types of studies because most of them are 
	5	oral administration of DEHP and what we are concerned about 
	6	is IV administration of DEHP, and there may be different

	7	metabolic pathways that act on DEHP by different routes. 
	8		DR. MITCHELL:  And, what about epidemiological 
	9	studies that may be linking DEHP to the decrease in sperm 
10	counts that are found in people? 

11		DR. VOSTAL:  I think those would be great studies
12	to do.  Right now there aren't any being conducted.  You 

13	know, I think there is a lack of funding for that right now. 
14		DR. HOLLINGER:  Thank you.  Our third topic is the 
15	report on blood supply monitoring, and Dr. McCurdy is going 
16	to give us an update on the monitoring.
17		   Report on Blood Supply Monitoring 
18		[Slide] 
19		DR. MCCURDY:  As there were a number of new things 
20	that came along leading to increased blood donor deferral 
21	and increased loss due to testing, the Surgeon General asked
22	the Public Health Service to determine how the blood supply 
23	was responding to these and to do some monitoring.  That was 
24	a fairly high priority item that was put forth first by an 
25	internal advisory committee and accepted by the Surgeon 

			27 1	General.
	2		The National Heart, Lung and Blood Institute 
	3	arranged to contract with the National Blood Data Resource 
	4	Center of the American Association of Blood Banks to collect 
	5	and supply the data, and we made an attempt to overcome some 
	6	of the problems in the past in selecting how we would
	7	collect the data. 

	8		[Slide] 
	9		We opted to do a sample of blood centers, and 
10	beginning in the next one to three months we will do the 
11	same thing for hospital transfusion services.  For blood
12	centers, we utilized data from the national surveys that 
13	were originally conducted by Dr. Douglas Surgenor and are 
14	now being conducted periodically by the AABB blood data 
15	center to select, by region of the country, a number of 
16	centers that are within one standard deviation of the mean
17	collection for that particular part of the country. 

18		There were 27 selected.  We had three kinds, as I 
19	recall, of samples.  One was totally random, which generally 
20	is preferred.  One was selected, not quite random but 
21	selected in slightly different fashion, and we opted to do
22	this one because it was weighted to the cities and our major 
23	purpose was to determine whether there was a blood shortage 
24	and, if possible, to predict by trend analysis what is going 
25	to happen. 

			28 1		There were 27 selected, 6 were unable to comply
	2	with the data requirements and there were 6 substitutes, and 
	3	there was 1 late dropout so that the final sample was 26 
	4	centers.  The objective was to get data reported by the 10th 
	5	of the month for the preceding month and have data supplied 
	6	to the National Heart, Lung and Blood Institute for
	7	beginning analysis shortly thereafter.  We are doing, I 
	8	think, as well as might be expected with the timeliness, but 
	9	we are not getting data from all 26 centers by the 10th of 
10	the month. 
11		[Slide]
12		The centers that were selected came online at 

13	various different times.  We began to collect data in 
14	February for the month of January but we also asked the 
15	centers to go back three months and provide us with 

16	retrospective data for October, November and December.  You
17	can see that between 15 and 20 of the centers were able to 
18	do that, the others came online as time went on, with the 
19	last coming on in April, providing data in May. 
20		The data is being collected, as you will see, by 
21	blood group as well as total because most of us in blood
22	banking have long been aware that the groups O, O positive 
23	and negative were much more of a problem than groups A or 
24	particularly AB. 

25		[Slide] 

			29 1		Here you see the total number of red cells
	2	released for distribution.  This is after testing losses.  
	3	There was a little decrease in December and January and 
	4	increase in February, March and a little drop-off in April 
	5	and then a little climb back up in May.  These are 
	6	normalized, if you will, for 26 centers.  That is, we are
	7	dividing by the number of centers that actually provided 
	8	data and multiplying by 26.  So, these are "independent" of 
	9	the number of centers reporting.  On this slide you see not 
10	only the total, in the top line, but also the O positive and 
11	O negative in the bottom line.  We have data for the others
12	but it is not on this slide. 
13		[Slide] 
14		This is looking at the monthly amount of blood 
15	released as a percent of the total that has been released in 
16	this period, here, of 8 months.  So, between 12 and 12.5
17	percent of the blood released during this entire period was 
18	released for distribution in October, and so forth.  The 
19	peak here occurs in March; the drop-off in April.  Some of 
20	these figures, at least at this time, must be looked at with 
21	a bit of a jaundiced eye because there were I think between
22	15 and 20 centers involved here and the May data, which I 

23	got at the beginning of this week, only represents 10 
24	centers of the 26. 

25		[Slide] 

			30 1		We are also asking for inventories taken on the
	2	first and third Wednesday of each month.  These inventories 
	3	represent considerably fewer than the 15 to 20 centers that 
	4	reported at that time because many could not go back and 
	5	look at inventory, either total or by individual blood 
	6	group, several months before.  Again, you can see that there
	7	may be a slight trend upward overall in this but, although I 
	8	haven't analyzed it, I don't believe it is really 
	9	particularly significant.  These inventories are meant to be 
10	taken at a specific time of day on the first and third 
11	Wednesday, and ultimately I think we may be able to do some
12	trend analysis on this. 
13		[Slide] 

14		We are also able to look at inventories by region.  
15	We know which regions of the country the centers are in.  We 
16	do not know what the individual centers are.  They are
17	reported to us under code.  This was to remove any concern 

18	about Big Brother, Sister or whatever looking over the data 
19	and pointing fingers. 
20		[Slide] 
21		This is the mid-Atlantic and southeast sections of
22	the country -- eastern section of the country.  This is the 
23	central section.  Presumably, these are in mid-America where 
24	the blood supply has traditionally been more stable and less 
25	subject to fluctuation, whereas this is in the northeast, 

			31 1	mid-Atlantic and southeast where there is more fluctuation.
	2		I also did this in part because I received a 
	3	report from the America's Blood Centers that a number of 
	4	their centers had gone out with appeals in the month of May, 
	5	toward the end of May and early June.  This was earlier than 
	6	they usually did in the past.  It wasn't clear whether this

	7	was increased utilization for which we now have no data or 
	8	whether it was decreased collections.  We are not able to 
	9	detect decreased collections.  On the other hand, ours is 

10	macro data and individual centers are dealing with their own 
11	individual micro information.
12		I think I can stop here.  If there any questions, 
13	I would be glad to answer them. 
14		DR. HOLLINGER:  Any questions of Dr. McCurdy?  
15	Yes, Dr. Simon? 
16		DR. SIMON:  I think this information is extremely
17	useful, and I am pleased that the effort is being made to 
18	collect it and take a look at it.  I know that a lot of the 
19	focus is on the fallout in terms of donors from the 
20	exclusion from people who have been in the United Kingdom 
21	for six months, from 1980 to 1996.
22		I think one of the issues that we are dealing with 
23	in both plasma and the blood industry there is that the 
24	publicity caused many people to self-defer and not show up 
25	so that we can't get accurate data on just how many people 

			32 1	we are losing because that question was introduced.  So, I
	2	think the kind of data that Dr. McCurdy is giving us is the 
	3	kind of data on which we will have to rely, that is, what is 
	4	the final impact on the blood supply. 
	5		I would also point out that we have tended not to 
	6	monitor the supply of source plasma.  At our last liaison
	7	meeting we discussed this with the FDA but there is now data 
	8	showing a significant fall-off in source plasma donations, 

	9	possibly in the range of, you know, 10-20 percent over the 
10	last couple of years, which has not yet impacted final 
11	product but could.  So, I think there are a number of supply
12	issues that may be of importance to this committee and the 
13	agency in the upcoming months. 
14		DR. MCCURDY:  It is hard for me to speak off the 
15	cuff on this, but I think that the Institute would be quite 
16	willing to listen to proposals that might have a similar

17	type of approach to the plasma industry.  I don't know 
18	whether there is anything collected in that which is 
19	universal but we would at least be willing to talk. 

20		DR. SIMON:  The main universal is that all new 
21	plasma donors are checked through the National Donor
22	Deferral Registry.  So, ABRA does have a running total of 
23	those checks and of the new plasma donors who have shown up 

24	at centers.  There has been a bit of a problem getting other 
25	sources of data because they are proprietary in nature and 

			33 1	these centers do compete with each other in similar
	2	communities, but I think it is certainly something we need 
	3	to pay more attention to. 
	4		DR. MCCURDY:  In this, we tried to avoid some of 
	5	the proprietary issues and so forth by having it go through 
	6	a so-called neutral party and having us know by code and
	7	sections of the country but not by individual center what is 
	8	going on. 
	9		DR. HOLLINGER:  Dr. Epstein? 
10		DR. EPSTEIN:  Paul, looking at the last graph, the 
11	drop in mid-Atlantic and southeast looks precipitous and
12	large.  I just wondered if you could comment on how accurate 
13	the data are on that graph and then, secondly, a response to 
14	Toby Simon, the Canadians have tried to look at the question 
15	of measuring the impact of the U.K. related exposure 
16	deferral by doing surveys of donors, including non-returned
17	donors.  If, in fact, most centers in the U.S. which have 

18	implemented U.K. deferral have only done so in late March 
19	and April, it may very well be the case that what we are 

20	seeing in May is correlated, but I wonder if there has been 
21	any thought in the blood community about doing a survey
22	similar to what the Canadians did to actually find out if 
23	that is so.  Of course, if the dip goes away we perhaps 

24	don't care but if it doesn't go away it might help to know 
25	why it is happening. 

			34 1		DR. MCCURDY:  The sample for May which showed that
	2	is a sample that had six centers from the east area, 
	3	northeast, mid-Atlantic and southeast, and four centers from 
	4	the midwest.  There were no centers from the west that have 
	5	come in with reports yet.  And, it is only ten.  Ten are 

	6	extrapolated for the whole 26 sample.  I think the closer
	7	you get to the 26 the more comfortable I am with that 
	8	extrapolation.  So, I think we need more data and we will 
	9	certainly share that within the PHS and we will probably 

10	ultimately, when we get enough to make it meaningful, try to 
11	arrange to share it much more widely.
12		DR. HOLLINGER:  Paul, I like your metaphor but I 
13	don't think this committee ever wants to look at things with 
14	a jaundiced eye -- 

15		[Laughter] 
16		-- but, you know, one of the issues with the
17	apheresis donors -- I think Ron Gilcher commented that he 
18	was concerned about how that might make an impact.  I know 
19	you looked at whole blood and a few other things, but what 
20	has happened with the apheresis donors, or have you talked 
21	to him?  I am particularly interested in that because he

22	said a lot of these people are people who have traveled a 
23	lot, extensively, and have been gone. 
24		DR. MCCURDY:  I have not talked with Ron 
25	specifically on this issue.  About a week ago we made a 

			35 1	presentation in front of the TSE advisory committee, and
	2	that was focused primarily on what we could learn about the 
	3	U.K. deferrals and timing. 
	4		Unfortunately, most of the centers came on fairly 
	5	late, the largest number, and the others came on 
	6	intermittently throughout which made analysis a real
	7	challenge.  We could not detect anything that appeared to 

	8	happen before and after centers that provided that kind of 
	9	data came online with U.K. deferral.  In that, we looked at 
10	the apheresis situation.  We are collecting information on 
11	platelets and apheresis platelets, and we were unable to

12	detect any real change in the availability of apheresis 
13	products in that period of time.  But analysis is very 

14	difficult and this is macro data.  We heard some anecdotes 
15	at the TSE advisory committee that there were problems in 
16	collections and they did, at least in some instances, seem
17	to be related to U.K. deferral. 
18		DR. HOLLINGER:  Yes, Toby? 
19		DR. SIMON:  Just as an anecdotal addition, from 
20	our company with 64 centers, the thread that is most 
21	consistent is proximity to Air Force installations and a

22	little bit of some of the other services, but it is those 
23	centers that draw from that population, either active or 

24	retired, that are located geographically in such a way where 
25	we have seen the biggest impact.  That has been the only 

			36 1	consistent finding.  There has been a little bit also in the
	2	plasma industry to correlate with Dr. Gilcher's observation 
	3	that donors in specialty centers that tend to be higher 
	4	socioeconomic individuals and travel more, there is a slight 
	5	tendency to pick up a little more there, but the Air Force 
	6	one has been the most consistent marker.
	7		DR. HOLLINGER:  Thank you.  Thank you, Paul.  I 
	8	look forward to the next report.  The final report is the 
	9	summary of Transmissible Spongiform Encephalopathies 
10	Advisory Committee meeting, which was held June 1st and 2nd 
11	of this year, and Dr. Asher will give us an overview and
12	comments about that meeting.  Dr. Asher? 
13	    Summary of Transmissible Spongiform Encephalopathies 
14		       Advisory Committee Meeting 
15		DR. ASHER:  Thank you.  Good morning. 
16		[Slide]
17		The TSE Advisory Committee met on June 1st and 2nd 
18	and addressed two issues.  First, the issue of potential 
19	possible deferral of blood donors with a history of travel 
20	or residence in BSE countries other than the United Kingdom, 
21	as well as a look back, obviously, concerning the U.K. 
22	Second, the possible effects of leukoreduction on reducing 
23	the risk of transmitting CJD by blood. 
24		As you may recall, although the risk of 
25	transmitting CJD via blood and blood products is entirely 

			37 1	theoretical, the FDA has taken a very conservative position
	2	on the issue as recently as November of 1996 recommending 
	3	withdrawal not only of blood and components but also of 
	4	plasma derivatives where a donor was belatedly recognized as 
	5	having CJD or being at increased risk of CJD. 
	6		[Slide]
	7		However, by the end of 1997 it was clear that 
	8	there was no demonstrated risk, detectable by 
	9	epidemiological studies, of CJD in implicated plasma 
10	derivatives in transmitting disease.  The withdrawals were 
11	recognized as not substantially reducing the theoretical
12	risk, at least for recipients receiving multiple exposures 
13	when at least 25 percent of large plasma pools used to 
14	produce derivatives were likely to contain a contribution 

15	from at least one donor who would ultimately get sporadic 
16	CJD.  There was no screening question that could defer such

17	a donor and no laboratory test available to detect the risk.  
18	Withdrawals had failed to retrieve most CJD implicated 

19	products anyhow, and CJD withdrawals were contributing 
20	significantly to shortages of some plasma derivatives.  So, 
21	in January of 1998 the PHS Advisory Committee on Blood
22	Safety and Availability recommended that the FDA could relax 
23	policy sufficient to relieve those shortages without 
24	seriously endangering public health. 
25		[Slide] 

			38 1		In August of 1998 the Surgeon General, Dr. David
	2	Satcher, announced the new policy which was then elaborated 
	3	in guidance issued by the FDA in September of 1998.  The 
	4	agency recommended continued deferral of donors with CJD or 
	5	increased risk of CJD and continued quarantine and retrieval 
	6	of blood and components, but no longer recommended
	7	withdrawal of plasma derivatives prepared from pools to 
	8	which those donors with classical CJD or increased risk had 
	9	contributed.  However, withdrawal of plasma derivatives and 
10	quarantine of intermediates prepared from pools to which any 
11	donor who developed new variant CJD -- CJD attributable to

12	infection with bovine a spongiform encephalopathy agent -- 
13	those derivatives would still be withdrawn. 
14		[Slide] 
15		The reasons for increased concern about donors 
16	during the incubation period of CJD are as follows:  First,

17	less is known about the pathogenesis of new variant CJD than 
18	sporadic CJD. 
19		Second, new variant CJD is an emerging infection 
20	not yet recognized in the United States and lymphoid tissues 
21	of patients with CJD, and even at the end of the incubation
22	period of new variant CJD, contain detectable protease 
23	resistant prion protein while those in patients with 
24	sporadic CJD do not, which implies that the blood which 
25	contains lymphoid cells might be more infectious in patients 

			39 1	with new variant CJD than it is in sporadic CJD.
	2		Finally, authorities in the United Kingdom decided 
	3	not to source plasma for preparing derivatives from their 
	4	own U.K. donors which implied a certain lack of confidence 
	5	in the safety of the plasma.  The FDA then felt compelled to 
	6	consider the issue of donors who had been potentially
	7	exposed to the BSE agent while traveling or residing abroad. 
	8		[Slide] 
	9		 Following consideration by the TSE Advisory 
10	Committee in December of 1998 and June of 1999, the agency 
11	recommended deferral of donors who had resided in the United
12	Kingdom for six months or more cumulative between January 

13	1st, 1990 and end of December, 1996, and deferral of donors 
14	who had received injections of bovine insulin from the 
15	United Kingdom, but did not recommend withdrawal of plasma 
16	derivatives for U.K. residents at any period or for exposure
17	to injectable bovine products. 
18		Finally, there was a commitment made that the 

19	Public Health Service would monitor the effects of this 
20	revised broad policy on the blood supply, and as part of 
21	that commitment the TSE Advisory Committee meeting was held
22	on June 1 and 2. 

23		[Slide] 
24		There is reason to think that exposures to the BSE 
25	agent in the United Kingdom have been markedly reduced after 

			40 1	1996 and, in general, recent news from the United Kingdom is
	2	guardedly good.  Perhaps it is fair to say that at least it 
	3	is not bad news in that cases of BSE, after peaking at the 
	4	end of 1992, have continued to decline although there were 
	5	over 2200 cases diagnosed in cattle last year, and this year 
	6	in the first third of the year there have been more than 300
	7	cases of BSE recognized, but the various precautionary 
	8	measures to reduce exposure are well in place and the rate 

	9	of recognition in cattle continues to drop markedly.  Cases 
10	of new variant CJD continue to increase but not at an 

11	accelerating rate and interim results of a survey of
12	lymphoid tissue from normal, healthy, younger patients, 3000 
13	of them, have not revealed any protease-resistant prion 
14	protein. 
15		[Slide] 
16		But concerns about BSE in some other European
17	countries are increasing, and I just want to remind you that 
18	since January of 1998 the United States Department of 

19	Agriculture has considered all European countries to be 
20	suspect as BSE countries. 
21		[Slide]
22		During the past year diagnosed BSE cases have 
23	increased in several European countries and a new country, 
24	Denmark, has been recognized as having the disease in its 
25	native-born cattle.  It has also been recognized that 

			41 1	substantial exports of U.K. cattle beef and beef products
	2	continued from the U.K. to several European countries during 
	3	the high BSE years.  France may have imported at least 5 
	4	percent of its meat and meat products from the U.K. during 

	5	that period.  The Netherlands also imported a significant 
	6	amount of beef, and other countries did as well.  Finally,
	7	cases of new variant CJD have increased.  There are now 
	8	three cases confirmed and others are under suspicion. 
	9		[Slide] 
10		So, on June 1, the TSE Advisory Committee was 

11	asked to evaluate new information concerning new variant CJD
12	and BSE in the United Kingdom, France, as well as BSE in 
13	other European countries besides France and the U.K. 
14		[Slide] 
15		And, to look at any effects that recent changes in 
16	blood deferral policy might have had on the blood supply and
17	blood products in the United States, as well as effects to 
18	be anticipated if additional deferral of donors was to be 
19	recommended.  Dr. McCurdy presented earlier information from 
20	the same survey that you heard this morning. 
21		[Slide]
22		The committee reviewed recent events concerning 

23	new variant CJD and BSE in the United Kingdom.  They looked 
24	at projections of potential exposures to BSE and cases of 
25	new variant CJD recognized and expected to occur in France 

			42 1	and the Republic of Ireland, and CJD and BSE surveillance in
	2	Switzerland where there have been no cases of new variant 
	3	CJD recognized.  They also heard USDA estimates of BSE 
	4	occurrence in various European countries. 
	5		[Slide] 
	6		They looked at estimates of possible human
	7	exposure to the agent elsewhere in the European Union and 

	8	heard results of a very interesting assessment by Canadian 
	9	authorities of the risk of new variant CJD in Canadians who 
10	had traveled to the United Kingdom and to France, and 

11	finally reviewed the effects of recent policies on the
12	supply of blood and blood products in the United States. 
13		[Slide] 
14		When asked if the committee thought that the 
15	available scientific data on the risk of transmitting CJD 
16	and new variant CJD warranted a change in the current FDA
17	policy regarding deferrals of blood and plasma donors and 

18	product retrievals based on their travel or residence in the 
19	United Kingdom, the committee members voted three in favor 
20	and 15 opposed.  The members felt that insufficient time had 
21	passed since the implementation of the new policy to assess
22	its effects on supply and they were, therefore, reluctant to 
23	advise any further changes at the moment.  There were a 

24	couple of contingent questions concerning it.  They felt 
25	comfortable staying with the current policy concerning 

			43 1	deferral of donors resident in the U.K.
	2		[Slide] 
	3		When asked if FDA should recommend deferral from 
	4	blood or plasma donations for persons with a history of 
	5	travel or residence in France, the vote was 17 against such 
	6	deferral and only one in favor.  The committee seemed
	7	impressed that both the assessments of exposure to U.K. beef 
	8	and beef products in France and the rates of new variant CJD 
	9	both suggested that the risk to residents of France was only 
10	about 5 percent of that in the U.K.  The apparently 
11	concluded that such a risk was not sufficiently significant
12	to recommend any deferral even for much longer periods of 
13	residence in France. 
14		[Slide] 
15		Essentially the same advice was offered for donors 
16	resident in other BSE countries, although there was concern
17	about the lack of information concerning potential exposures 
18	to BSE in some of those countries. 
19		[Slide] 
20		The secondary issue of possible effects of 
21	leukoreduction on CJD risk was addressed.  Since a large
22	part of the infectivity in blood of rodents experimentally 
23	infected with TSE's is in the buffy coat, it has been 

24	proposed that leukofiltration might reduce the risk of 
25	blood-borne transmission of CJD, and several European 

		44 1	countries have decided to do that as a precautionary measure
	2	to reduce the risk of transmitting CJD.  So, the committee 
	3	was asked to consider evidence that leukoreduction might be 
	4	expected to reduce the theoretical risk of transmitting CJD 
	5	and new variant CJD by human blood, blood components and 
	6	plasma derivatives and whether the reduction in risk is
	7	likely to be substantial enough to have practical value and, 
	8	consequently, whether universal leukoreduction of blood and 
	9	blood components should be recommended by the FDA for that 
10	purpose. 
11	          [Slide]
12	          The committee reviewed information on the work of 
13	this committee, that is, recent recommendations and 
14	prospects for the implementation of universal leukoreduction 
15	techniques and theoretical applications of leukoreduction to 
16	remove TSE agents from blood, and the possible role of
17	leukocytes in experimental pathogenesis of TSEs in rodents 
18	and the implications for human blood, the main one being 
19	that since circulating cells of lymphoid origin seemed to be 
20	obligatory for pathogenesis of TSEs in rodents, it was to be 
21	expected that there would be infected cells in the blood of
22	humans as well, although that has never been convincingly 

23	demonstrated.  They also looked at TSE infectivity in the 
24	blood of experimentally infected rodents and that 
25	implementation for human disease as a model.  The available 

			45 1	information was very limited and one small but troubling
	2	study even suggested that animals infected by the 
	3	intravenous route cleared infected cells better than they 
	4	did the same amount of infectivity presented in a cell free 
	5	form. 
	6		[Slide]
	7		So, when asked if leukoreduction can be expected 
	8	to reduce significantly the infectivity theoretically 
	9	present in blood of persons during the course of CJD and new 
10	variant CJD, the committee concluded that available data 
11	were simply insufficient to decide and, with two dissenting
12	votes, they advised that leukoreduction not be recommended 
13	as a precaution to reduce the risk of transmitting CJD until 
14	its potential effects are better understood.  Thank you very 
15	much. 
16		DR. HOLLINGER:  Thank you, Dr. Asher.  Any
17	questions for Dr. Asher on the issues raised on TSE?  If 

18	not, thank you.  Are there any general comments from the 
19	committee before we move into the next major portion of our 
20	meeting today?  If not, we are going to move into the next 
21	portion of our meeting.  This is going to be a discussion on
22	plasma pool screening by nucleic acid tests for HAV.  Robin 
23	Biswas will give us an introduction and background to this 
24	issue.  Robin? 
25	        Plasma Pool Screening by Nucleic Acid Tests 

			46 1		         for Hepatitis A Virus
	2		      Introduction and Background 
	3		DR. BISWAS:  Good morning.  This will be music to 
	4	your ears -- 
	5		[Laughter] 
	6		[Slide]
	7		The FDA has received a submission from a 
	8	manufacturer for plasma derivatives for the plasma screening 
	9	of minipools by using nucleic acid tests for hepatitis A 

10	virus and human parvovirus B19.  Currently, the agency has 
11	articulated policies for NAT plasma pool testing for
12	parvovirus B19, human immunodeficiency virus, hepatitis B 
13	virus and hepatitis C virus, but has not yet developed a 
14	policy in regard to HAV plasma pool testing, and that is 
15	what we will be discussing for the rest of this morning, 
16	namely, plasma pool screening by nucleic acid tests (NAT)
17	for hepatitis A virus (HAV). 
18		[Slide] 

19		The issues that will be discussed here stem from a 
20	manufacturer's intention to perform testing of minipools of 
21	samples from donated plasma units by HAV NAT and then
22	discarding the HAV positive units, thereby withholding them 
23	from the manufacturing pool from which plasma derivatives 

24	are made.  The intention is to lower the viral load in the 
25	manufacturing pool from which the plasma derivatives are 

			47 1	made.  This should enhance the margin of safety for these
	2	plasma derivatives. 
	3		[Slide] 
	4		While transmission of HAV by plasma derivatives is 
	5	not a major clinical problem, plasma derived volume 
	6	expanders and immunoglobulins have been historically safe,
	7	rare transmissions by coagulation Factors VIII and IX have 
	8	been reported, and Dr. Farshid will go into this in a little 
	9	more detail later on. 
10		I should say at this point that there is a 
11	recommendation for persons receiving coagulation factors to
12	receive vaccine hepatitis A.  Stephen Feinstone will go into 
13	this in a little bit more detail later. 
14		[Slide] 
15		Solvent/detergents are widely used in the 
16	manufacture of coagulation factors, and immune globulins to
17	inactivate lipid-enveloped HIV, HBV and HCV, and are very 

18	effective in doing this, but HAV is a non-lipid-enveloped 
19	virus and is not inactivated by these solvent/detergents. 
20		[Slide] 
21		There is an underlying general plasma pool NAT
22	testing assumption here:  If a certain pool of samples from 
23	donated units is NAT positive, then a particular positive 
24	unit and donor can be identified. 
25		[Slide] 

			48 1		In the past, FDA has viewed plasma NAT pool
	2	testing of samples of units as either in-process control in 
	3	which the donor is not identified or as donor screening 
	4	where the donor is identified. 
	5		[Slide] 
	6		In 1997 when NAT pool testing was under
	7	development for HIV, HBV and HCV, the Blood Products 
	8	Advisory Committee endorsed FDA's position that NAT pool 
	9	testing for these three viruses should be considered donor 
10	screening and that the donor should be identified.  Clinical 
11	studies to validated the clinical efficacy of NAT for these
12	viruses under IND is required. 
13		In the case of parvovirus B19 NAT pool testing, in 
14	September last year the committee agreed with FDA that 
15	studies to validate clinical efficacy of B19 NAT under IND 
16	for plasma for further manufacture need not be required. 
17	This was considered then to be in-process control testing 
18	and the donor need not be identified.  In this case, the NAT 
19	test requires validation as an analytical test only in 
20	regard to sensitivity, specificity and reproducibility, and 
21	Sheryl Kochman will be going into this a bit later.  In
22	regard to parvo B19 NAT testing, no clinical correlates need 
23	be established if no decisions regarding donor or recipient 
24	management are taken. 
25		[Slide] 

			49 1		I would now like to describe briefly, in a bit
	2	more detail, some of the decisions that need to be made when 
	3	NAT pool testing of samples of donated units for a 
	4	particular virus are introduced, and also the types of data 
	5	and information that need to be considered to make those 
	6	decisions.
	7		[Slide] 
	8		The first decision -- do you go ahead an identify 
	9	the individual donor? 
10		[Slide] 
11		Are you going to retrieve products from that
12	donor? 
13		[Slide] 
14		Are you going to retrieve previously collected, 

15	non-pooled plasma units in the case of source plasma, over 
16	on the left of the slide?  If it is recovered plasma that is
17	under question from volunteer donor whole blood units, does 
18	one then retrieve transfusable components from the current 
19	donation?  The previous donation? 
20		[Slide] 
21		Are you going to notify the donor that the donor
22	has a positive test result? 
23		[Slide] 
24		Are you going to then defer that donor for a 
25	finite period, or perhaps I should also have added 

			50 1	indefinitely?  These are questions.
	2		[Slide] 
	3		Are you going to notify the recipients of the 
	4	transfusable components? 
	5		[Slide] 
	6		These considerations used for deciding whether
	7	viral NAT pool testing for a particular virus is in-process 
	8	control or donor screening can be broken down into these 
	9	three items:  Donor-related criteria, product-related 
10	criteria, and recipient-related criteria. 
11		[Slide]
12		In regard to the donor-related criteria, decisions 
13	need to be based on the medical and technical feasibility of 
14	donor deferral from donation and donor counseling as to 

15	treatment and avoidance of transmitting infections to 
16	others.
17		[Slide] 
18		In regard to product-related criteria, decisions 
19	should be based on the medical benefit and technical 

20	feasibility of quarantining or destroying the positive 
21	plasma unit, and that is actually what we are doing here;
22	quarantining or destroying other transfusible components 
23	from whole blood donations from the same whole blood 

24	donation; and quarantining and destroying of unused, 
25	previously collected window period donations. 

			51 1		[Slide]
	2		In regard to the recipient-related criteria, 
	3	decisions should be based on the usefulness of notifying 
	4	recipients of previously collected window period 
	5	transfusible products in regard to recipient testing of 
	6	diagnostic procedures, treatment if available and necessary,
	7	and counseling in avoidance of transmitting the infection to 
	8	others. 
	9		[Slide] 
10		To provide a basis for decision-making, one needs 
11	to consider the relevant aspects of the particular viral
12	infection.  In the case of HBV, HCV and HIV and B19, here 
13	are the criteria that were examined to come to the two 
14	different ways of handling pool testing.  I have left HAV 
15	blank. 
16		The criteria that we used were severity of
17	disease, window period and chronic infections.  In the case 
18	of HBV, HCV and HIV, it can be fatal or causing significant 
19	morbidity.  In the case, of B19 it is mild or asymptomatic 
20	in most cases. 
21		The window period for the "big three" -- there can
22	be a long period before seroconversion, and prior donations 
23	may be infectious despite negative tests.  For B19, there is 
24	a short period before seroconversion, and there is a short 
25	duration of disease. 

			52 1		In regard to chronic infections, individuals may

	2	remain infectious for life.  This is true for HIV; it is 
	3	true for 85 percent of HCV cases and 5 percent of HBV cases.  
	4	In regard to B19, the disease is usually self-limiting.  
	5	Another consideration was that anti-B19 could be beneficial 
	6	for IG products so if somebody has a NAT positive test and
	7	they are going to quickly seroconvert, then it may be 

	8	beneficial actually to have their units in the pool.  
	9	Symptomatic disease is rare but the infection and antibody 
10	prevalence is not rare.  So, what we are saying there is 
11	that there is a high prevalence of immunity in the
12	population.  So, if somebody gets B19 they will most likely 
13	be immune to it. 

14		[Slide] 
15		In regard to donor-related criteria for HBV, HCV, 
16	HIV and B19 NAT pool testing, it was decided, because of the
17	slide that I showed you earlier on the nature of the 
18	diseases, that deferral was appropriate for HIV, HBV and HCV 
19	and not really necessary for B19.  We also took into account 
20	that treatment is generally available for HBV, HCV and HIV 
21	in this country and for B19 there is none usually indicated. 
22	In regard to avoidance of secondary infections, of course, 
23	people should be counseled to do that in case of HBV, HCV 
24	and HIV, and it can be done and should be done.  In the case 
25	of B19 there is nothing really you can do about that. 

			53 1		[Slide]
	2		In regard to product-related criteria and NAT pool 
	3	testing for these viruses, the following decisions were 
	4	made:  Quarantine and destroy the positive plasma unit, yes 
	5	in both of the cases.  Quarantine and destroy components 
	6	from the same donation when that is possible.  It is being
	7	done.  In regard to lookback, I should say that in regard to 
	8	HBV, HCV in regard to components, they are not used and 
	9	source plasma units, they aren't used.  So, previous 
10	donations are not used.  This is all being done under IND 

11	for HBV, HCV and HIV.  In regard to notification, it does
12	take place if the previous unit is undiluted, that is, if a 
13	single unit does have a NAT-positive test notification is 
14	apparently taking place.  In regard to B19, there is no 

15	lookback. 
16		[Slide]
17		In regard to recipient-related criteria for NAT 
18	pool testing, it would be appropriate to consider all of 
19	these criteria -- testing, treatment and avoidance of 
20	secondary infections, if a person received transfusible 
21	components from a NAT-positive collection.  In the case of
22	B19, this is really not necessary or not considered the 
23	thing to do. 
24		[Slide] 
25		I think at this stage, I will go through FDA's 

			54 1	current thinking.  I will do this so that when you hear the
	2	other speakers you can put the information that they will 
	3	give you into this framework. 
	4		Well, our current thinking is that validated HAV 
	5	NAT minipool testing enhances the margin of safety for 
	6	plasma derivatives.  So, we do encourage that.
	7		We believe that donors of HAV NAT positive units 
	8	should be informed.  If a person knows that they are HAV NAT 
	9	positive, it is possible that they could take preventive 
10	measures to prevent transmission to others in close 
11	contacts, to their family members.  Of course, this begs the
12	question whether persons who are HAV NAT positive and 
13	without symptoms, whether they are, in fact, infectious.  

14	This is a little bit controversial and Steve Feinstone will 
15	go into that later today.  Donors could possibly benefit 

16	from a timely administration of immune globulin.  I should
17	also say that this is not an established practice and it is 
18	not a recommendation, but a patient with an HAV NAT positive 
19	test result could go and talk to his or her physician about 
20	it. 
21		Another reason that we believe that donors with

22	HAV NAT positive units should be informed is that their 
23	close contacts could also possibly be given preventive 

24	immune globulin.  There are a number of technical problems 
25	with this but, basically, I think it is correct to say that 

			55 1	at the FDA at the moment we believe that people who are HAV
	2	NAT positive should be informed of the result.  Steve 
	3	Feinstone wanted me to mention to everyone that HAV 
	4	(hepatitis A) is a reportable disease in most states. 
	5		Unpooled units donated in the last three months 
	6	should be retrieved, and donors should be deferred for three
	7	months.  The basis for this was that the incubation period 
	8	for HAV, from exposure to symptoms, varies from about two 
	9	weeks and the longest that has been reported is eight weeks, 
10	with the majority of cases three to six weeks incubation 
11	period.
12		Recipient tracing in the case of transfusible 
13	components is not necessary because of the extremely few HAV 
14	transmissions by transfusion that have been reported in the 
15	world literature.  Individual donations, therefore, also 
16	need not be HAV NAT screened.
17		So, that is all I have to say at the moment, and 
18	there will be other speakers going into greater details 
19	about how we regulate certain types of kits and also more 
20	detail about hepatitis A infection.  Thank you. 
21		DR. HOLLINGER:  Thank you, Robin.  I forgot to
22	mention that for this section we have a guest, Dr. Raymond 
23	Koff, from the University of Massachusetts.  Ray, just raise 
24	your hand so we can see you.  Ray will be offering any 

25	expert comments as an expert in hepatitis A.  So, we are 

			56 1	delighted that you are here, Ray.  Thank you.  Yes, Toby?
	2		DR. SIMON:  Can I ask a question of Dr. Biswas?  I 
	3	know this is a matter under discussion but at the present 
	4	time anyone who has had hepatitis after the age of eleven is 
	5	permanently deferred.  Are you suggesting through this that 
	6	either that would be changed to three months or that there
	7	would be a distinction between those who had a case of 
	8	hepatitis versus those who had an HAV NAT? 
	9		DR. BISWAS:  Currently, the way we are 
10	interpreting that is that somebody who has a history of a 
11	clinical, symptomatic hepatitis after the age of eleven is
12	deferred.  You know, for certain test results we have said 
13	that just a positive test result, for example, ALT or just 
14	an anti-core with no symptoms, in those cases the donor need 
15	not be deferred.  So, I would think that if one just had an 
16	HAV NAT positive test result without any symptoms at all,
17	you know, I think that that would be then for a three-month 
18	deferral. 
19		DR. HOLLINGER:  Yes, Jay? 
20		DR. EPSTEIN:  I think the problem, Toby, is that 
21	it would conflict with the current recommendation and that

22	we might want a center to request a 641-20 exemption.  As 
23	you are aware, the whole issue of dealing with history of 
24	hepatitis has been under discussion with the advisory 
25	committee and we hope to bring it to the fore with a rule- 

			57 1	making initiative on donor suitability.
	2		We recognize that we really have not harmonized 
	3	all our thinking.  One of the options that we did discussion 
	4	with the advisory committee -- which the committee actually 
	5	did not favor, much to my surprise -- was that if you had a 
	6	well-documented hepatitis with no known chronic risk
	7	implications you need not have a permanent deferral.  You 
	8	might still want a temporary deferral because of acute 
	9	illness but that there wasn't a need for permanent deferral. 
10	The committee's feeling was that was probably too 
11	complicated, and that the data to support such an exception
12	would be difficult to acquire, and that you would never 
13	actually be sure in the majority of cases so it wasn't going 
14	to be useful. 
15		Basically, what you are pointing out is that if we 
16	are not concerned about chronic disease in the donor why are
17	we deferring the donor?  At this point in time, it is just 
18	not a well-resolved issue.  So, I think the bottom line is 
19	that one might be captured and we might seek exemption 
20	requests but we would almost certainly honor requests based 
21	on well-described data.
22		DR. HOLLINGER:  I think we will move on to the 

23	next section, which is on the regulatory options for HAV 
24	nucleic acid testing, and Sheryl Kochman will discuss this. 
25		     Regulatory Options for HAV NAT 

			58 1		[Slide]
	2		MS. KOCHMAN:  One of the logical next questions 
	3	that you would ask yourself after determining whether or not 
	4	we are going to test for HAV NAT is how would we regulate 
	5	those test kits?  How would FDA expect those test kits to be 
	6	handled?
	7		The routine regulatory options for test kits used 
	8	in testing blood for transfusion include the biologics 
	9	license application.  This was formerly a product license 
10	application and an establishment license application but we 
11	have recently harmonized with the Center for Drugs and we
12	now have one application.  In most cases this is preceded by 
13	the submission of an investigational new drug application or 
14	an IND. 
15		Another approach that has been taken is the pre- 
16	market approval approach.  This is the case where the device
17	is a novel device.  There is no predicate and it comes in as 
18	a Class III device and is reviewed according to pre-market 
19	approval regulations. 
20		Probably what would be considered the least 
21	burdensome form of review would be the pre-market
22	notification or 510(k) submission.  In this case you have a 
23	new device that can be considered substantially equivalent, 
24	or SE, to a predicate device.  A predicate device basically 
25	is a device that has been legally on the market. 

			59 1		[Slide]
	2		Robin focused on what we have done with NAT tests 
	3	in the recent past, but I thought it would be good to give a 
	4	historical approach to how FDA has regulated a number of 
	5	tests that are currently done on the blood supply.  You will 
	6	notice that the tests are sort of up here in the order that
	7	they were implemented in the blood community. 
	8		So, the very first that was done was a syphilis 
	9	test.  It is a required test at this time.  It involves 
10	donor notification, deferral and/or lookback.  
11	Unfortunately, this one is the outlier.  It has been
12	regulated by the 510(k) mechanism, probably largely because 
13	it was the very first kit and the regulatory mechanisms 
14	weren't as well defined at that time. 
15		You will see that the next tests that came along 
16	were tests for HBV.  They were required.  They involved
17	notification, deferral and/or lookback, and we have handled 
18	those previously as PLA and now I am going to refer to them 
19	all as BLA. 
20		The same thing goes then for any other test that 
21	has been required or recommended by FDA where we have
22	recommended notification, deferral or lookback.  We have 
23	generally had those come in as BLAs. 
24		When we get down to ALT, you note that this test 
25	is not a required test.  It is a test that is done 

			60 1	voluntarily by the blood organizations.  Some of them have
	2	notification, deferral and lookback procedures; some of them 
	3	don't.  This kit is handled through the 510(k) mechanism. 
	4		Also, similar to ALT tests are the CMV tests where 
	5	the testing is done voluntarily.  It may not even be done on 
	6	all units.  It may be done on selected units.  There is
	7	generally no notification, deferral or lookback.  The unit 
	8	is simply not used for a particular intended recipient.  
	9	That, again, is handled as a 510(k). 
10		The most recent addition to the list is the Parvo 
11	B19 test kits.  As Robin mentioned in his talk, they are not
12	required.  There is no donor notification, different or 
13	lookback, and they are an in-process control. 
14		[Slide] 
15		As an in-process control, these Parvo B19 test 
16	kits -- normally the plasma fractionator develops and
17	manufactures the test kit in-house.  They then supplement 

18	their biologics license application for their fractionated 
19	product to include an additional in-process test.  FDA 
20	reviews that BLA supplement for the scientific soundness of 
21	the in-process control, and then has the opportunity to

22	review the test and the results during post-approval 
23	inspections to ensure that the test has continued validity.  
24		[Slide] 
25		I also wanted to compare and contrast standards 

			61 1	that are applied under the various mechanisms.  Under the

	2	BLA mechanism we have a dual set of standards.  Both the 
	3	biologic standards and the medical device standards apply.  
	4	The biologics standards include standards for safety, 
	5	purity, potency, sterility, identity and lot release.  The 
	6	medical device standards include compliance with the quality
	7	system regulations, or they are also known as the current 

	8	good manufacturing practices.  There is a substantial number 
	9	of labeling requirements under the medical device standards 
10	and there is a requirement for registration and product 
11	listing.
12		[Slide] 
13		If you look at the standards that are applied for 
14	a PMA, we have only one set of standards that apply here, 
15	and that is the medical device standards but more of them 
16	apply than applied to the BLA.  We have performance
17	standards, sometimes voluntary and sometimes not voluntary.  
18	We have to sorry about safety, effectiveness, quality system 
19	regulations, the labeling requirements and registration and 
20	listing. 
21		[Slide]
22		The standards that are applied under the 510(k), 
23	if it is a Class I it is just general controls and safety, 
24	effectiveness and the rest.  If it is a Class II we add in 
25	the special controls.  So, the Class II 510(k) would be more 

			62 1	stringent than a Class I.
	2		[Slide] 
	3		So, what does this mean in terms of the regulatory 
	4	burden both for FDA and for a manufacturer of the test kit?  
	5	With a BLA there would be extensive clinical trials.  As I 
	6	mentioned before, those clinical trials would have to be

	7	performed under an IND.  There would be a pre-approval 
	8	inspection by Center for Biologics staff.  There would be 
	9	post-approval inspections by the team Biologics staff, and 

10	the kits would be subject to routine lot-by-lot lot release. 
11		For a PMA you can have pretty much the same level
12	of clinical trial testing performed.  There would also be a 
13	pre-approval inspection, but those inspections would be done 
14	by the field.  Post-approval inspections would also be done, 
15	and they would also be done by the field.  But we have no 
16	mechanism built in for lot release for PMA products,
17	although sometimes if we feel the need for it we can request 
18	it. 
19		Finally, the 510(k) mechanism -- there can be 

20	limited clinical trial data.  There are no pre-approval 
21	inspections for 510(k)s and post-approval inspections are,
22	at this point of time, only done on a for-cause basis.  The 
23	limitations on resources are such that the field has pretty 
24	much said they will expend their resources on Class III 

25	devices, which would be the PMA devices, and those other 

			63 1	devices for which there is a need to go out and inspect. 

	2	So, they would be for cause and, again, there is no lot 
	3	release for 510(k) products. 
	4		[Slide] 
	5		So, where does HAV testing right now fall?  The 
	6	current HAV tests that are available have been regulated by
	7	CDRH.  Their current indication for use is detection of 
	8	antibodies to HAV in human serum or plasma.  They are 

	9	regulated as Class III devices, which means that general and 
10	specific controls are insufficient to assure the safety and 
11	effectiveness of the device.  So, they are reviewed under
12	the PMA mechanism.  That was the middle one on the previous 
13	slide. 
14		[Slide] 
15		For the purposes of how CBER might choose to 

16	regulate HAV NAT tests, if for some reason we thought we
17	could review them by other than a PMA mechanism, we do have 
18	the opportunity to utilize Section 207 of FDAMA 1997.  This 
19	is known as the evaluation of automatic Class III 
20	designation or also known as do novo classification. 
21		[Slide]
22		In this case the kit manufacturer would submit a 
23	complete 510(k) for an HAV NAT test, and their specific 

24	intended use would have to be different for it to qualify 
25	for the de novo.  We would recommend that the intent 

			64 1	indication for use be something along the lines of testing
	2	plasma pools for the presence of HAV DNA.  After receipt of 
	3	the 510(k), CDER would review it and determine is there a 
	4	predicate; are there deficiencies in the submission; is the 
	5	device considered low risk; and if there is no predicate, 
	6	could it qualify for de novo classification?
	7		[Slide] 
	8		Under the current system there would not be a 
	9	predicate for a device that is intended for use in testing 
10	of plasma pools for the presence of HAV DNA.  So, CBER would 
11	have to prepare an NSE letter, which means not substantially
12	equivalent.  We would list any deficiencies that we may have 
13	found in the review of the submission.  We would state that 
14	there is no predicate, and we would also state that the 
15	device might qualify for the de novo classification.  After 
16	the firm receives that letter, they have 30 days to submit a
17	request to FDA for a Class II designation under the de novo 
18	classification mechanism. 
19		[Slide] 
20		FDA then reviews that request, and a response to 
21	that request must be made within 60 days.  The things that
22	are reviewed at that time are the previous review of the NSE 
23	510(k); whether or not there were deficiencies; whether or 
24	not they can be addressed.  They base it on the review of 

25	the request for classification.  If the firm has requested 

			65 1	Class II, does the FDA feel that it fits appropriately into
	2	Class II, and there is a risk evaluation made. 
	3		[Slide] 
	4		If, for some reason, the FDA determines that the 
	5	new test kit has to be classified as a Class III, then there 
	6	would be a submission of a PMA or a PDP required.  If, on
	7	the other hand, FDA agreed that the test could be classified 
	8	as Class I or Class II on the basis of the fact that a 
	9	510(k) has already been submitted and reviewed, assuming it 
10	is acceptable, it can be deemed to be cleared.  It can go to 
11	market immediately, and it then serves as the predicate for
12	future submissions of similar kinds of test kits. 
13		[Slide] 
14		Lastly, in all of these cases the kind of data 
15	that will be needed would have to cover accuracy, 
16	specificity, sensitivity, precision and stability.  The data
17	requirements could be different though based on the kind of 
18	submission that would come in.  They would be most 
19	burdensome for a BLA and the least burdensome for a 510(k).  
20	In any case, the applicant would be advised to seek guidance 
21	from CBER to know just how much testing needed to be done. 
22	That is it. 
23		DR. HOLLINGER:  Is this clear to the committee, 
24	how this works?  Are you saying that the FDA prefers this to 
25	be a 510(k) because it requires less extensive evaluation? 

			66 1		MS. KOCH:  I don't think we have made that
	2	decision, that we prefer it that way, but if we follow 
	3	current thinking it would make sense to review it as a 
	4	510(k).  So, there was a little bit of a focus on 510(k) but 
	5	it is not a done deal. 
	6		DR. HOLLINGER:  And what would be the predicate
	7	device for that decision? 
	8		MS. KOCH:  In this case, that is why I was 
	9	explaining the de novo classification.  There is no 
10	predicate for this device.  So, we have to utilize the new 
11	mechanism available to us under FDAMA, the de novo
12	classification.  So, normally when there is no predicate the 
13	device is automatically classified as Class III and 
14	automatically has to come in as a PMA, but just to present 
15	the fact that there is an option if the committee were to 

16	recommend, because of the level of importance of the test,
17	that we could go with a lower regulatory mechanism, the 
18	510(k) mechanism is available to us.  It is just not a 
19	straightforward one. 
20		DR. HOLLINGER:  Thank you.  Jay? 
21		DR. EPSTEIN:  I think that Dr. Koch answered the
22	question, but basically what we are saying is that should 

23	the committee recommend, and should we concur, that there is 
24	not a need for routine donor screening, if you concur that, 
25	nonetheless, when that is done on a minipool you should 

			67 1	identify the positive unit and the infected donor and inform
	2	the donor, that is then medical testing. 
	3		Well, medical testing for hepatitis A has 
	4	precedence in the agency.  It is reviewed as a Class III PMA 
	5	in CDRH.  So, we wouldn't see a real difference between a 
	6	NAT test versus an antibody test versus an antigen test.  It
	7	should be treated as a medical diagnostic.  So, what we are 
	8	trying to explain is that if we get that recommendation from 
	9	the committee and concur, we wanted the committee to 
10	understand what was at stake with oversight of that test as 
11	a medical diagnostic, and what we are saying is that the
12	current system would require that it be a Class III PMA but 
13	that there is a legal mechanism under the FDA Modernization 
14	Act for it to be, if you will, down-classified to a 510(k), 
15	which would then make the oversight more consistent with the 
16	way we deal with other non-required tests which are,
17	nonetheless, sometimes reported as medical information to 
18	the donor, and that would include CMV, syphilis and ALT. 
19		So, what we are saying is if you go that route and 
20	concur that this need not be a routine donor screen, because 
21	it should still be viewed as a medical diagnostic, we are
22	suggesting that there is a route for harmonizing it with the 
23	other tests that are viewed similarly.  Is that helpful, 
24	Blaine? 
25		DR. HOLLINGER:  Yes.  Dr. Koerper? 

			68 1		DR. KOERPER:  Could you please just briefly
	2	refresh my memory as to the difference between Class I, 
	3	Class II and Class III? 
	4		MS. KOCH:  A Class I device is considered a low 
	5	risk device such that general controls, which would be 
	6	registration, listing and adherence to GMPs, are sufficient
	7	to ensure the safety and effectiveness of the device.  A 
	8	Class II device has a little bit higher risk, and it has 
	9	been deemed insufficient to have just general controls.  We 
10	think that there are special controls in addition to general 
11	controls that may be necessary.  A Class III device is
12	considered the highest risk device, and general controls and 
13	special controls alone are inadequate or insufficient to 

14	ensure the safety and effectiveness of the device so we 
15	require the clinical trials and a pre-approval application, 
16	and there are usually some sort of performance standards
17	that are developed along with that application. 
18		DR. HOLLINGER:  Yes, Dr. Chamberland? 
19		DR. CHAMBERLAND:  Perhaps the presentations later 
20	on will help address this point but I wanted a 
21	clarification.  Can we assume that the manufacturer who has
22	approached FDA with his application for HAV NAT testing is 
23	really only providing the agency with data that addresses 
24	the sensitivity, the specificity, the accuracy of the test 
25	itself and has not provided or is intending to provide the 

			69 1	agency with data about the donor notification?  We are all
	2	in the middle of this giant IND trial, if you will, for HIV, 
	3	HCV NAT testing that includes not just how good the test 

	4	works but this whole notification process etc.  So, are 
	5	there any data that are going to come now or at a later 
	6	date?

	7		MS. KOCH:  I think some of the future speakers are 
	8	going to address that a little more. 
	9		DR. CHAMBERLAND:  Okay, because to me that would 
10	be a big consideration as to how frequently donor 
11	notification might happen and how timely that might occur
12	because all of that will impact on whether or not the 
13	potential preventive measures for secondary transmission 
14	could be practical or effective. 
15		DR. BISWAS:  Mary, what we got was basically like 
16	the B19 NAT.
17		DR. CHAMBERLAND:  Okay. 
18		DR. HOLLINGER:  And the agency will probably have 
19	a standard for HAV for sensitivity that can be utilized in 
20	these tests, because that will be critical. 
21		DR. BISWAS:  That is certainly something that we

22	will do.  You know, we haven't got there yet but that is 
23	something we will do. 
24		DR. HOLLINGER:  Just in case this goes into the 
25	record down the line, on your slide 11 for the de novo 

			70 1	classification you had testing of plasma pools for presence
	2	of HAV DNA and it should be HAV RNA. 
	3		MS. KOCH:  Oh, I am sorry. 
	4		DR. HOLLINGER:  If there are no further questions, 
	5	we will go on to the next speaker, and this is a review of 
	6	history of hepatitis A transmitted by transfusion.  Dr.
	7	Farshid? 
	8	 Review of History of Hepatitis A Transmitted by Transfusion 
	9		DR. FARSHID:  Thank you. 
10		[Slide] 
11		Hepatitis A virus, as we have heard already, is a
12	non-enveloped RNA virus, and it is almost always transmitted 
13	by the fecal-oral route through person to person contact or 
14	ingestion of contaminated food or water.  However, rare 
15	cases of transmission by blood and blood products have been 
16	reported, as we will see in the next few slides.   
17	Hepatitis A virus causes only acute infections.  In certain 
18	rare cases there is some prolonged and relapsing infection 
19	which Dr. Feinstone will probably discuss those with you. 

20		[Slide] 
21		As mentioned earlier, the blood-borne transmission
22	of hepatitis A is very rare.  This is based on the absence 
23	of documented cases of hepatitis A in studies of post- 

24	transfusion hepatitis.  These are studies which were 
25	performed in the '70s and '80s to assess post-transfusion 

			71 1	hepatitis due to non-A/non-B.  In those studies, which were
	2	large studies, no cases of hepatitis A were detected.  Also, 
	3	there were studies in the '70s and '80s which showed a lack 
	4	of any differences between serological prevalence in rate of 
	5	hepatitis A in a transfused and non-transfused population. 
	6		[Slide]
	7		What are the causes of rare transmission by blood 
	8	transfusion?  There are a number of factors involved.  There 
	9	is a short viremic period and absence of n HAV carrier state 
10	or persistent infection, and also low concentration of HAV 
11	in the blood and overall low incidence of HAV infection. 

12	Also, we need to consider that almost 50 percent of the 
13	population is already immune to HAV. 
14		[Slide] 
15		As mentioned earlier, there are cases in the 
16	literature which indicate transmission by blood by either

17	packed cells of fresh-frozen plasma.  This is not all that 
18	are reported.  I think there are probably three excellent 
19	reports which I did not include here.  But overall as we 

20	see, the number is not large.  The striking feature that we 
21	see here is that large number of the newborn or neonates and
22	also the large number of the secondary infections. 
23		The report in 1983 by Dr. Hollinger and his 
24	colleagues is particularly important because it represents 
25	the first clear demonstration that hepatitis A virus from a 

			72 1	donor sample can produce post-transfusion hepatitis A.  This
	2	is the case, right here, where a 10-year old child developed 
	3	acute hepatitis A, as indicated by jaundice and also by IgM 
	4	anti-HIV and the infection was traced back to a donor who 
	5	donated and also developed acute hepatitis 7 days after 
	6	donation, and died of hepatic failure.  HIV antigen was
	7	detected in the plasma from the original samples and also in 
	8	the liver of the donor.  There were also chimp studies where 
	9	the chimpanzees were transfused with the plasma from the 
10	original sample and they developed hepatitis A and 
11	seroconverted 3 weeks after infusion.
12		The other interesting case which underscored the 
13	importance of secondary infections, by Noble, were packed 

14	cells were given to a number of neonates and 11 of them 
15	developed acute hepatitis A.  Also, the studies showed that 
16	the first case that actually came to attention was when one
17	of the nurses developed acute hepatitis A.  Further 
18	investigation showed that 16 percent of nursery personnel 
19	had hepatitis A as the result of this one particular case, 

20	and 4 percent of the physicians who were in contact with the 
21	patient also developed hepatitis A, and 25 percent of the
22	family members.  That 25 percent rate of secondary infection 
23	among family members has also been reported by others. 
24		[Slide] 
25		This table shows transmission into clotting 

		73 1	factor.  There has not been any report of transmission by

	2	clotting factor until the late '80s where outbreaks were 
	3	reported from Europe, in Italy, Germany and Ireland, and 
	4	other places like South Africa and later, in 1994, in the 
	5	U.S.A. and also the latest one from Germany. 

	6	          Because time is short, I will not go through these
	7	one by one, but overall the common feature among all of them 
	8	is that all the patients received highly purified solvent- 

	9	detergent treated clotting factor concentrate.  The earlier 
10	reports from Italy and Germany and Ireland relied primarily 
11	on epidemiological evidence to indicate transmission. All

12	the product was manufactured by one single manufacturer in 
13	the corresponding countries.  There were no other risk 

14	factors for hepatitis A among patients, and the patients 
15	were geographically dispersed.  There was also a correlation 
16	between the quantity of Factor VIII concentrate received by
17	the patient and the HAV infections.  There was very little 
18	sequence analysis in the early cases, but in the most recent 
19	ones, the ones from South Africa, the U.S.A. and Germany, in 
20	addition to epidemiological studies that I mentioned there 
21	were also some sequence analyses.  Viral sequence analysis
22	was done from samples from the patient, from the product and 
23	also from the plasma source, and the sequence identity was 
24	determined in these three samples. 
25	          [Slide] 

		74 1	          Basically, I just want to say that the sequence

	2	analysis was done in different regions of the HAV genome 
	3	including the VP1 and VP2 and, in addition, in the VP1 and 
	4	2A region which are variable regions of the genome.  It is 
	5	important that the sequencing be done in different parts. 

	6	          In all those studies, it was shown that there were
	7	identical strains in the patient product and the source 
	8	plasma.  Also, there were some laboratory studies, done by 
	9	Stanley Lemon, which basically looked for the fate of HAV 

10	during the manufacturing process.  This is the process which 
11	uses ion chromatography and solvent detergent treatment.  He
12	has shown that neutralization reduced the viral load by two 
13	logs and as a result of the cryoprecipitation almost 99 
14	percent of the virus will remain in the supernate and only 
15	one percent will go to the cryoprecipitate.  The supernate 
16	will be used to develop Factor IX concentrate and the
17	cryoprecipitate will be for Factor VIII.  Solvent-detergent 
18	treatment basically showed no reduction.  However, it is 
19	important to mention that he also found that solvent- 
20	detergent did not interfere with the neutralization, as has 
21	been suggested by some investigators.  In fact, it may even
22	enhance the neutralization to a certain degree, probably by 
23	stripping the virus of some of the host lipids.  Subsequent 
24	steps in the manufacturing process had little or no effect 
25	on overall viral reduction.  The conclusion from his study 

			75 1	is that the margin of safety provided by this manufacturing
	2	process is not sufficient to prevent HAV infection if one or 
	3	two HAV-contaminated units get into the plasma pool. 
	4		[Slide] 
	5		Then the question is what is the cause of these 
	6	outbreaks?  Overall, it can be summarized as simultaneous
	7	changes in the purification process, change in viral 
	8	inactivation techniques, and change in epidemiology of HAV.  
	9	The purification process to provide low purity and 
10	intermediate purity product contain sufficient amounts of 

11	HAV to confer immunity to the recipient.  However, in the
12	highly purified product by high purification you actually 

13	remove the antibody so there is no more passive protection.  
14	As we saw in the viral inactivation technology, the solvent- 
15	detergent had no effect on viral reduction.  As far as 

16	epidemiology, there seems to be a shift toward the older
17	population and the donor age group also.  Overall, the 

18	prevalence of HAV is declining which indicates that there is 
19	less antibody in the plasma pool.  Since the donor age is 
20	more vulnerable, it is more likely that they will get 
21	infected, and if they are a donor they can pass on the
22	infection. 
23		[Slide] 
24		What will be the implication?  This also will most 
25	likely be covered by Dr. Feinstone, but just to mention that 

			76 1	HAV is a mild infection, however, in those who already have
	2	preexisting chronic liver disease it may exacerbate the 

	3	problem and in certain cases cause death.  It has been 
	4	reported that 95 percent of U.S. hemophilia patients between 
	5	the age of 20 to 40 are already infected with HCV, and 8 
	6	percent are chronically infected with hepatitis B.
	7		[Slide] 
	8		Then the question is what should be done about it.  
	9	There are a number of suggestions.  There is vaccination 

10	against HAV in anti-HAV negative hemophilia.  The experts 
11	agree that using vaccination is cheap, inexpensive and very
12	effective in preventing infection.  Also, terminal heat 

13	treatment for Factor VIII has been suggested.  I should 
14	mention that although HAV is relatively heat stable, heating 
15	may reduce effectiveness of Factor VIII and may cause 
16	denaturation and also produce inhibitor perhaps as a result
17	of formation of new antigen.  So, it is more complicated 
18	than simple heating.  Also, the use of recombinant Factor 
19	VIII without use of plasma derived product has been 
20	suggested.  I should mention that in some of the recombinant 
21	factor they use albumin as a stabilizer and that
22	theoretically will produce risk for HAV.  Therefore, it is 
23	suggested that vaccination should be done in this group of 
24	recipients as well. 

25		[Slide] 

			77 1		Also, screening of plasma pools for HAV has been
	2	suggested, and that is what we are discussing here.  I tried 
	3	to come out with a rough and crude estimate, and 0.67 is the 
	4	fraction of the population that is not infected with HAV, 
	5	and 9 is the prevalence of HAV.  This is the notification 
	6	rate for HAV by CDC, 9 per 100,000 per year.  If we estimate
	7	the average window period to be 3 weeks in a year, the rate 
	8	will be 0.35 per year.  So, it will be 3-4 units per million 
	9	per year.  I must mention that the numbers that are there 

10	may change, especially the one that says 9 per 100,000 per 
11	year.  It is fluctuating, and I think I got this from 1994
12	estimates by CDC. 
13		Finally, development and implementation of viral 

14	inactivation are steps that are effective in removal of non- 
15	enveloped viruses, and there are a number of methods which 
16	are currently being investigated.  Thank you.
17		DR. HOLLINGER:  Thank you, Dr. Farshid.  Any 
18	questions?  Yes, please, Dr. Koerper? 
19		DR. KOERPER:  I would just like to comment on your 
20	slide about improving product safety for HAV for hemophilia 
21	patients.  First of all, the Medical and Scientific Advisory
22	Committee of the National Hemophilia Foundation has strongly 
23	recommended that all hemophilia patients be vaccinated for 
24	hepatitis A, and that is currently being implemented and the 
25	effectiveness of the vaccine is being tested in a nationwide 

			78 1	study.
	2		Secondly, while in the early '80s, when heat 
	3	treating Factor VIII and IX was first proposed, there were 
	4	concerns about the possibility that Factor VIII and Factor 
	5	IX would lose some of their potency and that neoantigens 
	6	would be exposed, resulting in increased inhibitor
	7	formation.  Those concerns have been negated.  In other 
	8	words, the Factor VIII and IX are still completely active 
	9	and we are not seeing an increase in inhibitor formation due 
10	to the heat treatment process.  So, that was universally 
11	recognized as a first approach toward eliminating viruses in
12	factor concentrates.  It has been supplemented by such 
13	things as solvent-detergent and column chromatography, but 
14	heat treating is an important adjunct to eliminate some of 
15	the viruses that are not eliminated by solvent-detergent, 

16	and most manufacturers include that in their processing of
17	product that does come from plasma. 
18		Thirdly, with regards to the recombinant factor 
19	products, while most of the Factor VIII products do contain 
20	albumin, to my knowledge, there has been no transmission of 
21	hepatitis A from albumin --

22		DR. FARSHID:  Yes, I mentioned that actually there 
23	has not been any report of transmission of hepatitis A by 

24	any of the fractionated product except for Factor VIII and 
25	Factor IX, which was from the U.S. 

				79 1		DR. KOERPER:  Right, by not from albumin --
	2		DR. FARSHID:  Not from albumin. 
	3		DR. KOERPER:  So, the feeling is that the use of 
	4	albumin as an excipient in Factor VIII is probably okay, 
	5	although the manufacturers are moving away from that.  So, I 
	6	feel that we have taken many steps to help eliminate this
	7	problem in our hemophilia patients. 
	8		DR. HOLLINGER:  Yes, Dr. Chamberland? 
	9		DR. CHAMBERLAND:  Could you please review one more 
10	time -- I didn't quite get it all -- your estimate of the 
11	number of donations per year that might be captured in that
12	formula?  You might want to put it back up. 
13		[Slide] 
14		DR. FARSHID:  The 67 percent of the population 
15	basically are not positive for anti-HAV.  So, these are all 
16	anti-HAV negative.  They have never been exposed to
17	hepatitis A.  This is the notification rate as determined by 
18	the CDC per 100,000 per year.  I think that was given from 
19	1994 or '92.  Maybe Dr. Feinstone will clear that estimate 
20	up.  It is important to determine that not all cases of HAV 
21	are reported to CDC, and they estimate that probably the
22	actual number will be 4-5 times what we see here.  The 
23	average incubation period for hepatitis A is estimated to be 
24	3 weeks.  As I mentioned, this is a very crude estimation 
25	and hopefully the other speakers will give us a more 

			80 1	accurate estimate, but I put it here basically to stimulate
	2	more discussion, and that what we are dealing with is a very 
	3	rare event. 
	4		DR. HOLLINGER:  Yes, Mr. Rice? 
	5		MR. RICE:  I just have a question.  I know that 
	6	HAV vaccinations have been recommended for persons with
	7	hemophilia, but I was wondering if there was any difference 
	8	in that recommendation for persons -- and this would be for 
	9	Marion probably -- who have HIV chronic infection and 
10	exacerbated HAV status as to whether or not they are also 
11	recommended also to get the HAV vaccination basically

12	because this risk of the lower purity products from 
13	recombinant bearing some risk of transmitting HAV is 

14	becoming to be more of a possibility in recent guidelines on 
15	reimbursement from DOJ.  It has actually forced some people 
16	on Medicaid to have to now not take recombinant product and
17	have to go to some lower-level purity product which 
18	conceivably, if that person has HIV infection and is not 
19	vaccinated against HAV, that puts that person at risk.  That 
20	is the real world coming in, basically now forcing people 

21	back from the highest technology for other considerations.
22		DR. FARSHID:  If I may defer that question to Dr. 
23	Steve Feinstone, he will talk about the pathology of the 

24	virus and he is more qualified to answer that question. 
25		DR. HOLLINGER:  Yes, Kenrad? 

				81 1		DR. NELSON:  I think the 9 per 100,000 estimate
	2	has to be taken with a huge grain of salt.  You don't get 33 
	3	percent prevalence of antibody with 9 per 100,000 attack 
	4	rate.  It is much higher than that because most infections 
	5	are asymptomatic, and asymptomatic infections may easily 
	6	transmit.
	7		DR. FARSHID:  That is true. 
	8		DR. NELSON:  I realize it was an estimate -- 
	9		DR. FARSHID:  Actually, as I mentioned, the number 
10	is probably five times what we saw here, but the CDC 
11	estimate is that the rate of infection is between 80,000 to
12	120,000 per year for HAV infection, and that will not come 
13	out to 9 per 100,000; it would be much higher.  But, I 
14	thought I would put a number where I have some documentation 
15	for that and, as I mentioned, it is much higher.  But even 
16	if we say five times what is there, still the rate would be
17	very low. 
18		DR. HOLLINGER:  Yes, Dr. Mitchell? 
19		DR. MITCHELL:  I wasn't clear about the relative 
20	risk of HAV between blood components -- whole blood versus 
21	fresh-frozen plasma versus Factor VIII and Factor IX.
22		DR. FARSHID:  Certainly, there is no data to show 
23	what is the rate.  I mean, the risk is so small and probably 
24	approaching zero.  If you look at transmission by blood from 
25	1981 until today, I think the total report is probably 13 or 

				82 1	14 cases that have been reported.  In case of the factor
	2	concentrates, from late 1980 until today there were about 

	3	116 reported transmissions, with some of them maybe even 
	4	questionable by factor.  So, the incidence is very small, 
	5	extremely small. 
	6		DR. MITCHELL:  I am still not clear.  Are you

	7	saying that it is higher in the factor concentrates than in 
	8	other products? 
	9		DR. FARSHID:  Your question is, is it higher in 

10	Factor VIII compared to other fractions in a product?  There 
11	is no report of transmission -- is that the question?
12		DR. MITCHELL:  No, that is not the question.  The 
13	question is compared to whole blood does Factor VIII, Factor 
14	IX, those types of components, do they have a higher rate of 
15	transmission of HAV? 
16		DR. FARSHID:  Actually, I don't know based on what
17	I see and the number of outbreaks, most likely there would 
18	be more in Factor VIII concentrate because you start from 

19	the pooled source.  If you compare the number of years and 
20	the number of infections, you have a much higher level of 
21	infection through clotting factor than you have through
22	blood transfusion.  Through blood transfusion mostly occurs 
23	in neonates, and there have not been that many. 
24		DR. HOLLINGER:  Thank you.  Our next speaker is 
25	Dr. Stephen Feinstone, who is going to talk on the 

				83 1	epidemiology, clinical implications, prophylaxis of
	2	hepatitis A virus.  You are going to do that in a short 
	3	time.  How can you do that, Steve? 
	4		DR. FEINSTONE:  Well, actually I wasn't planning 
	5	on taking a short time! 
	6		DR. HOLLINGER:  Oh, good!  I don't think you
	7	should. 
	8		[Laughter] 
	9		           Hepatitis A Virus: 
10	       Epidemiology/Clinical/Implications/Prophylaxis 

11		DR. FEINSTONE:  Actually, there is almost no
12	reason for me to be doing this with Dr. Hollinger and Dr. 
13	Koff here who are world experts in this problem, but I will 
14	try to just go through this very quickly because there is a 
15	lot to cover. 
16		[Slide]
17		So, as you see, hepatitis A is one of the five 
18	well-recognized hepatitis viruses and it is classified as a 
19	picorna virus, which are a group of viruses that have 
20	single-stranded RNA genomes. 
21		[Slide]
22		This is a list of picorna viruses.  It includes 
23	the enteroviruses, the rhinoviruses, cardeo viruses and 

24	apthoviruses of animals.  Hepatitis A is not classified as 
25	an enterovirus; due to some of its unique features, it is in 

			84 1	its own genus.
	2		[Slide] 
	3		This is the virus itself.  It has a small non- 

	4	enveloped di-icosa hedral structure of about 17-28 nm in 
	5	diameter.  Morphologically, it is virtually 
	6	indistinguishable from any of the other viruses that you saw
	7	in that list of picorna viruses.  But the important aspect 
	8	from this is that it is non-enveloped and, therefore, it is 
	9	not sensitive to lipid solvents. 
10		[Slide] 
11		I just want to make one point from this slide on

12	acid stability and heat stability.  This virus is relatively 
13	heat stable, even relative to many of the other picorna 

14	viruses, and heating the virus to 60 degrees for one hour 
15	would not be expected to eliminate total infectivity.  So, 
16	the processes that have been used to inactivate, say, HIV,
17	HCV and HBV have not been validated to inactivate hepatitis 
18	A virus completely. 
19		[Slide] 
20		This is hepatitis A in cell culture.  The point I 
21	want to make here is that the virus grows in the cytoplasm. 
22	I don't know if you can see from this immunofluorescence 
23	study but the fluorescence appears as cytoplasmic granules. 
24		[Slide] 
25		We think what these granules represent are small 

			85 1	vesicles inside the cell that contain the virus, here
	2	stained by peroxidase in a study done by Yoko Shimizo.  We 

	3	never actually see the virus free in the cytoplasm of the 
	4	cell.  We only see it inside these vesicles. 
	5		[Slide] 
	6		I must tell you this is only my conjecture, there
	7	is no real hard data for this but the virus replicates by 

	8	the same general mechanism of the other picorna viruses.  It 
	9	enters the cell.  The RNA genome functions both as a message 
10	molecule and a template for new RNA virus production, and it 
11	goes through a series of steps and virus maturation but

12	inside these vesicles.  I think what may be happening is 
13	that these vesicles themselves are extruded from the cell 
14	and typically into the bile where the action of the bile 

15	salt and detergents break down the vesicle and release free 
16	virus particles.

17		[Slide] 
18		However, in this picture, by Lucy Asher, in the 
19	serum of a primate with hepatitis A we see virus contained 
20	still within a vesicle.  So, this is free virus in the 
21	serum.
22		[Slide] 
23		This picture, by Yoko Shimizo, is of virus 

24	contained within a vesicle in a stool sample.  So, the virus 
25	may be contained, at least at times, within these vesicle 

			86 1	structures.
	2		[Slide] 
	3		Now, the epidemiology of this of virus -- and 
	4	first I want to thank Miriam Alter, from the CDC, for 
	5	sending me some updates on these epidemiology slides -- this 
	6	virus has a worldwide distribution but parts of the world,

	7	obviously, have much higher rates of infection than other 
	8	parts.  Generally tropical countries but also some northern 
	9	countries, such as Greenland, have very high rates of 
10	hepatitis A prevalence.  Then there are intermediate 
11	countries such as Asia, most of the former Soviet Union and
12	southern Europe, and then the low prevalence areas such as 
13	the United States, western Europe and Australia. 
14		[Slide] 
15		So, what has been seen worldwide are different 

16	disease rates but also different types of disease.  Where
17	the endemicity is very high, the infections, as most enteric 
18	viruses, are in early childhood.  Transmission is primarily 
19	person to person and we rarely see outbreaks amongst the 
20	indigenous populations in those situations.  Then, if you go 
21	to areas where there are moderate rates of infection, the
22	age of typical infection usually increases and we see 
23	actually more disease because the disease in young children 
24	is usually in a parent.  Then, you go to low and very low 

25	areas of the world and there, again, the age of infection 

			87 1	usually increases to young adults.  In the very low rates

	2	there is virtually no transmission within those countries 
	3	and most of the infections we see are imported or in 
	4	travelers.  The disease burden in these countries is not 
	5	very great because of the low rates. 
	6		[Slide]
	7		So, this again sort of depicts this.  This is the 
	8	high prevalence areas.  This is the time of acquisition of 
	9	antibody.  As you see, it is very, very early in life.  In 
10	one study I did in Kenya, we had 100 percent seropositivity 
11	by age two.  Then, in the very, very low rates you see
12	virtually no disease occurring in young people.  Then, in 
13	the older cohorts of people, and these probably represent 
14	childhood infections that occurred at a time when the 
15	epidemiologic situation was different.  Then you see these 
16	countries in the middle where there is probably a changing
17	epidemiologic pattern, where this curve begins to sag. 
18		[Slide] 
19		In this slide I just wanted to show sort of the 
20	public health impact of hepatitis A in these different 

21	countries.  In the developing world where the infections
22	occur mostly in children and where the infections are 

23	frequently in a parent, you see there is really not that 
24	much recognized public health impact.  But as the age of 

25	infection increases, the average time of acquiring hepatitis 

			88 1	A increases and the overt disease rate increases, you see a

	2	more pronounced public health impact.  Then, of course, in 
	3	the very low risk countries, again, it disappears because 
	4	there are so few cases. 
	5		[Slide] 
	6		This is simply some actual data to show that type

	7	of situation.  This is data from Chili in which they look at 
	8	the rates of typhoid fever and the rates of hepatitis, and 
	9	this was mostly hepatitis A, over many years.  As you see, 
10	as the epidemiologic situation improved the rates of typhoid 
11	fever decreased but the apparent rate of hepatitis A
12	increased because the age of infection was increasing and 
13	the rate of overt clinical disease increased. 
14		[Slide] 
15		In the United States, hepatitis A is estimated to 
16	account for 55 percent of acute hepatitis cases in this
17	country --  as has just mentioned, probably around 100,000 
18	cases a year although it is grossly under-reported. 
19		[Slide] 
20		This slide shows the risk factors.  As you can 
21	see, the largest groups of patients have no known risk
22	factor.  However, the most important way that this virus 
23	spreads is really person to person contact.  But other 
24	important means of spread are international travel, travel 
25	to endemic areas.  Daycare centers have become recognized as 

			89 1	an important nidus where infections occur.  Men who have sex
	2	with men are known to transmit the disease when the virus is 
	3	prevalent in those communities.  Injection and drug use has 
	4	also been associated with hepatitis A.  This may be a life 

	5	style relationship more than actual parenteral transmission 
	6	of the virus but that is not completely known.  I think you
	7	should notice from that that transfusions are not an 
	8	important means of transmission. 
	9		[Slide] 
10		These are the reported case rates in the United 
11	States over the years.  As you can see, the incidence of

12	disease tends to occur in waves over time and in recent 
13	times, as you can see, we have had declining rates of 

14	hepatitis A although it is still, as I mentioned before, an 
15	important disease in this country with probably about 
16	100,000 cases per year.
17		[Slide] 
18		Incubation period -- I think this is an important 
19	topic for this discussion.  These are analyses of 
20	experimental infections in primates, done in Bob Purcell's 
21	laboratory.  This shows the incubation period, the time to
22	the first ALT elevation after an intravenous inoculation of 
23	hepatitis A virus in varying doses.  What you can see is 
24	that the incubation period is generally dose related.  The 
25	higher the dose, the shorter the incubation period.  We can 

			90 1	see incubation periods a short as 1 week in marmosets given

	2	more than 108 infectious doses of virus, but stretching out 
	3	to 7 weeks or even a little more with very low doses. 
	4		[Slide] 
	5		If you go back to some of the old data when there 
	6	were human volunteer studies going on -- this is from some
	7	of the studies conducted by Saul Krugman at the Willowbrook 
	8	State School.  As you can see again, with greater doses of 
	9	the virus, in this case a stool extract, administered to 

10	volunteers the incubation periods ranged up to 70 days, I 
11	believe, 71 days.  These incubation periods are relatively
12	long but I think one thing we have to remember is that the 
13	tests that we had in those days were much less sensitive.  
14	He was looking at things such as thymol turbidity or 
15	bilirubin levels and most likely the ALT levels would 
16	reflect a somewhat shorter incubation period.  But I think
17	you can see that incubation periods can certainly range to 
18	greater than 6 to 8 weeks. 
19		[Slide] 
20		This is a cartoon of a typical case of hepatitis 
21	A, exposure being at time zero.  You see ALT elevations

22	occurring after the incubation period which averages about 4 
23	weeks.  About the same time that ALTs come up, one sees the 
24	first appearance of serum antibody which, if you analyze it, 
25	actually is a combination of IgG and IgM.  IgM levels 

			91 1	elevate very briskly in hepatitis A, both specific hepatitis
	2	A antibody as well as IgM in general levels go up. 
	3		So, about the time of symptoms one generally sees 
	4	serum antibody, especially IgM antibody, which is the basis 
	5	for the diagnostic tests for acute hepatitis A in which on a 
	6	single serum sample a patient reports with symptoms
	7	suspicious of hepatitis A.  A positive for hepatitis A, 
	8	specific IgM, is generally considered diagnostic.  There are 
	9	no approved nucleic acid tests for diagnosis of hepatitis A 
10	at this time.  Serum antibody is long-lasting; we think for 
11	a lifetime.  We think immunity is lifelong.
12		[Slide] 
13		Now, this is some studies that we did in 
14	experimentally inoculated chimpanzees.  They are very 
15	similar to some studies reported by Stan Lemon.  We looked 
16	at the response in these animals to intravenous inoculation
17	with hepatitis A virus.  Again, you see ALT levels.  It is a 
18	little hard for me to read this slide, but in this case IgM 
19	levels are here and this line is neutralizing antibody.  As 
20	you can see, neutralizing antibody comes up very early with 
21	the earliest antibody.  When we separated this serum into

22	IgM and IgG components, we found that the IgM itself was 
23	capable of neutralizing hepatitis A virus in vitro. 
24		[Slide] 
25		Now, some recent data by Bowers and colleagues at 

			92 1	the CDC, using a highly sensitive reverse transcriptase PCR
	2	assay, nested PCR assay, have looked at the time of viremia.  
	3	In this case, you can see that they were able to detect HAV 

	4	RNA in the serum for very long periods of time after acute 
	5	infection, up to 400 days. 
	6		[Slide]
	7		This is one of the cases that they studied.  
	8	Again, you see long-term RNA delectability.  This is ALT 

	9	levels and detection of serum antibody.  So, even in the 
10	face of serum antibody they are able to detect the HAV RNA 
11	in the serum.  What form this is in we don't really know.  I
12	won't to go back to those pictures I showed you of the virus 
13	contained in the vesicles but I think it is possible -- 
14	there is no data to support this but I am just saying that 
15	it is possible that some of this virus may exist protected 
16	from serum antibody because it is still within these
17	vesicles that have been extruded from the hepatocytes. 
18		[Slide] 
19		Again going back to some earlier data from Saul 
20	Krugman's studies on actual infectivity of clinical samples 
21	during the course of hepatitis A infection, and these are
22	from experimentally infected volunteers and then transmitted 
23	to new volunteers, as you can see, stools taken during the 
24	incubation period -- this is the incubation period, up to 40 
25	days; this was the time of disease; and this is after the 

			93 1	appearance of symptoms.  So, prior to the incubation period

	2	stools and serum were found to be infectious for hepatitis 
	3	A.  After the incubation period the serum was found to be 
	4	infectious for the first 3 days after the appearance of 
	5	symptoms, but after that was not infectious. 
	6		So, exactly what does this mean, the long-term

	7	viremia or at least HAV RNA positivity in the serum?  I 
	8	think we really don't know.  We can't really say that these 
	9	people are infectious at this point in time in these 

10	studies.  I should say that there have been other human 
11	volunteer studies with similar results which say that the
12	serum is not infectious for long periods of time after the 
13	appearance of symptoms.  Stools also seem to rapidly lose 
14	their infectivity, both from experimental studies and also 
15	epidemiologic studies, and seem to show that transmission 
16	doesn't occur for periods very long after the appearance of
17	serum antibody which coincides with the appearance of 
18	symptoms. 
19		[Slide] 
20		This is just some real data from Ian Gust, in 

21	Australia, in which they looked for virus by a much less
22	sensitive technique, electron microscopy, following the 

23	patient's arrival at hospital, which usually coincides with 
24	the appearance of dark urine.  As you can see, they were 

25	able to detect virus in the stools for a period of almost 

			94 1	two weeks in a very few patients after the appearance of
	2	symptoms, but most patients had lost the virus by that time.  
	3	Again, it is not clear that these patients are actually 
	4	infectious or liable to transmit the disease commonly at 
	5	this period of their disease. 
	6		[Slide]
	7		This is some other data from CDC showing what 
	8	bodily fluids contain virus.  The stools, of course, we know 
	9	are where most of the virus is shed; serum at a lower level.  
10	Virus has been detected in the saliva.  Those are the main 

11	places.  We don't really know if the virus in the saliva is
12	being excreted there or if this is low-level blood 
13	contamination. 
14		[Slide] 
15		Now, control of hepatitis A -- the best way to 
16	control hepatitis A on the large scale is to improve living
17	conditions, primarily sanitation.  Providing clean water 

18	supply, separated from sewage disposal, is probably the most 
19	important thing that we can do.  So, this is really a 
20	disease that can best be controlled by sanitary engineers. 
21		Beyond that, the classic way that this virus has

22	been controlled is by passive immunoprophylaxis with immune 
23	globulin.  Immune globulin has never been effective in 

24	really reducing the rates of hepatitis A in any endemic 
25	areas.  It is effective in controlling the spread among 

			95 1	contacts of cases, and intensive campaigns can be used in
	2	small community outbreaks of hepatitis A.  But now we have 
	3	the advent of active prophylaxis with hepatitis A vaccine. 
	4		[Slide] 
	5		So, the principles of this vaccine -- it is a 
	6	killed vaccine, very much analogous to the original killed
	7	polio vaccine.  The virus is grown in cell culture.  This is 
	8	the only one of the hepatitis viruses that grows reliably 
	9	into reasonable titer in cell culture.  So, the virus is 
10	grown in cell culture and the adaptation to cell culture has 
11	generally had the additional effect of attenuating the virus
12	for infection in man, which is kind of an extra safety 

13	factor.  The virus is then purified and inactivated by 
14	formalin, much like the killed polio vaccine.  In 
15	distinction from the killed polio vaccine, this vaccine, 
16	with alum, has been shown to be highly immunogenic in man,
17	such that in reality a single dose is generally sufficient 
18	to provide at least short-term protection. 
19		Studies are underway to determine whether or not 

20	this can provide long-term protection as well.  The current 
21	recommendations are for anyone who may have long-term
22	exposure to hepatitis A to get a single dose of vaccine and 
23	a booster dose at about 12 months, in which cases people got 
24	very high doses of antibody and should be protected most 
25	likely for life. 

			96 1		[Slide]
	2		Here are two licensed products in this country, 
	3	the SmithKline product and the Merck product.  There is very 
	4	little difference between them.  They were made originally 
	5	with two different strains of virus, but one of the features 
	6	of this virus is that there seems to be universal serologic
	7	cross-reactivity.  There is only one serotype of hepatitis A 
	8	that we know about.  So, both of these vaccines are highly 
	9	effective and both have been shown over the past few years 
10	to be very, very safe. 
11		These were the original efficacy trials performed
12	by these two companies.  There was a large-scale trial 
13	performed by the Army in Thailand in which there were nearly 
14	40,000 people who participated with a very high efficacy 

15	rate.  The study done in Monroe County, New York, by Merck 
16	was really one of the most classic vaccine trials I think

17	ever published, in which there was a very high endemic rate 
18	of hepatitis A in a Hasidic religious community in New York 
19	State.  They went in and started vaccinating, and within 
20	three weeks after initiating vaccination the cases just 
21	disappeared from the vaccinated group whereas they continued
22	in the non-vaccinated group.  Very quickly they broke their 
23	code and started vaccinating everyone.  So, this was really 
24	a beautiful demonstration of the effectiveness of this 
25	vaccine. 

			97 1		[Slide]
	2		So, these are the recommendations for the use of 

	3	the vaccine.  I think one of the most important uses now is 
	4	to sort of interdict these community-wide outbreaks of 
	5	hepatitis that can really smolder for years and cause 
	6	tremendous disruption in communities.  Then, beyond that,
	7	the vaccine is presently recommended for people who are at 
	8	increased risk of infection.  There is a long list of these 
	9	people but that group now includes anyone who is receiving 
10	blood products on a routine basis.  I certainly feel that 
11	this should be a very strong recommendation who receives

12	clotting factors or any other blood product. 
13		That concludes my presentation.  I think one thing 
14	I did forget to mention was the occurrence of the recurrent 
15	disease.  About 10 percent of patients who get acute 

16	hepatitis A end up having a recurrence of symptoms and
17	usually ALT elevations.  This can happen with two or even 
18	three episodes over the course of as long as a year or a 
19	little longer.  However, all of these patients eventually 

20	recover.  Hepatitis A is only an acute disease.  There is no 
21	chronic stage, although fulminant hepatitis can be
22	associated with hepatitis A.  I believe in the Shanghai 

23	epidemic in which there were about 300,000 reported cases 
24	there were 47 deaths.  So, it is not a completely innocuous 
25	disease, and it certainly makes people sick for extended 

				98 1	periods of time.  I will be glad to take any questions.
	2		DR. HOLLINGER:  Thanks, Steve.  Questions for Dr. 
	3	Feinstone?  Yes, Col. Fitzpatrick? 
	4		COL. FITZPATRICK:  In individuals who have been 

	5	vaccinated is there a high enough level to be detected by 
	6	NAT DNA during a period of time after the vaccination?
	7		DR. FEINSTONE:  Well, first, this is an RNA virus.  
	8	The vaccine is administered intramuscularly.  I don't know 

	9	if anyone has actually done that.  I don't think anyone has 
10	actually done that.  You can clearly detect it in the 
11	original vaccine but, don't forget, this is an inactivated
12	vaccine and the thoroughness of inactivation is very 
13	carefully monitored.  They go through extensive long-term 
14	sub-cultures of this virus to prove that it has been 
15	inactivated.  Not only that, but both the virus that is in 
16	the SmithKline product and the Merck product are virtually
17	non-infectious for humans. 

18		COL. FITZPATRICK:  Right.  No, I realize that, but 
19	are we going to pick up donors who have been vaccinated for 
20	a period of time. 
21		DR. FEINSTONE:  I don't know of anybody who has
22	done that. 
23		DR. HOLLINGER:  Yes, Dr. Ohene-Frempong? 
24		DR. OHENE-FREMPONG:  Just a question about any 

25	long-term consequences of hepatitis A in the endemic areas 

				99 1	as far as liver disease.
	2		DR. FEINSTONE:  Hepatitis A is not associated with 
	3	chronic liver disease of any form.  In patients who already 
	4	have chronic liver disease, based on either chronic viral 
	5	hepatitis B or C or any other form of chronic liver disease, 
	6	should all definitely be vaccinated.  That is one of the
	7	current recommendations because an acute hepatitis A episode 
	8	on top of chronic liver disease can be fatal. 
	9		DR. HOLLINGER:  Yes, Dr. Chamberland? 
10		DR. CHAMBERLAND:  Just a point of clarification, I 
11	believe according the ACIP recommendations that were
12	published in the MMWR last fall, they were very specific in 
13	recommending that the vaccine be given to individuals with, 
14	quote, clotting factor disorders.  So, it wasn't a global -- 
15		DR. FEINSTONE:  Well, that is the ACIP 
16	recommendation.  The labels for both products indicate
17	anyone receiving blood products routinely. 
18		DR. CHAMBERLAND:  Does the FDA have reason to 

19	believe that other blood products, like IVIG etc., are at 
20	risk for this? 
21		DR. FEINSTONE:  No.  In fact, I am of the belief
22	that the episodes that occurred with clotting factors were 
23	more of an aberration.  We didn't see them before; we 

24	haven't seen them since.  I think that they are very 
25	unusual.  My personal feeling is that the nucleic acid 

			100 1	testing probably should not be done but this whole problem
	2	should be handled by vaccination, and that these people 
	3	should be vaccinated, not only to prevent them from getting 
	4	hepatitis A from any blood product, but also because they 

	5	frequently are chronically infected with other hepatitis 
	6	viruses and it is important that they be protected against
	7	hepatitis A. 

	8		DR. MACIK:  You mentioned as far as treatment that 
	9	heat treatment doesn't kill hepatitis A.  You mentioned that 
10	was one hour at 60 degrees.  Do you have any information 
11	about pasteurization or high temperature at a longer time?
12		DR. FEINSTONE:  Yes, I should have brought a slide 
13	on that.  Hepatitis A can be killed by heat.  It is 
14	partially inactivated by 60 degrees for one hour.  It is 

15	generally inactivated by 60 degrees for 10 hours, which I 
16	think is within some of the heat inactivation procedures. 
17	Certainly, 80 degrees kills the virus quite reliably.  But 
18	my point was that none of the heat inactivation procedures 
19	that have been proposed to eliminate HIV, HBV, HCV have 
20	actually been validate to inactivated hepatitis A virus.  I 
21	think if you  do killing curves, you would see that
22	hepatitis A would be killed more slowly than those other 
23	viruses. 
24		DR. MCCURDY:  I think the data you presented on 
25	persistence of RNA in these vesicles over a long period of 

		101 1	time is just very interesting.  Would it be possible in any
	2	sort of system that if somehow antibody was removed that 
	3	this RNA could become infectious?  I am thinking of any sort 
	4	of processing of blood product that might render the 
	5	persistent RNA to be infectious. 
	6	          DR. FEINSTONE:  One of the interesting things is
	7	that if you look at that study that I showed from Saul 
	8	Krugman in which at day 3, after the appearance of symptoms, 
	9	there was infectivity in the serum.  That serum almost 

10	undoubtedly contained antibody at that time.  As I showed 
11	from my slide, that early antibody should neutralize the
12	virus. 

13	          In another study, published by Lou Barker in 1977, 
14	in which he looked at a family outbreak of hepatitis A and 
15	transmitted acute-phase sera to marmoset monkeys -- tamarins 
16	we call them now -- they showed that those samples that
17	transmitted hepatitis A infection to tamarins did contain 

18	pretty good levels of serum antibody.  Now, it is possible 
19	that that virus is protected by these vesicles.  But it is 
20	possible that the solvent-detergent treatment breaks down 
21	those vesicles and actually makes it more infectious because
22	by that time maybe much of the antibody has been eliminated 
23	or the solvent-detergent itself prevents the neutralization 
24	by serum antibody.  We really don't know.  This is all 

25	conjecture; we don't know the answers to any of these 

			102 1	questions.  But we do know that acute-phase serum with
	2	antibody can be infectious if inoculated parenterally.  We 
	3	also know that that antibody in an in vitro assay, in a cell 
	4	culture assay, can neutralize hepatitis A virus. 
	5		DR. HOLLINGER:  Thanks, Steve.  We are going to 
	6	move on to the last speaker.  This will be on HAV
	7	transmission by Factor VIII concentrates, Dr. Michael Chudy, 
	8	from the Paul Erhlich Institute, Germany. 
	9	        HAV Transmission by Factor VIII Concentrates 
10		DR. CHUDY:  Ladies and gentlemen, I would first 

11	like to thank the FDA for inviting me to this meeting to
12	present our data for the HAV transmission by Factor VIII 
13	concentrates. 
14		[Slide] 
15		This table summarizes all episodes of HAV 

16	transmission by solvent-detergent treated Factor VIII
17	concentrates.  In most of these episodes it was not possible 
18	to reconstitute the chain of infection from plasma pool to 
19	product to patients.  You see here that in this incriminated 
20	lot from the Italian episode and the Ireland episodes animal 
21	studies were performed but they were not successful.  This
22	large episode in Germany happened in 1997. 
23		[Slide] 
24		This is the prehistory.  Let me focus your 
25	attention to the right part of this slide.  Production pools 

			103 1	from several manufacturers were tested by NAT for HAV.  That
	2	is a screening procedure.  You see that manufacturer C has a 
	3	pasteurization step for inactivation and there were 2 out of 
	4	132 pools positive for HAV but no transmissions were 
	5	reported from final products manufactured from these 
	6	positive starting materials.
	7		You see here that we have tested from manufacturer 
	8	D the solvent-detergent inactivation procedure.  From 43 
	9	tested pools, none were active by NAT but from one starting 
10	material there were 6 HAV transmissions by Factor VIII. 
11		[Slide]
12		This is a genome of HAV.  For a screening 
13	procedure we use the conserved region of the terminus VP3; 
14	and for sequencing we use the junction of VP1-2A. 
15		[Slide] 
16		I now come to the last episode of transmission in
17	Germany.  It was in 1997, and seven hemophilia patients had 
18	an infection of HAV, and six of them developed acute 
19	hepatitis A.  All of them were recipients of Factor VIII 

20	from a batch from the manufacturer I showed earlier.  The 
21	plasma pools were screened by NAT and were negative in our
22	lab and also in the lab of the manufacturer.  But in 
23	retrospective studies we see that pool A was positive in 7 
24	out of 11 runs.  The incriminated lot was positive in 6 out 
25	of 17 runs.  You see that the virus is in the limiting 

			104 1	dilution.  Not every run will give us a positive result in
	2	the NAT.  So, we can calculate the viral load by the percent 
	3	distribution, and we get a viral load of the plasma pool of 
	4	600 genome equivalents/ml and of the incriminated lot of 300 
	5	genome equivalents/ml. 
	6		[Slide]
	7		This summarizes 9 patients, all of them anti-HAV 

	8	negative who received the same incriminated lot.  The first 
	9	6 developed acute hepatitis A.  I should mention that 
10	patient 6 received a bolus infection of only 4000 units of 
11	Factor VIII.  I should also mention that the bleeding date
12	for our retrospective studies is done at a time point very, 
13	very late, nearly 40 days after onset of the symptoms. 
14		[Slide] 
15		Here are the results of our molecular approaches 
16	in the two regions.  You can see there is 100 percent
17	homology between pool A, the incriminated lot and all the 
18	patients and for the VP1-2A junction and also for the VP3 

19	region.  I should have mention that we have used PCR control 
20	in this matter to exclude wild contamination.  You see that 
21	there is only homology in this region of nearly 90 percent
22	and 94 percent in this region. 
23		[Slide] 
24		For animal studies, usually chimpanzees or 
25	tamarins are susceptible animals for an HAV infection.  This 

				105 1	is a tamarin, a New World monkey, and we use it for our
	2	animal studies.  Animal transmission studies performed in 
	3	the context of earlier transmission episodes were not 
	4	successful because larger amounts of Factor VIII preparation 
	5	had to be administered.  Nevertheless, the manufacturing 
	6	question initiated an animal study again.
	7		[Slide] 
	8		This slide shows us the study design.  We used 
	9	three tamarins.  They were caged individually but they had 
10	acoustic contact with each other, and the Factor VIII 
11	product was carefully concentrated and each animal received
12	an equivalent of approximately 28,000 units of Factor VIII 
13	of the implicated lot.  That corresponds approximately to 
14	104 HAV particles.  The animals were observed up to 132 days 
15	post-infection.  The following parameters were investigated, 
16	from the feces the HAV antigen and HAV RNA, and from the
17	sera the liver enzymes, ALT and also all serological markers 
18	and HAV RNA. 
19		[Slide] 
20		Unfortunately the first tamarin died after 30 days 
21	post-infection, but no signs of HAV infection were observed. 
22	These are the results of animal two.  You can see classical 
23	HAV infection with seroconversion.  With the first marker we 
24	could detect HAV in the serum and later also in the feces.  
25	The ALT was detected nearly four weeks after PI, and after 

			106 1	seven weeks seroconversion could be detected.
	2		[Slide] 
	3		The second animal -- there was only in feces 
	4	samples HAV RNA detected and later antigen, and only a 
	5	slightly elevated ALT but no seroconversion could be 
	6	observed.
	7		[Slide] 
	8		To come then to the summary, we have sequenced all 
	9	samples from the animals and we can now summarize all 
10	samples from the chain of infection and from the tamarins, 
11	all have 100 percent homology in the sequences.
12		[Slide] 
13		Summarizing data from the animal studies, it was 
14	for the first time that infectious HAV in a clotting factor 
15	concentrate, by experimental infection, could be detected.  
16	There was complete identity of the HAV sequences from the
17	animals and the chain of infection. 
18		[Slide] 
19		To summarize all the data, from the molecular 

20	approaches and from the animal studies -- there was 100 
21	percent homology of all HAV sequences in two different HAV
22	regions, and there was a singular sequence of a unique HAV 
23	strain.  So, we can calculate the titer if we assume there 
24	is one positive donor in the plasma pool, and we have 
25	calculated the titer of this donor and it was approximately 

					107 1	106 particles/ml.  That was the titer of the donor of the
	2	contaminated plasma pool. 
	3		DR. HOLLINGER:  Let me just ask you a question.  I 
	4	wasn't quite clear on the first part.  You said the plasma 
	5	pool, the screening by an HAV TPCR was negative -- 
	6		DR. CHUDY:  Yes.
	7		DR. HOLLINGER:  -- and then the other pools were 
	8	positive.  Can you clarify that for me? 
	9		DR. CHUDY:  Yes, it is from the statistical point 
10	of view.  If I perform a screening and I do one run, and for 
11	prospective studies you have several runs with survivals in
12	the limiting dilution.  So, it is a statistical problem to 
13	detect one particle in one assay.  But you have a chance to 
14	detect it if you repeat and repeat these runs and that 
15	happened in this case. 
16		DR. HOLLINGER:  So, a Poisson distribution --
17		DR. CHUDY:  Yes. 
18		DR. HOLLINGER:  -- the screening was negative but 
19	when you went back and retested it several times -- 
20		DR. CHUDY:  Maybe I can have the next slide.  I 
21	documented some titers in the window period and some
22	possible recommendations for pool testing. 
23		[Slide] 
24		We have a window titer from our donor of 106 
25	particles/ml and we have a detection limit of an assay of 

				108 1	nearly 1000 copies/ml.  Compared to HCV it is not so
	2	sensitive, but maybe it can be explained by not destroying 

	3	by lysis because it a virus without envelope.  For a pool 
	4	size, I would propose a minipool of not more than 100 

	5	because then we come in conflict with the titer in the 
	6	window period.
	7		[Slide] 
	8		That is the view of the manufacturer.  I have to 
	9	show that but it is not my view. 
10		[Slide] 
11		I especially have to thank Christina Stahl-Hennig
12	for her excellent handling of the tamarins.  Thank you for 
13	your attention. 
14		DR. HOLLINGER:  Thank you, Dr. Chudy.  Any 
15	questions for Dr. Chudy? 
16		DR. MACIK:  I just wanted to go back to the one
17	point that you made when you were looking at the different 
18	neutralization techniques.  In one it was a pasteurization 
19	process where you had 2 out of 100-and some odd -- 
20		DR. CHUDY:  Yes. 
21		DR. MACIK:  -- but they did not transmit disease.

22		DR. CHUDY:  Yes.  That is maybe the same question 
23	as earlier.  Maybe pasteurization of nearly 10 hours at 68 
24	degrees may be more effective than solvent-detergent.  If 
25	you look in the literature, there are no reports of Factor 

			109 1	VIII and Factor IX products inactivated by pasteurization.
	2		DR. HOLLINGER:  We have been going for a good long 
	3	time now so I think we are going to take a 20-minute break.  
	4	It is 11:20 now.  So, we will reconvene at 11:40 and we will 
	5	have the open public hearing and then we will discuss the 
	6	questions.  Thank you.
	7		[Brief recess] 
	8		DR. HOLLINGER:  We have two groups that have asked 
	9	to speak to the question on plasma pool screening by nucleic 
10	acid tests for hepatitis A virus.  The first one is Dr. 
11	Louis Katz, from the American Association of Blood Banks and
12	Chairman of the Transfusion and Transmitted Diseases 
13	Committee for that group. 
14		          Public Open Hearing 
15		  American Association of Blood Banks 
16		DR. KATZ:  Those of you who picked up the series
17	of statements that AABB will make over the two-day meeting, 
18	I will read this boiler-plate paragraph once, and Dr. 
19	Hollinger told me that I wouldn't be allowed to read it a 
20	second time. 
21		The American Association of Blood Banks (AABB) is
22	the professional society for over 9,000 individuals involved 
23	in blood banking and transfusion medicine and represents 
24	roughly 2,200 institutional members, including community and 
25	Red Cross blood collection centers, hospital-based blood 

		110 1	banks, and transfusion services as they collect, process,

	2	distribute, and transfuse blood and blood components and 
	3	hematopoietic stem cells.  Our members are responsible for 
	4	virtually all of the blood collected and more than 80 
	5	percent of the blood transfused in this country.  For over 
	6	50 years, the AABB's highest priority has been to maintain
	7	and enhance the safety and availability of the nation's 
	8	blood supply. 
	9	          The AABB appreciates this opportunity to provide 
10	comment to the BPAC.  The AABB supports the continued 
11	performance of HAV   NAT on plasma pools for further
12	manufacture as an in-process control, rather than as donor 
13	screening. 
14	          We arrive at this position from consideration of 
15	the rarity of transfusion-associated HAV infection from 

16	single donor blood components, the generally benign course
17	of the illness, and the lack of medical rationale for donor 
18	notification.  if required or performed as donor screening, 
19	with a requirement for tracing donors and components and 
20	counseling positive donors, the logistics and cost of HAV 
21	NAT would be multiplied.  Furthermore, those donors
22	notified, based on the current time lines for screening and 
23	reporting of NAT results on recovered plasma, would have 

24	recovered from their infection and their contacts would be 
25	outside any reasonable window for preventive therapy. 

			111 1		We applaud the effort of the plasma industry in
	2	the implementation of this testing designed to minimize the 
	3	input of virus in large plasma pools to which hundreds of 
	4	recipients are exposed.  Its value is especially obvious for 
	5	those products for which viral inactivation techniques are 
	6	not robust for non-enveloped pathogens.  Thank you.
	7		DR. HOLLINGER:  Thank you, Louis.  The next person 
	8	who asked to speak is Dr. Susan Stramer, from the American 
	9	Red Cross.  Dr. Stramer? 
10		           American Red Cross 
11		DR. STRAMER:  Thank you.  The American Red Cross

12	thanks the FDA for allowing us time to address the Blood 
13	Products Advisory Committee.  My name is Sue Stramer, and I 
14	am the Executive Scientific Officer, National Testing and 
15	Reference Laboratories, of the American Red Cross. 
16		The American Red Cross is composed of 36 blood

17	collection regions that collect approximately one-half of 
18	the whole blood in the United States.  Products from Red 
19	Cross collections are manufactured into transfusable 
20	components, platelets, red cells and fresh-frozen plasma.  
21	Additionally, the majority of the plasma that is recovered
22	from the collected units is used for pooling and further 

23	manufacture into virally inactivated, therapeutic products. 
24		The American Red Cross supports the continuing 
25	efforts to increase the safety of whole blood components and 

		112 1	plasma derivatives and, therefore, supports the performance
	2	of nucleic acid testing as an in-process control for the 
	3	detection of hepatitis A virus.  We believe, however, that 

	4	this testing should be managed in a fashion that does not 
	5	involve donor notification of the management of individual 
	6	donations.  HAV is a very infrequent contaminant of
	7	voluntary donations, estimated at much less than one per 

	8	million.  The infection is acute and self-limited due to the 
	9	production of neutralizing antibodies, and there is no 
10	carrier state.  Thus, there would be no benefit in notifying 
11	donors several weeks after donation, and infection among
12	recipients of single donor products does not appear to be a 
13	matter of current concern.  During the short window period 
14	that HAV is present in biological prior to clinical disease, 
15	that is, less than 7-10 days in most individuals, the 
16	concentration of HAV in blood is relatively low.  Infectious
17	virus is believed to be rapidly cleared by the appearance of 
18	antibody at the time of clinical symptoms.  In addition, 

19	immunity to the agent increases with age and there is the 
20	possibility that other transfused units or the transfused 
21	product itself may, in fact, contain anti-HAV.  Also, as has
22	been mentioned this morning, HAV vaccine is recommended for 
23	recipients of clotting factor concentrates. 
24	          The American Red Cross' proposed current strategy 
25	for the management of HAV in the context of manufactured 

				113 1	plasma products is designed to assure the absence of
	2	detectable HAV RNA in the final products.  HAV PCR will be 
	3	performed on pools of plasma prior to fractionation.  In the 
	4	event of a positive result, the manufacturing pool would not 
	5	be used and would be destroyed.  Red Cross has performed a 
	6	qualification run to determine the logistics and feasibility
	7	of this strategy.  A pilot study involved the equivalent of 
	8	540,000 donations that were pooled into 45 manufacturing 
	9	pools of 3200 L.  Each pool was tested for HAV RNA by PCR at 
10	National Genetics Institute.  All pools tested negative for 
11	HAV RNA.  We believe that this strategy for HAV screening

12	for recovered plasma from volunteer whole blood donors is 
13	the most reasonable approach at this time.  Thank you. 

14		DR. HOLLINGER:  Thank you, Susan.  Yes, Dr. 
15	Finlayson? 
16		DR. FINLAYSON:  John Finlayson, FDA.  Is the
17	procedure that you described the one that you would plan to 
18	continue to use, that is testing 3200 L pools? 
19		DR. STRAMER:  Yes, that is the stage at which the 
20	first pooling occurs, and that is the smallest pool size 
21	that we can get retrieval for a sample.
22		DR. FINLAYSON:  You didn't mention what level of 
23	detection NGI anticipated getting, but if I did my 
24	arithmetic correctly, this represents units of an average 
25	size of 266.66 ml being diluted to 3200 L. 

					114 1		DR. STRAMER:  Correct.
	2		DR. FINLAYSON:  So, that is approximately a 
	3	12,000-fold dilution.  My question is, depending on your 

	4	level of detection, you said in your statement that the 
	5	level is low in infected individuals, do you ever expect to 
	6	ever find any positives?
	7		DR. STRAMER:  The sensitivity of the NGI test, 

	8	coupled with the dilution factor -- you are right, we are 
	9	looking at 3.2 X 106 to 3.2 X 107 as the detection limit per 
10	milliliter of starting material.  So, the technique is not 
11	very sensitive, but in the event that there would be a very
12	high titer unit this would be the procedure to catch that 

13	unit. 
14		DR. FINLAYSON:  I guess my question is, is it 
15	worth doing? 
16		DR. STRAMER:  That is certainly a question. 
17	Currently we are doing it.  One could argue is it worth 

18	doing it at the frequency we see HAV in the donors.  But 
19	because the issue has come up and we do manufacture a 
20	product, the question has been asked how we should proceed 
21	and so this is one feasible way to proceed at this point.

22		DR. FINLAYSON:  Well, I wasn't asking the question 
23	in the sense that I was implying that one shouldn't do it.  
24	It is just that I had an uncle who used to recite over and 
25	over to me "if it's worth doing, it's worth doing well" and 

			115 1	I think we will leave it at that.
	2		DR. STRAMER:  Okay. 
	3		DR. HOLLINGER:  Thank you, John.  Is there anyone 
	4	else who would like to comment from the public at this time?  
	5	Yes, Dr. Miriam Alter, from the CDC. 
	6		DR. ALTER:  I guess the major issue that I would
	7	like to address is the benefit to the donor should 
	8	notification take place.  It would seem to me that most of 
	9	that discussion has focused around the opportunity to 

10	prevent secondary transmission to the donor's contacts.  
11	And, I would like to make sure that we have a realistic
12	picture of what that would mean after the donation took 

13	place.  We assume that the majority of these donors are in 
14	the window period.  We can make an assumption that they are 
15	in the early phase of their acute infection, let's even say 
16	the first two weeks of their infection.  Presumably fecal

17	shedding of virus, which is the phase of infection during 
18	which transmission to contacts occurs which is an issue 

19	separate from transmission through transfusion or through a 
20	blood product -- that is, prevention, the administration of 
21	immune globulin would have to be given to the contact within
22	two weeks of their exposure, that is, within two weeks of 
23	the time during which the donor was shedding virus. 

24		Even with rapid turn-around of testing results, is 
25	it realistic to expect that the donor can be notified and 

			116 1	that the donor will get evaluated, and the contacts will
	2	then be evaluated within, let's say, a four-week period of 

	3	time, such that the administration of Ig could even hope to 
	4	prevent infection or ameliorate disease in these 
	5	individuals?  Unless it could take place at a maximum, 
	6	actually, of that period of time, it would not benefit the
	7	contacts of that donor.  So, I think we need to take that 
	8	into account when discussing notification because the blood 
	9	collection group is going to have to write a letter of 
10	phrase the information.  They are going to have to explain 
11	to the donor what this means.  So, we need to be very sure
12	we understand what it means to that donor and what that 

13	donor is supposed to do about.  Thank you. 
14		DR. HOLLINGER:  Any other comments from the 
15	public?  Yes, please, and state your name. 
16		MR. HEALY:  My name is Chris Healy, and I am
17	Director of Government Affairs for ABRA.  We are the trade 
18	association for the source plasma collection industry.  I 

19	appreciate the opportunity to address this issue before you. 
20		We believe that there may be a substantial "right 
21	to know" interest in donors being notified about positive

22	HAV test results.  However, we don't think that the public 
23	health reasons support donor notification.  As Dr. Alter 
24	just described, we think that by the time NAT results are 

25	reported back to these collection centers and they are given 

			117 1	an opportunity to notify the donors, they are already
	2	probably fully symptomatic and would have encountered any 
	3	secondary exposures, and that would have already occurred.  
	4	So, the public health doesn't, we don't believe, support the 
	5	donor notification while there might be "right to know" 
	6	interest in donors being notified.
	7		Further, we don't believe that donor deferral and 
	8	lookback are warranted based on HAV by NAT.  As I think 
	9	probably most of the people on the committee know, temporary 
10	deferral really means permanent deferral for most donors.  
11	Once you turn them down, they are typically gone for ever. 
12	They are going to be symptomatic and sick, and are unlikely 
13	to donate, and should they come in after the symptoms clear 
14	up and donate still infectious units, that would again be 

15	picked up by the testing and could be eliminated. 
16		Given the short window period by NAT if we can
17	assume it is about two weeks, there would be virtually no 

18	donations to perform a lookback on and if there are any, it 
19	would simply be a single unit or two given the frequency of 
20	plasma donations and that could be managed in-house very 
21	easily.  So, we don't believe that lookback and donor
22	deferral are appropriate either.  Thanks. 
23		DR. HOLLINGER:  Thank you.  Jeanne, I didn't mean 
24	to cut you off.  Did you have a question for one of the 
25	people?  Yes, please. 

					118 1		DR. LINDEN:  I have a question for Dr. Stramer. 

	2	In light of Dr. Alter's comments about the time frame for 
	3	intervention, could you please explain to us the logistics 
	4	and time frame of the pooling and testing that you do? 
	5		DR. STRAMER:  The stage of pooling that I 
	6	presented, the 3200 L stage, that is within a manufacturing
	7	pool and at that time point those pools would not be broken 
	8	down, or they are not able to be broken down into the 
	9	individual donations.  If we were doing this on a minipool 
10	basis, then it potentially would be feasible, and the time 
11	frame of that, as we do for HIV or HCV NAT, would be donor
12	notification within several weeks of collection.  But that 
13	is still too late, as Miriam has discussed, as far as 
14	preventing secondary transmission and having any benefit to 
15	the donors themselves. 
16		DR. LINDEN:  How long is it before the pooling and
17	the testing occurs though? 
18		DR. STRAMER:  For the pool that I described? 
19		DR. LINDEN:  Yes. 
20		DR. STRAMER:  It is at least 30 days. 
21		DR. HOLLINGER:  I was going to ask Toby, but if
22	you are up here maybe you could do it -- and, Toby, you can 
23	jump in here too -- 
24		DR. SIMON:  I can do it for the plasma industry 
25	and then we can add for the blood banks.  We wanted just to 

			119 1	put this in a time frame for the committee to kind of
	2	understand the logistics of how we operate.  As Dr. 
	3	Chamberland said early on, this will be key in terms of the 
	4	notification.  But if several companies were to be doing 
	5	this testing, each would have a different protocol.  I tried 
	6	to do an informal survey to find out what they are at
	7	present with nucleic acid testing and so I will describe 
	8	several different protocols. 
	9		The earliest that any of the collectors are 
10	learning of a positive nucleic acid test result is in the 7- 
11	14-day range.  There are one of two companies that are doing
12	this testing in such a way that they are currently providing 
13	a positive test result in 7-14 days. 
14		There are several other company protocols where 

15	the material is shipped after it is negative for serologic 
16	testing.  Then, from the warehouse the samples are taken,

17	based on the crates or boxes, and then pool testing is done 
18	and then, of course, you have to test back to the individual 
19	unit.  The soonest, under those kinds of protocols, that you 
20	would be notified would be about four weeks. 
21		Now, the material from ABC goes to Switzerland and
22	is fractionated there and then sent back as final product, 
23	and we are looking at a minimum of four, probably as long as 
24	eight weeks before any notification could occur under those 
25	circumstances.  I gather that with your current plan at the 

				120 1	Red Cross it would be in the four to eight weeks range also.
	2		DR. STRAMER:  At a minimum, thirty days. 
	3		DR. SIMON:  That of course is the time until the 

	4	center gets a result back.  Then they have to, of course, 
	5	attempt to locate the donor either by mail or by phone and 
	6	get the donor in for counseling.  So, I think time frame-
	7	wise it is going to be uncommon, unusual to notify and 

	8	counsel a donor before two weeks have elapsed since the 
	9	positive test result, and more commonly it is going to be 
10	four weeks or longer. 
11		DR. HOLLINGER:  Thank you, Toby.
12		DR. STRAMER:  I think in any environment looking 
13	at less than a two-week period of notification post 
14	collection is truly unrealistic.  Even as we work with HIV 
15	and HCV and we have a yield sample and we aggressively try 
16	to contact the donor, especially for the purposes of follow-
17	up, we are always looking at a period of at least two weeks. 
18		DR. HOLLINGER:  Yes, Dr. McCurdy? 
19		DR. MCCURDY:  I think this time frame discussion 
20	is quite pertinent, but there is one question I would like 
21	to raise in a slightly different area.  That is, I think the
22	assumption is being made that these are window period 
23	donations, and I think they much more likely are going to be 
24	inapparent infections, that is, infections that never have 
25	clinical symptoms that are recognized.  I think there are 

			121 1	probably 3-5 inapparent infections for every one who
	2	actually gets jaundice and gets disease that is recognized.  
	3	So, I think the frequency we may not know.  I think the 

	4	duration of time is perhaps more pertinent in the self- 
	5	limited aspects of the disease usually. 
	6		DR. HOLLINGER:  But, Paul, most of the studies
	7	that have looked at clinical disease in adults, as distinct 
	8	from children, show that virtually 85-90 -- I mean, these 
	9	are large studies where they have looked at seroconversions 
10	so probably in adults 85-90 percent of patients, if not 
11	more, develop clinical symptoms as compared to children
12	where maybe it is only going to be 15 percent or less.  So, 
13	I would think that if a person had hepatitis A, clearly the 
14	vast majority would present with clinical disease some time 
15	after they donated the blood, so within a short time. 
16		DR. MCCURDY:  I think I was basing it, at least in
17	part, in the increased proportion of seropositivity in the 
18	population as they got older, which would imply, if they 

19	didn't have a history of hepatitis, that they either forgot 
20	or didn't have clinical disease.  But I think you are 
21	probably right, it is mostly in children.
22		DR. HOLLINGER:  Yes, Dr. Schmidt? 
23		DR. SCHMIDT:  We did a study some years ago of 
24	blood donors who, of course, denied any history of hepatitis 
25	and, as you went up on an age frame when you got up to age 

		122 1	70, 70 percent of them had their antibody and, of course, it
	2	increased over time.  So, it is what you are saying.  I 
	3	don't think one out of every five people who are infected 

	4	have clinical symptoms.  It must be a lot, lot less than 
	5	that. 
	6	          DR. LATER:  Miriam Alter, CDC.  Actually, I would
	7	sort of like to address that.  I agree that there is this 

	8	asymptomatic component, although we do think that adults are 
	9	much more likely to be symptoms certainly than children. 

10	However, going to the other extreme, even without symptoms 
11	one could presume for the purposes of preventing secondary
12	transmission that the maximum period of viral shedding in 
13	the stool was going to take place in the two weeks or so 
14	after the period of viremia, if one wanted to try and make 

15	some kind of estimate.  So, even without the symptoms people 
16	are still shedding virus in their stool.  That is the whole
17	problem with our outbreaks of hepatitis A.  We have all this 
18	fecal shedding of virus and a lot of people who aren't 
19	symptomatic, particularly children. 
20	          Anyway, the point is that presumably you could 
21	prophylax for contact and prevent infection based on
22	themselves fact that the donor was found to RNA positive 
23	and, therefore, at some in the next few weeks that donor was 
24	going to be shedding virus.  Therefore, you go ahead and 

25	give Ig to the contacts because presumably they have been 

				123 1	exposed.  However, regardless of whether the donor becomes
	2	symptoms or not, the time frame, as just stated in the 
	3	previous discussions, would probably be outside that which 
	4	would benefit the contacts regardless. 
	5		DR. HOLLINGER:  Yes, Col. Fitzpatrick? 
	6		COL. FITZPATRICK:  Dr. Feinstone presented data on
	7	individuals who had high levels of circulation antibody and 
	8	low levels of RNA.  Is there anything to tell us whether 
	9	those individuals are still infective or not? 
10		DR. HOLLINGER:  Doubtful, but I will let Steve 
11	answer that.
12		DR. FEINSTONE:  As I said, there really is no data 
13	on the infectivity of those individuals, to my knowledge 
14	unless somebody has tested them recently.  But the old data 
15	-- and there is nothing wrong with old data, just because it 
16	is not PCR-based.  I mean, these were carefully done studies
17	by some terrific investigators.  Those studies say that the 
18	serum and the feces are not infectious very long after the 
19	appearance of clinical symptoms.  I think that is still very 
20	reliable data. 
21		DR. HOLLINGER:  Yes, Dr. Simon?
22		DR. SIMON:  I just want to clarify, maybe while 

23	Dr. Feinstone is still there, as I understand it, we would 
24	not be detecting window cases.  Window cases would be the 
25	period before if the NAT is positive, I believe.  So, the 

					124 1	cases we would be detecting would be from the time of
	2	viremia, the first NAT positivity.  So, it is from the time 
	3	of our first detection until approximately two weeks 
	4	thereafter that would be useful in terms of interdicting 
	5	spread.  Am I correct? 
	6		DR. FEINSTONE:  I am not clear why you would not
	7	be detecting window cases. 
	8		DR. SIMON:  I think we used the definition of 
	9	window before a positive test result -- 
10		DR. FEINSTONE:  Okay, antibody appears at about 
11	the time of clinical symptoms.  The major period of viremia
12	and the major period of stool shedding is prior to the 
13	appearance of antibody and clinical symptoms. 
14		DR. SIMON:  So, we are calling that the window 
15	period? 
16		DR. FEINSTONE:  That would be the classic window
17	period. 
18		DR. SIMON:  So, it is from the first appearance of 
19	an NAT positive test until symptoms begin -- 
20		DR. FEINSTONE:  Yes, and that is the period when 
21	people are infectious.  That is when they are dangerous to

22	their contacts. 
23		DR. SIMON:  And that period is approximately two 
24	weeks. 
25		DR. FEINSTONE:  it is quite variable I believe, 

			125 1	but it is on the order or two weeks.
	2		DR. EPSTEIN:  Steve, could I press the point a 
	3	little bit?  I thought I heard you say that these 
	4	recurrences occur in about 10 percent of patients, and it 

	5	was not clear whether the recurrences were the same thing 
	6	also being observed with chronic, persistent detection of

	7	RNA.  The question is in the earlier studies that looked at 
	8	infectivity of plasma and stool, what were the numbers?  
	9	And, were the numbers sufficient to capture the relatively 
10	infrequent cases that might have the relapses or chronic 

11	viremia?  In other words, isn't there a statistical problem
12	here?  If you had a small number of volunteer studies and if 
13	only 10 percent or less might have actually had this chronic  
14	course, one simply could have missed them in the studies.  

15	So, I am not sure that the early studies are dispositive, 
16	although I don't think that in any way imputes the quality
17	of those studies.  It is a statistical problem. 
18		DR. FEINSTONE:  I understand what you are saying 
19	but, again, there is no epidemiologic evidence that these 
20	patients who have recurrent symptoms are infectious for 

21	their contacts.  I don't believe there have been any
22	secondary cases reported from those groups.  Is that right?  
23		DR. ALTER:  One, in a premature infant. 
24		DR. FEINSTONE:  One. 
25		DR. ALTER:  There has been one instance of 

			126 1	transmission due to fecal-oral exposure from an index case
	2	with prolonged viremias, and it involved a premature infant 
	3	who had an extended hospitalization in an intensive care 
	4	nursery, whose source of infection was actually a 
	5	transfusion.  Four months or so after the original infection 
	6	that infant transmitted to nurse.  It is the only instance
	7	and we believe that it is unique to that particular 
	8	situation and the immune competence of the premature infant. 
	9		DR. HOLLINGER:  Dr. Koff? 
10		DR. KOFF:  Yes, just to follow up on that, Dr. 

11	Epstein, I think the evidence is if you look at fecal-oral
12	transmission virtually all of the secondary cases occur 

13	within one incubation period.  So, even though there may be 
14	some kind of RNA that still is present in stool and maybe 
15	some kind of denatured RNA -- I don't know -- that in some 
16	instances is still present in blood, really evidence of

17	infectivity, other than this one instance, just isn't there, 
18	and that has been true now for about 30 years of looking at 
19	secondary cases.  Most of the secondary cases that occur 
20	that were shown, in fact, occurred in the neonatal intensive 
21	care unit.  Household cases have just been exceedingly
22	unusual. 
23		DR. HOLLINGER:  Thanks, Ray.  Is there anyone else 
24	who has not spoken and wants to speak from the public right 
25	now?  If not, what I would like to do at this point is to 

			127 1	have Robin Biswas present the questions that are going to be
	2	focused on here for the committee so we can sort of focus on 
	3	what we are really here for, and then discuss around those 
	4	parameters.  So, Robin, let's start with the first two 
	5	questions, 1a and 1b. 
	6		       Open Committee Discussion
	7		     FDA Perspective and Questions 
	8		[Slide] 
	9		DR. BISWAS:  Questions for the committee, 1a. 
10	Should the Food and Drug Administration recommend that, if a 
11	plasma pool or minipool is found to be HAV NAT positive, the
12	individual HAV NAT positive donor should be identified and 
13	notified of the test result? 
14		1b.  If so, should the FDA recommend that the 
15	implicated donor be deferred from donating for three months? 
16		[Slide]
17		2.  Should the FDA recommend that unpooled units 
18	from donors, that were donated within the three months prior 
19	to the HAV NAT positive collection, be quarantined? 
20		3.  Should the FDA recommend that recipients of 

21	transfused components from donors that were donated within
22	three months prior to the donor's HAV NAT positive 
23	collection be traced and notified? 
24		Committee Discussion and Recommendations 

25		DR. HOLLINGER:  Let's go back to the first 

			128 1	question, 1a, which is concerned with notification of the
	2	positive donor, identified and notified, and deal with this 
	3	issue right here.  So, I would like to sort of focus the 
	4	questions on this particular question.  Any comments?  Yes, 
	5	Dr. Linden? 
	6		DR. LINDEN:  Well, I have a question for Dr.
	7	Epstein.  Following up on what you said before in terms of 
	8	understanding the implications of this, if somebody is 
	9	identified and notified, that means that they would then 
10	have a history of hepatitis?  Maybe I misunderstood what you 
11	said earlier.
12		DR. EPSTEIN:  As Dr. Biswas stated, we currently 
13	interpret the regulation on history of viral hepatitis only 
14	to encompass clinical hepatitis, which means identified 

15	signs and symptoms and/or clinical diagnosis.  The sticky 
16	wicket here is that if you create a report of a positive NAT
17	test and then the donor is 80 percent likely also to then 
18	become recognized symptomatic, it would be captured as 
19	having had a history of clinical hepatitis.  So, then they 
20	would be captured by the current by the lifetime deferral 
21	policy, and there would be a 20 percent subset that might

22	not because they never had colleague symptoms but the 
23	majority would.  Since we don't currently have a policy 
24	whereby a well-established diagnosis of hepatitis for a 

25	hepatitis with no chronic implication can be exempt from the 

				129 1	lifetime deferral, there would have to be sought a case by
	2	case exemption.  So, that is what I was trying to explain.  
	3	But, I also stated that that entire policy is being 
	4	reexamined. 
	5		DR. HOLLINGER:  Jay, while you are still there, I 
	6	want to clarify for the committee that NAT testing for HAV

	7	is currently being done by the plasma industry.  Is that 
	8	correct?  We are not dealing with that issue here, are we? 
	9		DR. EPSTEIN:  No. 
10		DR. HOLLINGER:  The issue here is not whether it 
11	should be done but what should be done about the results,
12	and so on?  Is that correct? 
13		DR. EPSTEIN:  No, it is not correct.  There are 

14	some fractionators that have voluntarily introduced NAT and 
15	at different levels of their process.  We have one request 
16	for modifying the license specifically to include that
17	procedure.  Other companies have suggested that they may 
18	become interested.  So, we don't currently have an industry 
19	practice. 
20		DR. HOLLINGER:  But there are no questions here -- 
21	unless I am just missing them -- that specifically say
22	should the plasma industry test -- whatever, many pools or 
23	pools or a certain size for HAV by nucleic acid testing.  Am 
24	I correct in saying that?  I don't see the questions here.  
25	They are dealing with the assumption that it is being tested 

			130 1	and then what should be done with the results.
	2		DR. EPSTEIN:  Well, I think we are responding to 
	3	the fact that we have an application which requests approval 
	4	as an in-process procedure as part of a license.  So, that 
	5	is what we are trying to deal with. 
	6		Perhaps we should have also simply asked the
	7	committee should all donations be screened for HAV, but the 
	8	agency wasn't expecting that that would be our interest and 
	9	concern.  I mean, if you want to raise that question 
10	initially and have the committee vote, I think that is fine 
11	but we were reacting to a specific request to do this as an
12	in-house, in-process procedure and, therefore, how should 
13	the FDA view this?  Should we require that the scope be 
14	extended?  But we were really not envisioning moving that to 
15	a requirement to screen all donations.  But that is 
16	certainly a logical and pertinent question if you want the
17	committee to look at it. 
18		DR. HOLLINGER:  Well, I would just like to ask the 
19	committee.  I mean, I would think that the first question 
20	should be should plasma pool screening be performed by 
21	nucleic acid tests for hepatitis A virus, or should we not

22	deal with that?  I would like to hear what the committee 
23	would like to do about this.  Yes, Dr. Simon? 
24		DR. SIMON:  Well, just from the industry point of 
25	view, I am sure industry would prefer to be able to deal 

				131 1	with this on a voluntary basis.  My take on the
	2	presentations we have heard is that there is not an 
	3	overwhelming or highly compelling case in terms of recipient 
	4	safety for the FDA to mandate this, but one or more 
	5	companies may wish to do this as a further enhancement of 
	6	safety.  So, my preference would be that we not extend the
	7	discussion and that we stick to the questions FDA has given 
	8	us, which is how should they handle the situation when a 
	9	company wishes to introduce hepatitis A virus nucleic acid 
10	testing. 
11		DR. HOLLINGER:  Col. Fitzpatrick?
12		COL. FITZPATRICK:  Based on what we heard from the 
13	Paul Ehrlich Institute and the comments after, I question 

14	the utility of saying you have a safe process when the odds 
15	are you are doing a test that is going to detect nothing.  
16	So, I think we should address that question.
17		DR. HOLLINGER:  Which question? 
18		COL. FITZPATRICK:  Whether or not testing for HAV 
19	by NAT should be done. 
20		DR. HOLLINGER:  I think John's comments were that 
21	with pools of 3200 L and even a concentration of virus that
22	is 105 -- most are 104 or less, you know, you would have to 
23	have something that is going to detect 10 genomic 
24	equivalents/ml at best to even pick up one, and that would 
25	be without looking at the Poisson distribution.  I mean, 

			132 1	unless you do it multiple times that would be very
	2	difficult.  I think it is a good comment.  Yes, Dr. Schmidt? 
	3		DR. SCHMIDT:  I don't think the FDA can stop the 
	4	companies from doing it if they want to do it.  It just 
	5	brings up the question and becomes part of their SOP and how 
	6	you handle it from there.  Right?
	7		DR. HOLLINGER:  Yes.  Dr. Mitchell? 
	8		DR. MITCHELL:  I think it is a valid question 
	9	because I think it needs to be clear that presumably we are 
10	not recommending that this be done, and that there is sort 
11	of a discussion about the usefulness of HAV testing.
12		DR. HOLLINGER:  Yes, Dr. Ohene-Frempong? 
13		DR. OHENE-FREMPONG:  If the recommendation is made 
14	that those who receive plasma products that are likely to 
15	transmit HAV, they must be vaccinated against something that 
16	we presume exists.  If we are vaccinating or recommending

17	vaccination but we will not survey the products that they 
18	receive, it would seem to me that we are trying not to find 
19	out whether the problem exists at all.  Maybe at some point 
20	vaccination will no longer necessary. 
21		DR. MACIK:  I think part of the answer to that

22	though is that the vaccination is for HAV that they might 
23	contact in the community, not necessarily what they are 
24	getting from their concentrate.  So, if they already have 

25	hepatitis C from their blood product and you want to protect 

			133 1	them with the hepatitis A vaccine so if they get hepatitis A
	2	from a restaurant they are okay, and I don't know if the 

	3	idea to vaccinate them wasn't totally driven on the fact 
	4	that we are trying to protect them from their concentrates 
	5	on that one. 
	6		DR. HOLLINGER:  Yes, Dr. Boyle?
	7		DR. BOYLE:  I don't think we have heard enough 

	8	about what people are doing.  It sounds like there is a 
	9	variety of things out there.  Some are not doing 
10	minipooling; some may be proposing minipooling; and I don't 
11	think we really have enough information to speak to the
12	broader issue of whether or not people should be doing the 
13	HAV testing and how it should be done, but I think there is 

14	enough information to speak to the questions in front of us.  
15	And, I think depending on how we vote on 1a, that might 
16	determine whether people are doing HAV testing in the
17	future. 
18		DR. HOLLINGER:  I think that is fair enough.  
19	Let's look at it this way then, assuming that there might be 
20	testing or there might not be, it doesn't matter, the fact 

21	is that if there is testing then the issue would be should
22	the individual positive donor be identified and notified of 
23	the test result?  That is what the question is.  So, if 

24	there were testing, should you notify the donor?  That is 
25	one of the big issues.  So, let's deal with that question 

			134 1	and we will put it up for a vote if there are no comments. 
	2	Yes, Dr. Boyle? 
	3		DR. BOYLE:  The question I wanted to ask earlier, 
	4	Dr. Epstein, is if you are notifying donors of test results, 
	5	does that not require a higher level of approval than if you 
	6	were doing something that did not involve what would
	7	effectively be a diagnostic test? 
	8		DR. EPSTEIN:  Yes, that was the point of Miss 

	9	Kochman's presentation.  If we recommend and implicitly 
10	require donor notification, then we are not just looking at 
11	a process control procedure, we are looking at a medical
12	diagnostic test.  What we are saying to you in effect is we 
13	would like to hold that to the same standard as other 

14	medical diagnostic tests, which is at the very least a 
15	510(k).  Whereas, if it doesn't become part of donor 

16	notification, then it can be a process control.  We still
17	are concerned with it being validated and we still would be 
18	concerned with its performance characteristic including the 
19	setting of some standards for minimum sensitivity, but we 
20	would not require that it be validated as a medical 
21	diagnostic.
22		DR. HOLLINGER:  In comment though, I would think, 
23	again, why do we notify people?  We notify them because of 
24	some implication about their health -- chronicity, more 
25	serious liver disease and so on, for example, or we notify 

		135 1	them to prevent transmission or other things going on.  So,
	2	the big issue here is in a disease that does not cause 
	3	chronicity, and by the time you get the data, from what was 
	4	just described here, you are looking at weeks down the line 

	5	before you would probably be able to do anything beneficial.  
	6	Then, it looks to me like it is not very appropriate to
	7	notify somebody at that point and I think that is the 
	8	difference with this and the others, at least in my opinion.  
	9	 Other comments?  Yes, Dr. Mitchell? 
10	          DR. MITCHELL:  I agree with what you said but I 

11	also believe that there is a "right to know" and for people
12	to be notified about things that are found.  To me, it is 
13	sort of different and that is why I think we should address 
14	the first question, which is whether it should be done.  
15	Now, if we are saying that it shouldn't be done, then I can 
16	justify saying that people shouldn't be informed of the
17	results if it is positive.  That is why, you know, to me it 
18	is important to ask that first question.  Otherwise, it 

19	sounds like you are getting some information about an 
20	individual's health and you are sort of withholding that 
21	information.
22	          DR. HOLLINGER:  I guess the issue would be what 
23	information is that about their health.  I guess that is the 
24	issue.  Right now, for B19 apparently the donor is not being 
25	notified but you would feel that they should be also, I 

			136 1	presume from what you said.
	2		DR. MITCHELL:  I think, again, there is a 
	3	difference between recommended testing and not recommended 

	4	testing.  You know, if it is not recommended that the test 
	5	be done, then I think that the burden of notification is 
	6	different.
	7		DR. HOLLINGER:  Dr. Nelson? 
	8		DR. NELSON:  Not being a blood banker, I am not 
	9	too sure but if you had a positive pool for hepatitis A and 
10	the donor did not need to be notified or there was no 
11	recommendation for notification, would you still test down
12	to the individual unit or only that pool? In other words, 
13	depending on this recommendation, would the process be 
14	different with regard to what the blood bank or the plasma 
15	industry did? 
16		DR. SIMON:  The answer, I think unfortunately, is
17	going to vary between companies but I believe if you do not 
18	require notification, then it would be the choice of the 

19	company as to whether it would be preferable at some point 
20	to simply dispose of the pool and not use it in further 
21	manufacture to decrease potential infectivity but not
22	attempt to determine the particular donor, or whether they 
23	would go ahead to minipools and do the donor.  So, if you 
24	vote no on this and if the FDA follows that advice and the 
25	companies are allowed to use it as an in-process control, 

			137 1	then it would be the company's choice, as I understand it. 
	2	If anyone in the room feels I am in error -- but it would be 
	3	their choice, based on product cost issues and so forth, 
	4	whether they would identify the unit or simply eliminate a 

	5	small pool.  It sounds like the Red Cross has already made 
	6	that decision and that they were not planning to identify
	7	and they were just going to eliminate those pools.  If you 
	8	require notification then, obviously, the company would be 
	9	obligated to go down to the individual donor. 
10		DR. NELSON:  You know, there is always a concern 
11	about false positives but when we were talking about looking
12	at pools for hepatitis C or other agents, there were always 
13	instances where pools were positive but you couldn't 

14	identify the positive unit.  What that represented is 
15	unclear but if the pool would still have to be quarantined 
16	or destroyed, then we may not be as concerned about the
17	false positives or about testing individual units. 
18		DR. HOLLINGER:  Dr. Chamberland? 
19		DR. CHAMBERLAND:  Just a couple of comments.  It 
20	occurred to me when Dr. Mitchell was making his comments 
21	vis-a-vis the right to know, and Chris Healy has said this
22	earlier, given the demographics of the donor population, 
23	meaning that most of them are adults that will go on to 

24	develop symptomatic disease, most of them are going to know 
25	in a short matter of time that they actually have acquired 

			138 1	hepatitis A infection.
	2		Just in follow-up to Toby Simon's comment, I was 
	3	curious since our only precedent for in-process control that 
	4	I am aware of is the parvo B19, have any of the 
	5	manufacturers made the decision to go down to individual 
	6	donor notification, that you are aware of?
	7		DR. SIMON:  I am not aware -- I think some are 
	8	doing that in the validation phase of the test but I believe 
	9	it was the intention not to do it going forward. 
10		DR. HOLLINGER:  Yes, Mr. Rice? 
11		MR. RICE:  I just had a question.  If a company

12	can either choose to do the test or not do the test, I am 
13	just wondering are they going to be using that information 
14	in any sort of representations to consumers who use that 
15	product?  If that is the case, I am wondering, one company 
16	to the next, if we do HAV NAT testing, well, if you are a
17	consumer and you are choosing which product you will 

18	consume, I wonder how that communication is going to be made 
19	and what will that really mean for a difference in one 
20	product to the next, or are we trying to figure out whether 
21	that is something we are even concerned about?  I am just
22	saying if a company is doing the test, are they going to say 
23	to the potential consumer of their product that they are 
24	doing the test?  What will that really mean if we don't have 
25	some sort of guidelines?  Otherwise, maybe we shouldn't do 

		139 1	anything about it.  Let them do it internally but if they
	2	are going to reveal this as being something else they do, I 
	3	am just trying to picture how that can have an effect on a 
	4	person's choice of consuming the product. 
	5	          DR. KOERPER:  Certainly, the companies are doing 
	6	this so that they can have an added edge when they are
	7	marketing their product.  But I don't believe that this 
	8	committee should be in the position of somehow saying that 
	9	companies shouldn't do the testing.  I think that is the 
10	company's right, to decide whether that will add, even if it 
11	is a marketing edge as opposed to anything else.  I don't
12	think we can tell companies they can't do this testing. 
13	          With regards to the right to know, I was sitting 
14	here trying to think, well, why do they need to know this?  
15	As people have already said, it is not like this particular 
16	infection causes a chronic disease like HIV or hepatitis C. 
17	It is not like, therefore, there is a need to intervene with 
18	treatment.  Also, unlike HIV and hepatitis C, it is not like 
19	there is a potential for ongoing transmission.  So, the only 
20	reason why someone would want to know that is because, 

21	therefore, they are already immune and they don't need to
22	get vaccinated.  You know, I just can't see that as a valid 
23	reason for requiring that identification of individual 

24	donors who are positive should be a requirement of these 
25	companies.  I think if they want to test the pool, that is 

			140 1	fine but I don't think we should require them to find the
	2	individual donor and notify the donor.  I just don't think 
	3	there is any overwhelming health reasons why the donor needs 
	4	to be notified. 
	5		DR. HOLLINGER:  And let's not forget, I suspect 
	6	that 50 percent of patients that I see, and I think Ray
	7	would probably agree with this, you know, never knew that 
	8	they had hepatitis A in the first place.  So, they have had 
	9	hepatitis A in the past.  They have gotten over it and they 
10	have never known it.  It is an asymptomatic disease and so 
11	that has not made a difference in their life.   Yes?

12		DR. MCCURDY:  It seems to me that the most 
13	critical issue here is the notification of the donor to 
14	prevent secondary transmission.  I think the logistics we 
15	have heard of so far would suggest that this would be 

16	difficult, if not impossible, unless you changed how things
17	are being done.  Even if you were to test the donations 

18	immediately after you obtained them, as is being done in 
19	many pools for hepatitis C and HIV at the present time, it 
20	still would be not easy to get to the donor within the two- 
21	week window, which I think we have been told is necessary. 
22	So, to me, that is the critical issue there. 
23		There is one other comment and a question.  If we 
24	are discarding pools that are positive either, as John 

25	Finlayson said, we are loading the dice so that we never 

			141 1	find a positive or we have a pretty adequate plasma supply
	2	and can afford to toss 3200 L pools at random.  I suspect it 
	3	is not going to happen very often, but that seems to be a 
	4	little bit of a disconnect. 
	5		Blaine, I have a question that is largely directed 
	6	at you because I am quite sure that you are as close to this
	7	as anybody in the room.  In the studies that were done 

	8	looking at non-A/non-B hepatitis before hepatitis C was 
	9	found, I presume that the recipients at least were tested 
10	for antibody development to hepatitis A so that you could, 
11	indeed, say that whatever they got was not hepatitis A in
12	the non-A part? 
13		DR. HOLLINGER:  You know, we have said this on 

14	many occasions, that this was the case, but, very frankly, I 
15	am not sure if all of them were tested for anti-HAV.  I know 
16	the patients who seemed to get clinically ill were tested
17	for hepatitis A.  In terms of the whole population, I don't 
18	think they were tested. 
19		DR. MCCURDY:  About TDV, where there were serial 
20	ALTs done in follow-up -- 
21		DR. HOLLINGER:  No, those were tested but outside
22	of those, yes. 
23		DR. MCCURDY:  And I presume Harvey Alter has been 
24	testing all of his as well.  So, within the limits of the 

25	numbers of those several studies -- 

			142 1		DR. HOLLINGER:  But, remember, in the case of TDV,
	2	even though it was a large number, it was only 1500 
	3	patients.  So, that is not a large number. 
	4		DR. MCCURDY:  Yes. 
	5		DR. HOLLINGER:  Yes, Col. Fitzpatrick? 
	6		COL. FITZPATRICK:  I don't disagree with any of
	7	the implications to the donor about the need to know, and 
	8	the need to know and the right to know are not the same 
	9	thing.  The ABB Standards Committee struggled with "right to 
10	know" over a number of issues, and the new standards that 
11	are going to come out will state that any abnormal test
12	result is to be communicated to the donor when feasible.  
13	Now, by testing a 3200 L vat and making it very difficult to 
14	get down to the donor, the plasma industry can probably 
15	justify not notifying the donor. 
16		But I don't want to see the committee being
17	perceived as endorsing a procedure that provides little 
18	practical additional safety to the product by answering this 
19	question.  And there could be confusion on that issue.  If 
20	we say you don't need to notify the donor, fine.  Whether 

21	you test or not because there is very little implication to
22	improving the donor's health or reducing the risk to their 
23	associates, fine.  But is someone going to construe that as 
24	we are endorsing testing of pools as some perception of an 
25	improved safety in product?  That is a concern I have. 

			143 1		DR. HOLLINGER:  Yes, Dr. Alter, you had a comment
	2	on one of the questions that was asked? 
	3		DR. ALTER:  Actually, there are two issues.  One 
	4	is that although the sample size of the prospective studies 
	5	of transfusion recipients that identified patients with non- 
	6	A/non-B hepatitis were not sufficient, I suppose given the
	7	frequency of acute HAV infection in the donor population to 
	8	detect an infection, we do know that all of those cases that 
	9	were identified and labeled as non-A/non-B hepatitis did not 
10	have anti-HAV and did not develop serologic markers for 
11	acute HBV.  So we do know that -- symptomatic and
12	asymptomatic. 
13		The second issue is one to do with the sensitivity 
14	of the testing method for detecting HAV.  The outbreaks that 
15	occurred in persons who received clotting factor 
16	concentrates were related to pools -- were related to what

17	we call hot lots.  These pools had extremely high titers of 
18	virus.  There was an infected donor who was highly viremic 
19	at the time they donated.  In all of the episodes that I am 
20	aware of in which this was looked at, there was a lot of 

21	virus there.  So, presumably it would be detected by these
22	methods, whereas low levels of virus -- I am not aware -- in 
23	pools have been implicated in transmission.  So, that is 
24	just a piece of information. 
25		DR. HOLLINGER:  Dr. Tabor? 

			144 1		DR. TABOR:  In answer to Dr. McCurdy's question, I
	2	just want to say something similar to what Dr. Alter said.  
	3	All of the basic studies of non-A/non-B post transfusion 
	4	hepatitis included anti-HAV testing.  Even though the assays 
	5	were not commercially available when many of those studies 
	6	were done, they were available at research labs and there

	7	was a standard of the art at the time. You called it non- 
	8	A/non-B hepatitis if you had anti-HAV testing done. 
	9		DR. HOLLINGER:  Yes, Dr. Mitchell? 
10		DR. MITCHELL:  The point that I had with the 

11	"right to know" -- I agree with all the things that have
12	been said about that -- is, in fact about the interpretation 
13	of the public.  I think that most people who don't know 
14	would assume that the risk for hepatitis A is just as bad as 
15	the risk for hepatitis C and hepatitis B.  So, again, I 

16	think that there is a need to just be on the record to say
17	that it is not the same, and for us to say that it is not 
18	recommended -- you know, not that we are prohibiting any 
19	company from doing it, but not recommended and, therefore, 

20	we don't need to have the full "right to know" because it is 
21	not the same risk as hepatitis B and hepatitis C.
22		DR. HOLLINGER:  I guess I am somewhat concerned, I 
23	mean, the fact is if these pool sizes are such that you 
24	never detect anything that is positive, then there are not 
25	going to be any donors to notify anyway. 

					145 1		DR. SIMON:  I think that was Dr. Alter's point --
	2		DR. HOLLINGER:  Yes. 
	3		DR. SIMON:  -- that it takes such a high titer 
	4	donor to spread it -- am I interpreting it correctly? 
	5		DR. ALTER:  Yes. 
	6		DR. SIMON:  Okay, that was her point, that because
	7	it is such a high titer to cause these very sporadic 
	8	outbreaks, it is a way, in fact, to detect the case that it 
	9	might occur. 
10		DR. HOLLINGER:  I don't think we have any data to 
11	support that.
12		DR. SIMON:  Well, I have to depend on Dr. Alter. 
13		DR. HOLLINGER:  I mean, it is a hypothesis but I 
14	am not sure that the data is there.  Yes? 
15		DR. ALTER:  It is sort of looking at the opposite 
16	side of the coin.  The only episodes of transmission or
17	outbreaks -- actually, there have been outbreaks in Europe. 
18	There has been an outbreak here, and then there has been a 
19	cluster, a small number of cases associated with a 
20	particular product.  In all of those episodes the implicated 
21	lots had very high levels of virus, or the pools from which
22	the lots were made. 
23		You are right, we don't have the opposite 
24	information.  So, one could say that we don't know that but 
25	still we do know that what we have observed has been related 

			146 1	to very high-titer pools.
	2		DR. HOLLINGER:  Dr. Boyle? 
	3		DR. BOYLE:  Thanks.  I would just like to put my 

	4	two cents in here.  I think I agree with many of you that 
	5	what we have been hearing about the advantages of the 
	6	hepatitis A tests -- they appear to be marginal; they don't
	7	appear to be dramatic and they are only going to be good if 
	8	they are done properly.  How they are done properly is 

	9	something the FDA should be addressing in terms of its 
10	requirements for the specificity and so on, and would be 
11	done through the licensing process.  I think the key

12	question here is that from the standpoint of the question if 
13	we do the tests do we have to notify the donor?  Number one, 
14	I don't think we have heard any information that the donor 
15	really benefits from a clinical standpoint in terms of being 
16	informed or that we avoid spread, and it is very clear that
17	if we inform the donor then the test has to be put at a 

18	higher level and increase the logistics for those people 
19	doing it.  So, to a certain extent, it discourages the 
20	process. 

21		So, from what I am hearing here, I would say that
22	I don't want to discourage the process but leave it to the 
23	FDA to specify what is necessary to make sure that the 
24	process is done properly. 
25		DR. HOLLINGER:  John, I just want to come back 

		147 1	because you had mentioned before about the study that we had
	2	done sometime ago, just to give you sort of a feeling 
	3	because this is a simple case, but it happened to be a donor 
	4	who was a sanitation engineer who donated a unit of blood.  
	5	Two days after the blood was donated it was given to a 
	6	recipient, a ten-year old girl -- only a single unit -- who
	7	came down with hepatitis A.  Four days later, after he 
	8	donated, they had a birthday party for this individual with 
	9	all his family there.  Seven days after he donated he 
10	developed icteric hepatitis.  Now, with that alone, if we 
11	are on top of things all members of the family should have
12	been given gamma globulin or something should have been done 
13	at that point because it wasn't until 21 days after he 
14	donated that he was hospitalized.  That is 14 days after he 
15	became icteric.  And, it wasn't until about three or four 

16	weeks after that birthday party or after he became icteric
17	that his daughter developed icteric hepatitis, and then two 
18	of her children subsequently developed hepatitis about a 
19	week or so later. 
20	          So, the point is that as he got ill he would have 
21	been notified, without having any of this in place about

22	donor notification in that time period.  And, if it is 
23	taking two weeks to four weeks, and probably you would be 
24	fortunate if you could do it in two weeks, then I think it 
25	is probably not going to be appropriate to notify a donor. 

			148 1		DR. YU:  This is Mei-Ying Yu, from FDA.  I just
	2	want to add some information.  I wish Biotech's 
	3	representatives were here but they are not here.  However, 
	4	they did reveal the things that I am going to say in a 
	5	recent public meeting.  So, it is in the public forum.  I 

	6	just want to tell that they indicated that -- this is about
	7	ST-treated plasma -- of 520 lots they assayed, they found 3 
	8	lots positive.  But, as you know, each can be about 2500 

	9	units of plasma so the pool size would be a lot less than 
10	what Susan Stramer indicated.  It is not 3200 L; it is 

11	probably one-tenth or a little smaller because each is
12	approximately 2500 units of plasma. 
13		Anyway, what they said is that, you know, if they 
14	calculate -- so they found three lots positive.  And, just 
15	assuming one donation per pool, per lot, then they found 
16	about one out of maybe half a million will be positive among
17	all the donations.  And, the plasma level for that donor -- 
18	it has to be higher than 104 copies/ml in order to be 
19	detected.  Okay?  That is one piece of information. 
20		Another piece of information is heat-treated 
21	plasma.  In the Phase IV studies they have used quite a few
22	lots and they found no seroconversion.  This is for HAV.  I 
23	am not quite sure whether these three lots were involved or 
24	not.  Okay? 
25		DR. HOLLINGER:  Thank you very much.  Yes, Dr. 

		149 1	Nelson?
	2	          DR. NELSON:  To get back to the question, it 
	3	appears to me that given the question and the current status 
	4	that if the committee feels that individual donors need to 

	5	be notified, it may in fact inhibit HAV testing unless HAV 
	6	testing is also recommended and required.  I think that
	7	there have been outbreaks of hepatitis A related to pools, 
	8	pooled products, and it may be that it is worthwhile to 
	9	detect occasionally with a high viral load because all of 
10	these pools also have antibody similar to the B19.  So, I 
11	would think that not requiring testing of individual units
12	and, therefore, a lot more expense etc. would perhaps 
13	promote or open the road to perhaps increased safety by 
14	allowing testing of pools that otherwise might not occur. 
15	          DR. HOLLINGER:  All right, if there is something 
16	unique about the process, which is probably even more
17	correct because, I mean, if you believe that vaccination 

18	which produces antibody protects you against the disease, if 
19	you believe that giving gamma globulin, which is a very 
20	small quantity of antibody, protects you against getting the 
21	disease, then the antibody in the plasma ought to protect
22	you from getting it.  So, something happens after the plasma 
23	is pooled in the process of preparing clotting factor 

24	concentrates, I think, that resulted in these small 
25	outbreaks in these circumstances. 

			150 1		I think we will call for the question here -- yes,
	2	Dr. Chudy? 
	3		DR. CHUDY:  Maybe a comment to your view.  I see 

	4	also a difference between solvent-detergent treated plasma 
	5	and solvent-detergent treated plasma products.  I have not 
	6	heard of outbreaks of solvent-detergent plasma because maybe
	7	there are enough antibodies.  We have measured antibodies, 
	8	or tried to measure antibodies in Factor VIII and we could 
	9	not measure any antibodies because the pool has enough and 
10	maybe during the high purification drifted, and in the 
11	concentrates there are no antibodies.
12		DR. HOLLINGER:  I am going to read the question 
13	once again and then I am going to call for a vote from the 

14	committee.  The question that we have up there is should the 
15	Food and Drug Administration recommend that, if a plasma 
16	pool or minipool is found to be HAV NAT positive, the
17	individual HAV NAT positive donor should be identified and 
18	notified of the test result? 
19		On that question, all of those that agree with 
20	that statement and vote yes, raise your hand. 
21		[No response]
22		All those opposed? 
23		[Show of hands] 
24		Abstaining? 
25		[Show of hands] 

					151 1		The consumer representative?  Mrs. Knowles?
	2		MS. KNOWLES:  No. 
	3		DR. HOLLINGER:  And the industry representative?  
	4	Dr. Simon? 
	5		DR. SIMON:  No. 
	6		DR. SMALLWOOD:  The results of voting for question
	7	number 1a, there were no "yes" votes; 9 "no" votes; 3 
	8	abstentions.  The consumer representative, "no" vote.  The 
	9	industry representative, "no" vote. 
10		DR. HOLLINGER:  Thank you.  I guess based on that 
11	vote, 1b. would no be appropriate then.  I mean, there is
12	nothing to vote on that one.  Then, what about number 2? 
13		DR. SIMON:  The same problem, Blaine. 
14		DR. HOLLINGER:  Yes, exactly.  And, number 3., 
15	should the FDA recommend that recipients -- 
16		DR. SIMON:  It may be the same issue.
17		DR. HOLLINGER:  The same issue.  Any comments?  We 
18	kind of wiped that one out, didn't we?  Any comments?  I 

19	think the issue here, and the FDA will have to deal with 
20	this, the question is if you are going to do testing and it 
21	is going to be required, then what quantity -- oh, there is
22	a correction here. 
23		DR. SMALLWOOD:  There is a correction in the 
24	voting.  There are 13 eligible members here to vote and 
25	according to my original count there were 10 "no" votes and 

			152 1	3 abstentions -- 10 "no" votes and 3 abstentions.
	2		DR. HOLLINGER:  Thank you.  So, as indicated, I 
	3	think the issue then is whether there should be NAT testing 
	4	by HAV and, if there is, then I think the issues are going 
	5	to be about what size pools, sensitivity of the assays, and 
	6	so on down the line.
	7		Anybody have any other comments before we break 
	8	for lunch?  If not, it is one o'clock right now.  I think we 
	9	will break until two o'clock and be back here to start this 
10	afternoon, and the session is fairly heavy this afternoon so 
11	there will be a lot of information imparted today.
12		[Whereupon, at 1:00 p.m. the Committee recessed, 
13		to reconvene at 2:00 p.m.] 

				153 1		           AFTERNOON SESSION
	2		DR. HOLLINGER:  Why don't we just start with the 
	3	open public hearing?  Someone said that they have slides 

	4	that they could present.  Yes, if you would?  Could you 
	5	state your name and affiliation? 
	6		          Open Public Hearing
	7		       Guardian Scientific, Inc. 
	8		DR. CHOWDHURY:  My name is Afzal Chowdhury.  I am 
	9	from Guardian Scientific, Columbia, Maryland. 
10		[Slide] 
11		I am going to talk about our HIV-1 Quix M and O

12	and HIV-2 blood test.  The test is for the rapid detection 
13	of antibodies to HIV-1 and HIV-2. 
14		[Slide] 
15		This is less than six minutes.  The rapid test 
16	involves a number of reagents.  The first procedure is that
17	this is the device where all the reaction is going to 
18	happen, and the first step is adding buffer and the second 

19	step is where the plasma sample can be added.  Then you wash 
20	it through the same buffer again and then take the filter 
21	off which separates the whole blood, then wash it again
22	using coidal gold conjugate.  Then finally it is resolved in 
23	five to six minutes. 
24		[Slide] 
25		This is the procedural control line here and I am 

			154 1	explaining to you the principle of the procedure.  The six

	2	o'clock position will indicate the HIV-1 including group M 
	3	and O if it is reactive.  This is at the three o'clock 
	4	position for the HIV-2 if it is reactive.  In principle, 
	5	this product is peptide based.  It will detect any 
	6	antibodies against the immunodominant region of GP41 and for
	7	HIV-2 it will be the GP36 region. 
	8		[Slide] 
	9		The interpretation of the result is that if this 
10	part is lighted, then you call it HIV M or O, and if this 
11	part is lighted, then it is HIV-2.  This would be negative
12	but it has to have a control line. 
13		[Slide] 
14		Since this product is peptide based, the peptide 
15	was designed in-house at Guardian Scientific.  We tested 
16	this peptide in rapid membrane based format as well as the
17	ELISA format to find out if the peptides are specifically 
18	reactive with the specification of the samples.  We tested 
19	HIV group M and O samples, like 92 samples.  Then we tested 
20	HIV-2 samples, and then some selected negative samples.  A 
21	total of 219 samples were tested in this study.  At the end

22	we found that the peptides were specifically reactive and we 
23	could move forward with our in-house preclinical studies 
24	using the peptides in the rapid test format. 
25		[Slide] 

			155 1		So, we took the peptides designed into our rapid

	2	format and then we used samples from different countries 
	3	including the U.S. and all over the world to cover all the 
	4	subtypes of HIV-1 and HIV-2 to see if we covered the whole 
	5	thing. 
	6		[Slide]
	7		Included in the samples of HIV-1 group M, all 
	8	different possible available subtypes of HIV-1 group O and 
	9	from all different variants that were available, HIV-2 from 
10	the BBI panel and other sources from the Ivory Coast, and 
11	then HIV negative samples including different disease
12	conditions. 
13		[Slide] 
14		The samples included in our in-house study with 
15	this peptide-based test is that we used 10 finger stick, 50 
16	whole blood, 380 plasma, over 1000 serum and a total of 58
17	samples were tested in-house. 
18		[Slide] 

19		The results appear to be that HIV-1 group M and O, 
20	total samples is 723 and total HIV O positive samples tested 
21	were 39.  HIV-2 samples, we tested 169 and both peptides is
22	a negative sample of 627.  So, a total of 1558 samples were 
23	tested. 
24		[Slide] 
25		Our in-house studies all indicated that the Quix 

			156 1	HIV-1 M and O rapid test correctly identified all the HIV
	2	positive and negative samples.  We did not find any false 
	3	positive or false negative in our study.  However, we had 28 
	4	unlinked samples from only one source, Uganda, that were 
	5	unresolved because they were not linked from Uganda.  And, 
	6	we did Western Blot but all were indeterminate.  So, we
	7	excluded them. 
	8		[Slide] 
	9		Based on the fact that we were quite satisfied 

10	with the in-house study, we gave our product for external 
11	evaluation to the Institute of Human Virology and Dr. Niel
12	Constantine did the study.  In his study, he included HIV-1 
13	group M, 75 positive samples for a total of 270 samples.  
14	And, he included HIV-1 group O, 20 samples and HIV-2, 160  

15	samples from the Ivory Coast and he used non-U.S. origin HIV 
16	positive 98 samples from different countries.  He concluded
17	his study as no false positive and no false negative, 
18	however, he also had some discordants that could not be 
19	resolved. 
20		[Slide] 
21		So far I have talked about this product, which is
22	Quix peptide-based product.  As some of you may know, we had 
23	a product which was recombinant-based, which we called the 
24	first generation product of Quix 1-2-0.  The product was 

25	submitted for FDA approval and the clinical was completed, 

			157 1	and the study was done with close 10,000 samples.
	2		The result of the study was that it was 100 
	3	percent sensitive and there was 99.8 percent specificity.  
	4	So, since this is our second generation product that is 
	5	peptide based, in our study we always compare our product 

	6	with our first generation product to make sure that this is
	7	as good or better than our first generation product.  The 

	8	only place we had this equivalence study done outside was at 
	9	the Walter Reed Army Institute.  They did the study using 

10	1679 samples.  They used both first generation and second 
11	generation.  As far as the result is concerned, there was

12	concordance.  Both products showed equivalence.  They had a 
13	number of discordants but the discordants also in 
14	concordance as far as these two products are concerned -- 
15	side by side. 
16		So, at this point we are moving forward with this
17	new generation peptide-based product.  We had a pre-IND 
18	meeting with FDA.  So, we are hoping to submit the IDE and 
19	move forward with that product.  Thank you. 
20		DR. HOLLINGER:  Thank you, Dr. Chowdhury.  We may 
21	come back and ask some questions in a minute.  I think we

22	will go ahead now and start with the regular presentations 
23	so we can move through because I think in those regular 
24	presentations there will be some background with the 
25	different types of tests that are being used and so on out 

			158 1	there with the rapid tests.  So, to start off is Dr.
	2	Poffenberger, who will give us a background and 
	3	introduction. 
	4		     Development of Rapid HIV Tests 
	5		      Background and Introduction 
	6		DR. POFFENBERGER:  While we are wrestling with
	7	technology, I want to thank Dr. Chowdhury for leaping into 

	8	the fray and filling in on the spot.  Thank you very much. 
	9	What he presented was an example of a rapid test that his 
10	company is developing.  What I am going to do today is to 
11	essentially give you an introduction to these tests and how
12	FDA is handling them. 
13		[Slide] 
14		So, welcome to our session which has already 
15	started.  You will be reviewing a lot of information this 
16	afternoon so my presentation is aimed at providing an
17	introduction and frame of reference for the rest of the 
18	talks. 
19		[Slide] 
20		The rapid HIV tests under development are not 

21	intended for blood screening.  They are intended as an aid
22	in diagnosis for use in various healthcare settings.  These 
23	sites include public health settings, outreach clinics, 
24	hospitals and other clinical settings. 
25		[Slide] 

			159 1		What is a rapid HIV test?  You had a real quick
	2	introduction to one kind.  What the class of rapid HIV tests 
	3	is, are tests which provide results within 20 minutes, and 

	4	many tests can be done in less than 10 minutes.  This test 
	5	is provided as a complete kit with all reagents included.  
	6	No specialized equipment is needed for the tests.  In fact,

	7	some of the tests do not require refrigeration.  A rapid HIV 
	8	test is an immunoassay that detects antibodies to HIV.  The 
	9	result is based on visual detection of an HIV antibody spot 
10	or line. 
11		[Slide]
12		Although there are four formats for rapid tests 
13	available worldwide, two formats are the primary focus in 
14	development of tests for the U.S. market.  These formats are 
15	flow-through membrane immunoconcentration and lateral flow 
16	immunochromatographic strips.
17		[Slide] 
18		The committee has a sample of the licensed flow- 
19	through membrane immunoconcentration test cassette on the 

20	table in front of them.  This type of test includes a 
21	cassette that houses a permeable membrane.  HIV antigens are
22	bound to the membrane in specific spots.  The specimen for 
23	these tests is typically serum or plasma, although some 
24	tests have a pre-filter to allow their use with whole blood 
25	specimens.  A sample is added to the well of the cassette 

			160 1	and flows through the membrane to an absorbent pad.  After

	2	sample addition, multiple steps are performed to wash away 
	3	non-specific interactions and to detect HIV antibody.  
	4	Development of a spot or line indicates the presence of HIV 
	5	antibodies in the sample.  The flow-through immuno- 

	6	concentration tests are typically considered to be of
	7	moderate complexity by CLIA guidelines. 
	8		[Slide] 
	9		This is a photo of the licensed Murex SUDS 
10	cassette indicating a positive sample result.  The SUDS test 
11	is a test of moderate complexity.  The center blue spot
12	indicates the presence of antibodies to HIV. 
13		[Slide] 
14		The other type of rapid HIV test under development 
15	is the lateral flow immunochromatographic strip test.  These 
16	tests consist of a nitrocellulose strip, with absorbent pads
17	attached, that has HIV antigens applied as a line.  In these 
18	tests the sample is applied at one end of the strip where it 
19	mixes with signal reagents and then migrates, by wicking 
20	action, along the strip.  These are very simple one or two- 
21	step tests.  Again, the development of a visible line
22	indicates the presence of HIV antibody.  The tests include a 
23	control line to indicate that the sample has migrated far 
24	enough.  These are typically considered to be low complexity 
25	tests.  Everyone on the committee and in the audience will 

			161 1	get a little more information about these types of tests in
	2	a later talk. 
	3		[Slide] 
	4		In addition to the tests under development, FDA 

	5	has licensed two tests for use in the United States.  The 
	6	first to be licensed was the Cambridge Biotech Recombigen
	7	HIV-1 latex agglutination test.  The second test licensed 
	8	was the Murex single-use diagnostic system, HIV-1 test, 
	9	known as the SUDS test which you saw in an earlier slide. 
10	I need to mention that Murex is now a part of Abbott. 
11		These tests were licensed with the limited claim

12	for blood screening in facilities where EIA plate tests are 
13	impractical.  The Recombigen test has been withdrawn, 

14	leaving the SUDS test as the only rapid HIV test on the 
15	market in the U.S.A. today. 
16		[Slide]
17		In contrast to the test on the market, the rapid 
18	HIV tests under development that we are discussing today are 
19	not seeking a claim for blood screening.  As diagnostic in 
20	vitro devices for the detection of antibodies to HIV, these 
21	tests are considered to be Class III devices.  The
22	regulations pertaining to rapid HIV tests intended for 
23	diagnostic use are different from those pertaining to 
24	licensed blood screening tests.  These regulations are found 
25	in the sub parts of the 21 CFR 800 series.  Manufacturers of 

			162 1	rapid HIV tests follow the path of investigational device
	2	exemption (otherwise known as IDE) and pre-market approval 
	3	(known as PMA) submissions to get to market. 
	4		Although IDE approval is only required for some 

	5	studies of rapid HIV tests, depending on trial design, FDA 
	6	encourages manufacturers to submit IDEs to obtain guidance

	7	on their clinical trial design and to assure that the trial 
	8	will lead to product approval.  The inter-center agreement 
	9	places responsibility for these tests at the Center for 
10	Biologics and review is conducted in the Office of Blood 
11	Research and Review.  That is why the committee is hearing
12	about these tests today. 
13		[Slide] 
14		Several studies have demonstrated that there is a 
15	public health need for having more rapid tests available.  
16	In particular, there is a need to provide a test result
17	during a single visit to individuals seeking testing and to 
18	individuals presenting for care in clinics, hospitals and 

19	emergency rooms.  The current practice for providing results 
20	is to use an ELISA assay to screen samples and to supplement 
21	a Western Blot test to confirm ELISA positive samples.  This
22	algorithm takes up to two weeks to provide results.  
23	Individuals do not get results unless they return for a 

24	second visit.  CDC has estimated that up to 8000 positive 
25	individuals per year do not return for their results.  

			163 1	Letting these individuals know they are positive should
	2	prevent them from causing secondary infections.  You will 
	3	hear more about this from Dr. Robert Janssen. 
	4		[Slide] 
	5		Having HIV test results available quickly should 
	6	help in making treatment decisions for individuals with
	7	percutaneous exposures to blood from patients with 
	8	previously unknown HIV status.  Dr. Nancy Wade, one of this 
	9	afternoon's speakers, has shown that treatment intervention 
10	for neonates begun within 48 hours of birth can reduce 

11	perinatal transmission of HIV by as much as 50 percent. 
12	Treatment begun during birth might improve this benefit.  

13	Dr. Wade will discuss the New York State Health Department's 
14	experiences with testing and perinatal transmission. 
15		[Slide] 
16		Meeting the public health needs I have described

17	presents some challenges to rapid test characteristics.  
18	Rapid HIV tests must be able to provide results quickly.  
19	They should be easy to perform and to read.  They should be 
20	safe and effective and should provide meaningful results in 
21	the intended use populations.
22		[Slide] 
23		FDA has been taking action to facilitate approval 
24	of rapid HIV tests.  These actions include maintaining an 
25	ongoing dialogue with sponsors.  This dialogue includes 

			164 1	holding pre-IDE, pre-PMA and other meetings and
	2	participating in conference calls.  FDA has also been 

	3	working with sponsors to enable access to rapid tests 
	4	through treatment IDEs and expanded access routes.  In 

	5	March, 1999 FDA postponed the requirement for inclusion of 
	6	group O antigens in rapid HIV tests.
	7		[Slide] 
	8		FDA has also reduced the sample size requested for 
	9	clinical specificity studies in low risk populations.  The 
10	sample size requested for rapid HIV tests is 6000 as 
11	compared to the sample size of 10,000 that is a requirement
12	for donor screening assays.  Today, FDA is seeking to 
13	clarify approval standards for sensitivity and specificity 
14	of rapid tests.  FDA is also proposing specific labeling for 
15	use of these tests. 
16		[Slide]
17		FDA recognizes that the public health needs for 
18	rapid HIV tests are different than those for blood screening 
19	tests.  Because these needs are different, the standard for 
20	approval of rapid tests is different.  FDA is seeking to 
21	clarify its approach for approving rapid HIV tests according
22	to a separate standard from blood screening tests. 
23		[Slide] 
24		These approval standards are based on data which 
25	will be discussed in presentations by Drs. Zahwa and 

			165 1	Janssen.  Published studies in developing countries have
	2	shown that rapid tests can be reliable and that sensitivity 
	3	and specificity vary among populations and among tests.  

	4	Data from U.S. populations is much more limited.  FDA has 
	5	been working with CDC to determine state-of-the-art 
	6	performance of rapid tests in U.S. sites.
	7		[Slide] 
	8		The approval standards for rapid HIV tests will 
	9	assure that each test achieves state-of-the-art clinical 
10	performance levels for sensitivity and specificity.  This 
11	current state-of-the-art performance level in U.S.
12	populations for serum or plasma specimens is 98 percent 
13	sensitivity and 98 percent specificity. 
14		[Slide] 
15		FDA is proposing a two-part sensitivity standard 
16	for rapid HIV tests.  Each test should demonstrate 100

17	percent sensitivity, correctly identifying 11 of 11 positive 
18	samples on the FDA HIV-1 panel.  Each test should have a 

19	lower bound for the 95 percent confidence interval for 
20	sensitivity studies of at least 98 percent.  This lower 

21	bound is based on confirmed positive samples from two study
22	populations, from known positive individuals with a total 

23	sample size of 1000 and from positive individuals identified 
24	in testing of high risk populations with a total sample size 
25	of 500.  The number of positive individuals in this last 

			166 1	study depends on the prevalence of HIV infection in the high
	2	risk population. 
	3		[Slide] 
	4		FDA is proposing a specificity standard based on 
	5	clinical studies, to total 6000 studies from low risk 
	6	populations.  The lower bound for the 95 percent confidence
	7	interval must be at least 98 percent. 
	8		[Slide] 
	9		How will these rapid tests be used after they are 
10	approved?  These tests will be used in non-donor settings.  
11	They will provide a preliminary result for HIV serostatus
12	during an initial visit. 
13		[Slide] 
14		This means that when a sample has a negative rapid 
15	test result no further testing of the sample is performed.  
16	The individual is counseled that they are negative for
17	antibodies for HIV. 
18		[Slide] 
19		When a sample has a positive rapid test result the 
20	sample will be sent for confirmatory testing.  The 
21	individual will be counseled that their preliminary result
22	is positive and they will be advised to return for a second 
23	visit to get the results of the confirmatory test. 
24		[Slide] 
25		Approval of additional rapid tests will also offer 

			167 1	the option in the U.S. to use a multiple rapid test
	2	algorithm during a single visit. 
	3		[Slide] 
	4		The multiple HIV antibody test algorithm is a 
	5	combination of screening tests for HIV antibodies.  This 
	6	combination was initially a mix of ELISA and rapid test.  It
	7	was developed to be used instead of the EIA and Western Blot 
	8	algorithm in developing countries, where the 
	9	instrumentation, complexity and cost of the EIA-Western Blot 
10	algorithm were prohibitive.  In 1997, the World Health 
11	Organization revised their recommendations for using this
12	algorithm in three different strategies.  There is 
13	substantial field data for performance of different multiple 
14	rapid test algorithms from developing countries.  Much of 

15	this data has been collected under the auspices of the CDC. 
16		[Slide]
17		The multiple rapid test algorithm can be designed 
18	toward improving accuracy of the test result.  The factors 
19	that influence accuracy of the algorithm result are the 

20	sensitivity and specificity of the test chosen for the 
21	algorithm, the order for performing tests, that is, whether
22	they are done sequentially or simultaneously.  Another major 
23	factor is the decision rule for determining the algorithm 
24	result. 
25		Two of the possible rules are listed here.  In the 

			168 1	first case, sensitivity is optimized by letting any single
	2	individual test positive result yield a positive algorithm 
	3	result.  In the second case, specificity is optimized by 
	4	requiring that all individual test results must be positive 
	5	to yield a positive algorithm result. 
	6		[Slide]
	7		This table provides an example for results 
	8	expected from using a two-rapid test algorithm.  In this 
	9	case, I am showing the worst case expectations for two tests 
10	that have the minimum sensitivity and specificity according 
11	to the proposed standards.  So, for this chart, test A and

12	test B are both at 98 percent sensitivity and 98 percent 
13	specificity.  If they are combined into a two-test 
14	algorithm, using rule one, which is shown along the first 
15	row, both individual test results must be positive in order 
16	for the algorithm result to be positive.  The worst case

17	assumption that the individual test error is not overlapping 
18	yields a 96 percent sensitivity and 98 percent specificity 
19	for rule one. 
20		If rule two is applied to the two-test algorithm, 
21	sensitivity is optimized by having a single positive test

22	result yield a positive algorithm result.  In rule two, 
23	sensitivity is 98 percent and specificity is 96 percent. 
24		I want to emphasize that this is the worst case 

25	scenario.  Under typical circumstances a testing site would 

			169 1	combine tests with better sensitivity and specificity, and
	2	with varying sensitivity and specificity, in an algorithm 
	3	designed to improve the accuracy of testing. 
	4		[Slide] 
	5		Data from developing countries shows that multiple 
	6	rapid test algorithms can improve the accuracy of the HIV
	7	antibody test result.  The sensitivity and specificity 
	8	achieved in multiple rapid test algorithms approach and can 
	9	exceed that of the EIA and Western Blot algorithm.  Downing 
10	et al. reported achieving 100 percent sensitivity and 
11	specificity for certain populations.
12		[Slide] 
13		In the United States studies are ongoing under t 
14	he direction of the CDC.  Algorithms may be recommended by 
15	the CDC and/or the Public Health Service.  The combined data 
16	from field and current studies indicate that using a
17	multiple rapid test algorithm to improve the accuracy of HIV 
18	antibody test results may be appropriate in certain 
19	settings. 
20		[Slide] 
21		FDA is proposing to allow use of multiple rapid

22	test algorithms in conjunction with approval of individual 
23	rapid tests.  Review of submissions, approval and labeling 
24	will be done separately for each test.  Manufacturers must 
25	provide data to show that each test meets the approval 

			170 1	standards.  Manufacturers must also provide evidence of
	2	consistent manufacturing and test reproducibility. 
	3		[Slide] 
	4		The labeling will follow current practice to read, 
	5	"for use as an aid in diagnosis ..." 
	6		[Slide]
	7		The labeling may indicate that "this test may be 
	8	used as part of a multiple test algorithm to improve the 
	9	accuracy of testing in settings where the use of an approved 
10	supplemental test for HIV antibodies is impractical of 
11	unfeasible prior to patient counseling."
12		[Slide] 
13		This completes my introduction.  This session will 
14	continue with data presentations and discussions from other 
15	public health and private points of view.  You will hear 
16	more about the need for rapid HIV tests and the performance
17	of these tests.  You will hear data from multiple rapid test 
18	algorithm studies, and you will be more familiar with some 
19	of the different tests in development. 
20		[Slide] 
21		Through the rest of the presentations I would like
22	to ask the committee to keep in mind the questions that will 
23	be posed later this afternoon, namely, does the committee 

24	agree with the FDA standards for approval of a rapid test 
25	for use in the diagnostic setting?  And, does the committee 

		171 1	agree with the FDA proposal for labeling rapid tests, that
	2	is, to allow use of multiple test algorithms for each 
	3	approved test?  Thank you. 
	4	          DR. HOLLINGER:  Thank you.  The next presentation 
	5	is by Dr. Robert Janssen. 
	6	 Presentation by Robert S. Janssen, M.D., Div. of HIV/AIDS

	7	          DR. JANSSEN:  I am happy to have the opportunity 
	8	to address BPAC on what we feel is an extremely important 

	9	issue, that of rapid HIV testing.  Before I begin my formal 
10	presentation, I want to take a moment to talk about a "Los 
11	Angeles Times" article yesterday that was reprinted in "The
12	Washington Post," in which it quoted a CDC employee.  I want 
13	to be very clear that the quote in the paper does not 
14	reflect CDC's position, that although CDC strongly supports 
15	the need for rapid testing, we respect the critical role 
16	that FDA must play in assuring all new HIV tests meet
17	standards of accuracy and consistency of manufacturing.  It 
18	is not in the best interest of CDC, nor in the best interest 
19	of the FDA, or the federal government, or the people in this 
20	country to have tests available and on the market that 

21	cannot provide consistent, high quality performance in a
22	variety of settings.  We have worked closely with our 
23	colleagues at the FDA for a long time.  They share our 

24	passion for ending the epidemic and getting these tests to 
25	the market as soon as possible, and this close work has 

			172 1	brought us here today to make a case for the importance of
	2	rapid tests for your consideration. 
	3		It is unfortunate that the articles in the paper 

	4	yesterday painted a different picture.  Please know that we 
	5	made sure all media following up with us on this article 

	6	understand CDC's position, and we have also apologized to
	7	our FDA colleagues.  We offer similar apologies to this 

	8	advisory committee, and hope that CDC and FDA can continue 
	9	to move forward together on this and many other important 
10	issues. 
11		[Slide]
12		I am excited to have this opportunity to talk 
13	because I think, to some extent, this is an unusual 

14	situation.  When I talk about or think about a test, I think 
15	sort of about the standard uses of tests, and I think this 
16	committee particularly looks at blood screening, a very sort
17	of regimented testing scenario.  And, what I am going to 
18	talk about is actually way beyond that.  Where we would like 
19	to go with rapid testing is to the streets, and that is a 

20	very different place from where people have been thinking 
21	about testing, and I am going to give you why we think that.
22		[Slide] 
23		Simple rapid tests, as Kim pointed out -- I won't 
24	belabor the point -- are really critical tests.  The test 
25	that is on the market now is not a simple test.  It is a 

			173 1	rapid test and it does qualify as that.  It doesn't enable
	2	us to get out of the laboratory easily and that is what we 
	3	need to be able to do.  Tests need to have minimal equipment 
	4	requirements, and need to have also the opportunity for 
	5	immediate test results.  Kim touched on a single test result 
	6	-- and I will mention the algorithms later as well -- as the
	7	direction in which we eventually want to go.  We want multi- 
	8	rapid test algorithms so that you can tell somebody when 
	9	they come to see you, whether it be in a mobile van or in an 
10	emergency room -- within a half hour you can give that 

11	person a confirmed HIV diagnosis.  They wouldn't have to
12	wait for two weeks. 
13		[Slide] 
14		The context of all this for us is in the very 
15	important HIV prevention initiative that we have just 

16	launched, that we call "The Serostatus Approach to Fighting
17	the HIV Epidemic."  We have targeted our prevention programs 
18	on a lot of different factors -- risk factors, geographical 
19	factors and a number of other factors.  Now what we want to 
20	do is expand our prevention focus by using serostatus. 
21		[Slide]
22		What is SAFE?  SAFE is a new CDC prevention 

23	initiative that is designed to complement our existing 
24	prevention activities.  It is based on the knowledge that 
25	services and interventions for high risk negative 

			174 1	individuals may not address the needs of HIV-infected

	2	individuals, and it is specifically intended to more 
	3	directly target the prevention needs of HIV-infected 

	4	individuals and their partners.  HIV prevention money is put 
	5	out through the community planning process throughout the 

	6	country.  Only 30 percent of HIV community planning groups
	7	in this country identify HIV-infected individuals as 
	8	priority populations for HIV prevention activities. 
	9		[Slide] 
10		Why do we need it now?  Our estimates of HIV 
11	incidence have been stable at about 40,000 since 1992.  In
12	addition, because of treatment advances, more people are 

13	living better and longer lives and, thus, the potential for 
14	more HIV transmission.  Finally, treatment advances have 
15	also contributed to complacency and increased risk behavior 
16	in communities at highest risk, particularly this has been

17	noted by outbreaks of syphilis among gay and bisexual men in 
18	a number of cities across the country.  It started out on 

19	the West Coast; it is now seen across the country -- men in 
20	their 30s, where 50 to 75 percent of these individuals are 
21	HIV infected.
22		[Slide] 
23		If you are going to take a serostatus approach to 
24	fighting epidemic, then serostatus obviously is important.  
25	Well, what do we know about serostatus?  We estimate that 

			175 1	800,000 to 900,000 people currently live in the United
	2	States with HIV infection; that about 625,000 know that they 
	3	are HIV-infects; and then we estimate that 175,000 to 
	4	275,000 don't know they are infected.  That is a critical 
	5	number and that is why rapid tests become important. 
	6		How do we reach those people?  We believe that the
	7	majority of new infections are occurring from people who 
	8	don't know their HIV serostatus.  Only one study has 
	9	addressed this at all.  It is the OPTION study, in San 
10	Francisco, where they have linked 17 people, source 
11	recipient pairs and 11 of those 17 infections were caused by
12	people who did not know they were infected.  This was in San 
13	Francisco.  This was last year, in an area where testing is 
14	very high. 
15		[Slide] 
16		There are advantages, both personal and public
17	health advantages to knowing the serostatus for HIV-infected 
18	individuals.  The first is a personal benefit -- people are 
19	living longer and better lives.  HIV treatments to date now 
20	have improved life expectancy by at least 5 years from the 
21	untreated natural history.
22		But there are also public health benefits.  This 
23	slide demonstrates one of the public health benefits.  This 
24	will be published tomorrow in the MMWR.  Basically what it 
25	says is that people who find out they are infected don't 

			176 1	want to infect other people, and they reduce their risk-
	2	taking behavior.  This is a study of men who have sex with 
	3	men and women, and what they did in the 12 months after they 
	4	were in their serostatus, and 60 percent used condoms more 
	5	often, 49 percent had sex less often, 36 had not had any 
	6	sex, and 10 percent had sex only with other HIV-positive
	7	persons. 
	8		We also have data from several other studies.  
	9	Some of them have been submitted; some of them are in 
10	preparation, none of them have actually been published yet, 
11	that substantiate this as well and over time -- not true for
12	everyone.  There are definitely HIV-infected people who do 
13	not reduce their risk behavior and who we definitely want to 
14	try to get into prevention services. 
15		The third reason that people who are infected 

16	should know their serostatus is a potential public health
17	benefit, and that is where HAART reduces HIV transmission.  
18	There is a lot of indirect data that suggest that people 

19	with undetectable viral load due to HAART may actually be 
20	less infectious.  It is not clear to this point.  It is just 
21	a potential benefit.

22		[Slide] 
23		 So, what is SAFE then?  SAFE has five action 
24	steps.  The first one, which is where rapid tests comes in, 
25	is to increase the number of HIV-infected individuals who 

			177 1	know their status as early after infection as possible.  The
	2	second then is, once you identify these people, you need to 
	3	link them into healthcare and prevention services.  Once 
	4	they are there, you need to increase the number of infected 
	5	people who are receiving appropriate care and treatment 
	6	services.  You need to support them in adhering to their
	7	prescribed antiretroviral medications and support the 
	8	adoption and maintenance of HIV risk reduction behavior. 
	9		[Slide] 
10		I want to focus on action step one for this talk, 
11	and that is to increase the number of infected people -- how
12	we think we want to approach this is in two ways: encourage 
13	people to seek testing but the second is to provide testing; 
14	make testing more available, and we see that that is where 
15	the critical role of HIV rapid testing comes in, and it is 
16	getting into alternative settings, settings that can be
17	reached by community-based organizations. 
18		We are putting out about eight million dollars 
19	this year to community-based organizations, asking them to 
20	form partnerships with health departments to provide 
21	innovative testing strategies for people in their
22	communities.  We hope that rapid tests will be available for 
23	these community-based organizations because we really 
24	believe that that is the technology that will enable us to 
25	reach some very hard to reach populations.  We have also 

			178 1	been thinking about where you can find HIV-infected people
	2	who don't know their serostatus, and another place is 
	3	hospital emergency rooms. 
	4		[Slide] 
	5		This is a slide that gives the seroprevalence in 

	6	several hospital emergency rooms across the country, ranging
	7	from 6.4 percent in the ER at Johns Hopkins, 5.4 percent at 
	8	Bronx Lebanon in the South Bronx, down to 2.3 percent at 
	9	Grady Hospital in Atlanta, and Cook County in Chicago, and 
10	we also have done a study.  So, there is high prevalence in 
11	these ERs.  But we have also done a study called the
12	Sentinel Hospital Study, which finished in 1996, and in 
13	1996, in 14 high prevalence hospitals across the country 
14	half of the HIV-infected people, going through those 
15	emergency rooms, did not know they were infected. 
16		So, we think an important place to do routine
17	voluntary testing is in hospital emergency rooms.  There is 
18	no way you can do that and wait two weeks to get a test 
19	result.  Rapid tests offer that opportunity. 
20		[Slide] 
21		Finally, the other point I wanted to mention also
22	is where rapid tests could be very valuable, where can you 
23	find HIV-infected people?  There are a number of injecting 
24	drug users who traffic through our correctional facilities 
25	and increasing, again, routine voluntary testing in 

			179 1	correctional facilities may be another way to help people
	2	learn their status. 
	3		[Slide] 
	4		Now, there are additional public heath needs for 

	5	rapid tests, which I will just barely mention because Kim 
	6	mentioned it and Nancy Wade will be talking about perinatal
	7	but the first is high rates of non-returned for test 
	8	results.  The second is need for immediate information or 
	9	referral in two settings that Kim mentioned so I won't talk 
10	about them. 
11		[Slide]
12		We did several studies in the mid-1990s, looking 
13	at rapid tests.  There is a problem in publicly funded 
14	counseling testing sites where people don't come back for 

15	their test results.  About 28 percent of HIV-infected people 
16	don't return for their test results.  Overall it is about 50
17	percent. 
18		This is based on data -- Bill Kassler did a study 
19	in which he was able to provide rapid testing in a single 

20	test.  So, someone got a preliminary result if they were 
21	positive or if they were negative they got the result. It
22	increased the proportion of people who knew their status 
23	dramatically, including HIV-infected people.  Just giving 

24	them a preliminary result, they came back two weeks later to 
25	get their confirmed result. 

			180 1		When you apply those data to our overall
	2	counseling testing system, which pays for about two million 
	3	tests in this country a year, you see an increase here if 
	4	you added rapid testing, an increase of 8000 to 9000 or 

	5	almost 10,000 people learning they were HIV-infected who 
	6	would not have learned it otherwise -- I am sorry, up to

	7	700,000 who were HIV negative who would have learned their 
	8	test results.  So, we feel it is very important in a routine 
	9	testing facility -- rapid tests can give us a tremendous 
10	impact. 
11		I just want to say once again that people in the
12	HIV prevention community are looking at rapid tests as 

13	having the potential for transforming HIV testing, and I 
14	think there is a real opportunity for that.  Thanks. 
15		DR. HOLLINGER:  Any particular questions for Dr. 
16	Janssen at this time?  If not, the next presentation is by
17	Dr. Zahwa. 
18		     Presentation by Lt. Zahwa, DOD 
19		LT. ZAHWA:  First and foremost, I would like to 

20	thank the organizing committee for inviting me to present on 
21	the topic of HIV rapid diagnostics.
22		[Slide] 
23		My name is 1st Lt. Zahwa.  I am from Walter Reed 
24	Army Institute of Research.  We belong to the Medical 
25	Research and Material Command.  The reason I am here today 

			181 1	is to describe to you why we are doing this rapid testing
	2	and to describe our experience with rapid testing.  We have 
	3	worked very closely with the CDC and the FDA and many of the 
	4	collaborators our there in industry regarding this issue. 
	5		[Slide] 
	6		The objective of being here today is to explain
	7	why we are doing rapid testing; describe how we are doing 
	8	rapid testing; present the testing platform very briefly and 
	9	summarize the test results.  And, it is up to the organizing 
10	committee as to how they want to open up the questions and 
11	answers, or whatever, after my session or later on.
12		[Slide] 
13		As we say in the military, we use the acronym 

14	BLUF, which is "bottom line up front," why are we doing 
15	rapid testing?  We are doing rapid testing because our 

16	deployment rate has quadrupled over the past ten years.  We
17	are deploying to more places; we are deploying more troops 
18	to places that we have never been to before.  Our number of 
19	peace-keeping missions has also increased dramatically, the 
20	peace-keeping missions where our soldiers interact directly 
21	with the endogenous population, and in these peace-keeping
22	missions we are not in a war scenario but we are also 

23	exposed to the population under hostile conditions sometimes 
24	and our soldiers are exposed in these conditions.  Last, but 
25	not least, which might be a concern for this committee here, 

			182 1	is that when we deploy to an area overseas each one of us
	2	wearing this green suit is considered "a walking blood bag," 
	3	meaning if we run out of supply and we have to use blood or 
	4	come up with more blood, then the soldiers are our next 
	5	choice here.  We are screened on a routine basis for HIV.  
	6	We are screened every two years for HIV.  We are screened
	7	within six months of deployment for HIV.  So, we are 
	8	considered a low prevalence, pretty much safe population, 

	9	however, when we are deployed for periods of 90 days and 
10	more we are exposed to the population out there and we have 
11	seen soldiers who have contracted HIV when they are
12	overseas. 
13		[Slide] 
14		With a disease that is spreading like brushfire, 
15	you can see that the newly infected HIV during 1998 is 5.6 
16	million.  The point I am trying to bring with these slides
17	is how the disease is spreading worldwide, and we are going 
18	to these places.  If you look at Africa, where we are 
19	deploying people now for peace-keeping missions, or to 
20	Europe where we are also deploying people for peace-keeping 
21	missions, we are being exposed to individuals who are
22	infected with HIV.  We are doing that on a daily basis. 
23		[Slide] 
24		I must first apologize for the quality of the 

25	slides.  Being from a sister agency to the FDA, I did not 

			183 1	expect the high quality and the high technology.  I was
	2	shocked to see 35 mm slides, audiovisuals and cameras. 
	3		[Laughter] 
	4		Over the past decade or over the past five years, 
	5	the vision of the Army of how we fight has changed.  We are 
	6	no longer an army that is controlled by the terrain or
	7	limited by the knowledge that we know today to go into war.  
	8	We are an army that is expanding the battlefield, and 
	9	controlling the battlefield with satellite feeds and PVAs 

10	held by soldiers that feed information back to the line to 
11	make decisions.
12		What I am trying to say here is we are no longer 
13	fighting a way in Kosovo and staying there and not knowing 
14	what is there.  We are expanding the whole theater of 

15	operation.  It is a European theater now that we are 
16	deploying soldiers to, and these soldiers move from one area
17	to the other. 
18		[Slide] 
19		This is the most important slide -- I am just 
20	kidding!  This is the combat service support comparison.  
21	This shows why we are involved in rapid diagnostics.  In the
22	past, the way we used to fight wars, the medical hospitals, 
23	the main medical units used to be in the rear of the 
24	battlefield where we could supply them with generators, air 
25	conditions -- it used to be the best job in the field to be 

			184 1	a medical service corps officer.  Now when we are deploying
	2	we are moving these things to the forefront of the 
	3	battlefield where we have individual teams, surgical teams, 
	4	etc., etc. taking care of our wounded soldiers, and we are 
	5	being exposed to populations so we need to know, in exposure 
	6	prophylaxis situations, whether we need to administer that
	7	or not. 
	8		[Slide] 
	9		How are we getting samples?  How do we do this?  
10	As I mentioned earlier, we are screened in two-year cycles 
11	so we have access to over 25 million samples right here,

12	down the street from us.  These samples were previously 
13	screened with EIAs and Western Blots, FDA approved, and/or 
14	non-FDA approved nucleic acid testing.  The samples are 
15	frozen at minus 80 degrees, and the samples were collected 
16	from active duty National Guard or Reserve individuals. 
17	Every sample we collect, we keep.  We do not throw anything 
18	away.  That is the mentality of the federal government -- 
19	"we might need it one day so we might as well keep it." 

20		[Slide] 
21		As was mentioned earlier today, the acceptability
22	criteria -- this is not by any means the FDA's or the CDC's 
23	acceptability criteria; this is what we set for ourselves to 
24	be acceptable.  What we set to be acceptable is a 100 

25	percent sensitivity platform and a 99 percent or better 

			185 1	specific platform that is easy to use by the soldiers.  We
	2	want a positive predictive value of 100 percent.  We want a 
	3	test efficiency that is close to 100 percent. 
	4		As you will see later on in the slides, these 
	5	criteria that we set up were near impossible to achieve.  We 
	6	set the bar to be way too high, but we figured out a way how
	7	to fix that -- not by fudging data but there are other ways 
	8	of doing it. 
	9		[Slide] 

10		The way we evaluate platforms is we design panels.  
11	We looked at our freezer.  These are all frozen samples. 
12	This is not the intended use of these tests, therefore, the 
13	sensitivity and specificity speaks only to the trials that 

14	we performed.  There are other trials that are being done by 
15	the CDC that are prospective trials that are for the 

16	intended use of this test.  However, the collaboration
17	between us and the CDC allowed us to do this, and for them 
18	to have a better idea instead of deploying a platform 
19	prospectively when the sensitivity and specificity is not 
20	acceptable. 
21		First of all, we designed a panel of 100 samples. 
22	If we are approached by company X that says they have a 

23	platform and this platform works like a miracle and it is 
24	100 percent sensitivity and 100 specific, we will be glad to 
25	evaluate that.  We will obtain 175 devices.  We will 

			186 1	evaluate it on this panel that has 25 reactives and 75 non-
	2	reactives.  We will repeat all of our reactives in 
	3	duplicates under all platforms that we will discuss today. 

	4		Again, I apologize for the poor quality.  There 
	5	are two colors on this slide, a red color and a green color.  
	6	The red color is a "no-go" and the green color is a "moving
	7	forward."  At the end of this evaluation we will look at our 
	8	sensitivity and specificity and ease of use. 
	9		If we decide that a product is worth our time and 
10	is promising, we will move over to 1000 panels where we have 
11	250 and 750.  Again, we will look at the product, if it is

12	sensitive and specific, and meets some other criteria that 
13	we insert here in the 1000 panel, such as HIV-1 subtype E, 
14	subtype O we will move over to an 11,000 panel.  The 11,000 
15	panel is 10,000 non-reactives, 1000 reactives.  At this 

16	point, our generals made a commitment not to deploy a test
17	that is not FDA approved, and we stand behind our generals 
18	on that, we will not deploy a test that is not FDA approved. 
19		So, when we get to this point and we obtain the 

20	sensitivity and specificity, if the product is not good or 
21	is not performing well in our hands we will discourage use. 
22	We will discourage all our medical facilities from using 

23	this product and we will hold discussions with the FDA and 
24	the CDC.  If the product is good, meaning that it has the 
25	acceptable sensitivity and specificity, we will only 

			187 1	recommend the use of this product after the FDA approves it. 
	2	Again, my boss, who is Lt. Col. Nelson Michaels and some of 
	3	you might know him, is talking about a 100,000 panel, that 
	4	we might expand these studies to 100,000 samples to test the 
	5	sensitivity and specificity before we deploy it. 
	6		[Slide]
	7		As was mentioned earlier, the two platforms are 
	8	well-known, the flow-through device and the lateral flow.  
	9	As was mentioned earlier also, the control line in the 
10	lateral flow devices is crucial here.  It tells us whether 
11	the sample has been added and if the test is completed. 
12	Some of the newer flow-through devices have a control dot on 
13	them that will also show the same thing. 
14		[Slide] 
15		I will move through these slides pretty fast.  
16	These slides are not meant to be detailed.  They are just to
17	show you what platforms are out there and by no means are 

18	these all the platforms out there.  These are the ones that 
19	we evaluated.  This is SUDS, Murex and Abbott now.  This is 
20	the only FDA approved product on the market today for HIV 
21	testing.  Again, SUDS works on the serum and plasma.  It

22	takes 30 mcl and, as was mentioned earlier, it is a moderate 
23	complexity test. 

24		[Slide] 
25		Another product by Abbott -- Abbott is a well- 

			188 1	known company, as you might well know.  They make Determine,
	2	which is made in Japan and brought over here.  Determine is 
	3	another good product.  It has serum, plasma and whole blood. 
	4	It takes 50 mcl.  I want to take a few minutes to describe 

	5	these tests because it is crucial to understand how simple 
	6	they are and how detrimental the results can be if they are
	7	not read correctly and if they are not within acceptable 
	8	criteria. 

	9		You apply 5 mcl of serum or plasma down here.  The 
10	test migrates on its own.  There is a control line all the 
11	way out here, as you see in the tannish or red color.  That
12	indicates the completion of the test.  The test bar is down 
13	here.  A positive test will be something like this, where 

14	you read a bar, and a negative test will be nothing at all. 
15		Abbott's test, the Determine, needs a reagent to 
16	be added for the whole blood, and the whole blood has to be
17	measured to be 50 mcl before it is added to the strip. 
18		[Slide] 
19		The next test that we are very interested in is 
20	the Hemastrip, made by Saliva Diagnostics Systems.  I 
21	believe they used to be out of Washington State and now they
22	are in New York.  Again, this works on serum, plasma or 
23	whole blood.  It takes 3 mcl, and the start to finish time 
24	of these tests, as was mentioned earlier, is less than 20 

25	minutes.  This is a fairly simple test to perform in the lab 

			189 1	that can be done with a finger prick.  You can collect the
	2	sample, perform the test, see the result and, hopefully, 
	3	provide a physician with the results when it is FDA approved 
	4	for counseling. 
	5		[Slide] 
	6		This test is UniGold, by Trinity Biotech.  They
	7	are in Jamestown, New York but the test is manufactured in 

	8	Ireland.  Again, it works in serum, plasma or whole blood, 
	9	50 mcl.  As you can see, it is a similar principle but this 
10	one is in a casket.  You apply the sample here and you add 
11	buffer to it and it migrates through.  This is a good
12	picture where it shows the control line and the test line, 
13	the control line in a negative sample. 
14		[Slide] 
15		Epitope is another good product that we evaluated 
16	briefly before and we are looking at now in a full
17	magnitude.  I will explain that later.  Epitope is a test 
18	that works on saliva.  Our colleague, Bernie Branson from 
19	the CDC, showed at previous meetings how simple it is and 
20	how well it works by actually taking one out of is pocket, 
21	performing the test, setting it on the table in front of him
22	and by the end of the talk the test result was available.  
23	This is a test that has a pad on the front of it, right 

24	here, which you stick in the patient's mouth and collect the 
25	saliva.  You stick it in the buffer and it migrates through 

			190 1	-- the same principle; it just works much faster.
	2		[Slide] 
	3		Multispot is a test that differentiates between 
	4	HIV-1 and 2, and it can be performed with 40 mcl of serum or 
	5	plasma.  This is another platform that we are looking at in 
	6	full scale now.
	7		[Slide] 
	8		The Cambridge Biotech, which is now Trinity 
	9	Biotech -- this is the Capillus platform latex agglutination 
10	that was mentioned earlier. 
11		[Slide]
12		Quix by Universal Health Watch, serum, plasma or 
13	whole blood, 50 mcl.  They added a control line, which you 
14	can see here, and two dots for HIV-1 and HIV-2, one of the 
15	few tests out there on the market that can distinguish 
16	between HIV-1 and HIV-2.
17		[Slide] 
18		When I first took over this job about three years 
19	ago, this was the first test we evaluated, latex 
20	agglutination based on particle size that will make it or 
21	not through this filtration membrane.  I am not sure if the
22	company is still around today to provide us with a test but 
23	you will see the results later. 
24		[Slide] 
25		Last but not least, HIV 1/2, and this is not to be 

			191 1	confused with the Maryland test HIV 1/2.  This is an HIV 1/2
	2	test that is made out of New Jersey.  I was in a meeting 

	3	down in San Antonio a couple of years ago, and some guy 
	4	approached me with a very promising test.  We obtained 175 
	5	devices, performed the test and you will see that the 
	6	results were very discouraging, and that is why we developed
	7	panels in the manner that we did -- 100, 1000, then 11,000. 
	8		[Slide] 
	9		This is where the rubber hits the road.  This is 
10	our experience.  This is what we have done and this is what 
11	we are here to show you today.  So, I will spend a few
12	minutes talking about this slide.  These test platforms are 
13	in no order whatsoever, and the testing is not done 
14	simultaneously at the same time, meaning that when tested 
15	the Hemastrip or UniGold we did not test Hemastrip and 
16	UniGold at the same time.  These 10,000 samples are not
17	tested at the same time with Hemastrip and UniGold, and may 
18	not be the same 10,000 samples but you will see a 
19	discrepancy table that follows this one that shows 
20	comparison between platforms, which does not attest to the 
21	sensitivity of the product.
22		Let's read, for example, Hemastrip across the 
23	first line.  We have tested 10,290 samples.  We have tested 
24	511 reactives.  We had 1 false negative.  We have tested 
25	9779 non-reactives; 1 false positive which yielded a 

			192 1	sensitivity of 99.8 and a specificity of 99.9.
	2		One point I would like to mention on this table, 
	3	when you look at UniGold, this is one of the few tests that 
	4	had 100 percent sensitivity.  I want you to bear in mind the 
	5	number of positives that we evaluated.  We have looked at 
	6	the magnitude of 500, 700 or 300 for some of the tests and
	7	you will see the sensitivity a little bit less than 100 but 
	8	we have only looked at 122 with the UniGold.  This is one of 
	9	the platforms that we are looking at now with their new 
10	peptide generation. 
11		This is HIV 1/2 that I told you about.  You will
12	see why we developed panels that way.  Look at the 
13	specificity, 65 percent.  We were going to tell 30-some 

14	percent of our population that they are HIV positive when 
15	they need not be notified, and this is why platforms like 
16	that are being evaluated now.
17		Bear in mind that HIV 1/2 Abbott ELISA is 100 

18	percent sensitivity and 99 or 94 percent specific.  So, when 
19	you look at these things, put them in perspective with what 
20	the ELISA can offer you. 
21		[Slide]
22		This is a discrepancy table.  I have printouts of 
23	these slides for anyone who is interested.  The discrepancy 
24	table shows the samples that were discrepant on one 
25	platform, how they performed against other platforms, and 

			193 1	how they performed on EIA, Western Blot and we also did RNA

	2	PCR on these samples.  Pick any sample that you want, for 
	3	example one that was missed by Abbott, if you look at any 

	4	that was missed by Determine you will see that it was picked 
	5	by Epitope, for example, but the RNA was positive and the 
	6	Western Blot was positive.
	7		The reason I am putting this table up here is not 
	8	to show why one company missed a product, but this is the 
	9	point that I will drive to later, that two platforms are as 
10	good as an EIA and a Western Blot and this is what we want 
11	to show.  There are not two good tests that we feel are
12	promising that miss the same sample. 
13		[Slide] 
14		This is too much data to digest in one slide; this 
15	is just to give you an idea that the data exists.  So, what 
16	is next?  We are doing simultaneous testing.  We learned
17	from our first experience is that one of the biggest points 
18	against our trial, the first trial, is that we did not do 
19	the tests at the same time.  So, with this new trial that we 
20	are doing now we are doing testing at the same time.  We 

21	will pull the samples out of the freezer; thaw them out one
22	time; do all five or four platforms that we are evaluating; 
23	put them back in the freezer -- we are done.  We are not 

24	going to bring them out again and test another platform 
25	until we are done with that panel. 

			194 1		I prepared these slides yesterday, and we have
	2	completed testing on the 100 panel on Epitope, Multispot, 
	3	the second generation UniGold and MedMira.  We are going to 
	4	move forward with some of these products.  Again, they have 
	5	to meet our sensitivity and specificity criteria in order 
	6	for us to move forward.
	7		What I did not add in this slide is a product that 
	8	is made by -- I forgot the name!  It is made in Canada.  It 
	9	is HIV 1/2.  It is the one that I mentioned earlier that 
10	should not be confused with HIV 1/2 that we had on the 
11	screen.  We are going to add that to the panel and,
12	hopefully, the next time we meet or the next time you hear 
13	from me you will see results on that. 
14		[Slide] 
15		What do we want?  Why are we here?  Where do we 

16	see ourselves going?  What we want, we want one card.  In
17	the military we like to make life simple.  When we are out 
18	there in the field and we have to pack a million things to 
19	take with us that we may never use out there, we want one 
20	thing that we may use -- a card, one simple card that is as 
21	big as this thing right here, that can tell us some STD
22	diseases that we may encounter out there in the field -- 
23	HIV, hepatitis or any endemic disease that we may encounter 
24	in that theater of operation that we are deploying to.  
25	These cards can be modified to fit the theater of operation 

			195 1	that we are deploying to.
	2		This is where the idea started; this is how we 
	3	started.  Col. Hess, the Division Director of Blood Research 
	4	at Walter Reed, approached us with a similar idea.  He said 
	5	we need something out there to be able to see if our 
	6	soldiers are infected or not.  This is just a prototype that
	7	we developed.  We thought this would provide Col. Hess and 
	8	many others with an idea of what our soldiers have out there 
	9	in the field. 
10		We could not pursue this because there are too 

11	many things to evaluate at one time.  Since our division is
12	funded for HIV research and HIV diagnostics only, we 
13	concentrated on HIV virus.  We figured if a company can 

14	develop a platform that works on HIV, they can develop a 
15	platform that will work on any other communicable disease 
16	that we see.
17		[Slide] 

18		The conclusion -- it is a pretty strong conclusion 
19	that we drew after we evaluated the first 10,000.  We feel 
20	that there is not a single test out there that can give us 
21	the sensitivity and specificity that we want.  However,
22	combining two tests will give the sensitivity and 
23	specificity that we want. 
24		We also realize that evaluating rapid diagnostic 
25	tests is an ongoing process.  This is not a process that 

			196 1	will end when we finish this trial.  We will replenish the
	2	panel.  We will get another 12,000 and we will evaluate new 
	3	product. 
	4		Since the CDC had opened the doors with their 
	5	first MMWR publication that screening should be done with 
	6	rapid testing, and FDA has been very cooperative in looking
	7	at these things and working with the companies in evaluating 
	8	these products.  Many companies have jumped on the wagon.  
	9	Many of them are sold and approved overseas for this use but 
10	now they are bringing them here, to the United States, for 
11	PMAs or IDEs.
12		[Slide] 
13		Last but not least, as you can tell this work is 
14	huge and tremendous, and it cannot be done with one or two 
15	individuals.  This is work that is done in strong 
16	collaboration and guidance from Lt. Col. Nelson Michaels
17	who, regrettably, cannot be with us today.  You should all 
18	hate him for this, he is in Cape Hatteras, in North 
19	Carolina, on the beach as we sit here -- 
20		[Laughter] 
21		-- Miss Jennifer Malia, the laboratory supervisor,
22	who is with us here today, Scott Feese, who is the newest 
23	addition to our laboratory, Syad Zyad, who is also a newest 
24	addition to our laboratory.  If you wonder how we handle all 
25	this data and how we put it in the computer, it is by Mr. 

				197 1	Dennis Lucas.  He is our admin. person.
	2		With that, I would like to ask the committee 
	3	whether you would like to open it up for questions and 
	4	answers now or wait until all the presentations are done? 
	5		DR. HOLLINGER:  Are there any questions?  Yes, Dr. 
	6	Mitchell?
	7		DR. MITCHELL:  Yes, you said that you retested a 
	8	number of the samples that were positive with different 
	9	types of tests.  Did you do repeat testing using the same 
10	test and, if you did, then did you get the same result or 
11	different results?
12		LT. ZAHWA:  That is a good question.  The 
13	sensitivity and specificity results when we say a specific 
14	test missed one or two samples, this is after repeat 
15	testing.  We will test initially.  We will do repeat testing 
16	and we will draw a conclusion.  Two out of three positives
17	will make that test positive.  The repeat two negatives will 
18	make that test negative.  Therefore, yes, we included that 
19	in sensitivity and specificity.  We looked at repeat 
20	testing.  We did that in duplicates. 
21		Any other questions?  What I want you all to
22	remember is that the work we do is for those of us who are 
23	out there in the field, being exposed to HIV and other 

24	diseases, that we are safe here back home.  Thank you. 
25		DR. HOLLINGER:  Thank you.  The next presentation 

			198 1	is by Nancy Wade.  Dr. Wade?
	2	  Presentation by Nancy A. Wade., M.D., NYS Dpt. of Health 

	3		DR. WADE:  Good afternoon.  I want to thank the 
	4	committee for inviting me to participate in this session. 
	5		[Slide] 

	6		I am going to share with you some information from
	7	New York State Department of Health on the prevention of 
	8	perinatal HIV transmission, expedited HIV testing for 
	9	pregnant women in the labor, delivery and in the neonatal 
10	setting. 
11		[Slide]
12		I think you have to understand a little bit of the 
13	chronology of what has been happening in New York State to 
14	understand where we are today.  In November, 1987, a survey 
15	of childbearing women began, and that was basically blinded 
16	testing of all newborns.
17		In May, 1996 to January, 1997 by regulation, sites 
18	were required to offer prenatal counseling with recommended 
19	testing, and this was in all regulated settings so it really 
20	excluded some of the private practices but it was a standard 
21	of care at those sites.  Consented newborn testing began in
22	May, 1996.  What happened was, when this started to be 

23	offered, about 90 percent or more of the women who were 
24	actually offered the test results opted for the test result 
25	to be returned to them. 

			199 1		In February, '97 a new law came into effect.  This
	2	was that comprehensive newborn HIV testing program whereby 

	3	all newborn testing now was reported back to a designated 
	4	physician at the hospital who then, in turn, passed 
	5	themselves information on to a pediatrician who gave the 
	6	result to the mother and the family.
	7		Then, in August, 1999 there was a new regulation 
	8	and this basically said that if a woman came to labor and 

	9	delivery and she did not have an HIV result from the current 
10	pregnancy and she wasn't known to be HIV positive, she had 
11	to be offered HIV testing in the labor and delivery suite. 
12	If she declined testing, then her newborn, as an extension 
13	of newborn testing, was tested immediately after birth and 
14	that testing could be with counseling but it was without 
15	consent. 
16		[Slide]
17		The universal prenatal HIV counseling and testing 
18	program -- if you look at data from 1998, there were about 
19	250,000 women who delivered in New York State and 54 percent 
20	of them were tested during the current pregnancy.  This is 
21	at a time when regulation required counseling and voluntary
22	testing in all sites.  Of the 16 percent tested prior to 

23	pregnancy, some of those women would be infected; some of 
24	those women may have become infected and not known their 
25	accurate status.  About 24 percent had no prior testing 

			200 1	history and about 5 percent had an unknown testing history.
	2		[Slide] 
	3		The problem was that about 45 percent of women had 
	4	no documented HIV test from their current pregnancy, and 
	5	that translated to about 520 HIV-positive women who may not 
	6	have known their HIV status and that represented a serious
	7	missed opportunity for prophylaxis to prevent HIV 
	8	transmission. 
	9		[Slide] 
10		I think most of you are familiar when perinatal 
11	HIV transmission occurs.  About a third is thought to occur
12	in the antepartum period.  Two-thirds is thought to occur in 
13	the intrapartum period, and breastfeeding adds probably 14- 
14	16 percent to transmission. 
15		[Slide] 
16		Then, during 1998 and 1999 there were a number of
17	publications that came out that looked at abbreviated 
18	regimens.  The standard regimen for an HIV-infected pregnant 
19	woman resulted in the 076 regimen where women were given ZDV 
20	in the second and third trimester, intravenous infusion 

21	during labor and then the newborn was given 6 weeks of
22	zidovudine. 
23		The abbreviated regimens in Thailand -- ZDV was 
24	administered at from 36 weeks on and during labor.  
25	Transmission was 9.4 percent in the group receiving ZDV 

			201 1	versus 18.9 percent in the placebo group.
	2		The UNAIDS PETRA study looked at ZDV and 3TC 
	3	intrapartum and for 1 week postpartum for the mother and the 
	4	baby.  Transmission again, 10.8 percent in the group 
	5	receiving antiretrovirals, 17.2 percent in the placebo 
	6	group.
	7		HIVNET 012 came out in the last year where women 
	8	received either ZDV or Nevirapine intrapartum and then for 
	9	the newborn.  This was a very, very short course regimen.  
10	The transmission rate was 13 percent in the Nevirapine group 
11	and 25 percent in the ZDV group.  I believe that was at 14

12	weeks and, remember, this was a breastfeeding population. 
13		Then, our data from New York State -- this was 
14	observational data and it looked at ZDV intrapartum and in 
15	the newborn period or in the newborn period alone, and the 
16	transmission rate was 10 percent when it was initiated in
17	the intrapartum period, 9 percent when it was initiated in 
18	the newborn period, and 26 percent when no antiretroviral 
19	was administered. 

20		[Slide] 
21		I think if you look at reasons for having no HIV
22	test result at the time of labor and delivery, one would be 
23	no prenatal care, and among the HIV-infected pregnant women 
24	probably in the vicinity of 15-20 percent have either no or 
25	inadequate prenatal care.  Prenatal care without HIV 

			202 1	counseling, and that again was most commonly occurring in
	2	the private offices.  The women may have been counseled and 
	3	opted not to be tested, or the test result may not have been 
	4	transferred to the delivery medical record, and that has 
	5	sometimes been an issue just based on confidentiality of 
	6	transferring records.
	7		[Slide] 
	8		The current program, however, in New York State, 
	9	again, continues to require prenatal HIV counseling and 
10	testing is recommended.  It is consented testing. 
11		Then there continues to be routine screening of
12	all infants under the newborn screening program, and this is 
13	part of the metabolic screening that goes on in the hell- 
14	stick blood spot. 
15		Then the test results from the newborn screening 
16	program are available in one to two weeks and, again, that
17	is too late to actually initiate any prophylaxis. 
18		We can demonstrate strong linkages to care once an 
19	infant is identified.  Better than 99 percent of the infants 
20	are in care by our marker of a first diagnostic PCR test 
21	that comes to the state.
22		Then expedited HIV testing is required intrapartum 
23	with consent or of the newborn without consent if the HIV 

24	test result is not available from the current pregnancy. 
25		[Slide] 

			203 1		I think if you look at the rationale for expedited
	2	testing -- and I think we call this expedited testing 
	3	because we had one rapid test so in some instances 
	4	facilities were opting to use a STAT ELISA, or whatever.  It 
	5	promotes access to intrapartum and newborn ZDV prophylaxis.  
	6	If the mother is unable or declines prenatal or intrapartum
	7	ZDV the newborn may still benefit from prophylaxis, and it 
	8	promotes early identification of infected infants, allowing 
	9	the initiation of combination therapy as early as possible. 
10		[Slide] 
11		The regulation in New York State, again, applies
12	only when the mother's status is unknown at delivery, and it 
13	requires that birth facilities -- hospitals, provide 
14	immediate HIV testing of the mother with consent during 

15	labor and of the newborn immediately after birth if the 
16	mother has not been tested.
17		[Slide] 
18		It requires that the results be available as soon 
19	as possible, and the outside limit of this was 48 hours, 
20	although they are advised to get the testing done again and 
21	initiate treatment as soon as possible.  It is really fairly
22	similar to the hepatitis B surface antigen testing 
23	requirement for New York. 
24		This new regulation allows reporting of 
25	preliminary HIV test results when requested by a physician, 

			204 1	where in the past an ELISA which was positive couldn't be
	2	reported until the Western Blot was completed.  A positive 

	3	SUDS or a positive ELISA alone done in duplicate could be 
	4	reported and acted on while you were waiting for the 
	5	confirmatory test result. 
	6		[Slide]
	7		Again, the facility responsibilities I think I 
	8	have pretty well covered already. 
	9		[Slide] 
10		If you do have a positive preliminary HIV test 
11	result with our current rapid test, I think you have to

12	discuss the likelihood of a true positive based on the risk 
13	factors of the mother, as well as the seroprevalence in the 
14	facility that you are in; offer initiation of zidovudine 
15	prophylaxis; advise against breastfeeding pending the 
16	confirmatory test result.
17		[Slide] 
18		Then, on discharge from the hospital, it is 
19	important to be sure that the confirmatory test result is 
20	either back, arrange a follow-up clinic visit and advise the 
21	mother when the confirmatory test result will be back if it
22	is not back before discharge.  Ideally, it is returned 

23	before the woman is discharged, and we have encouraged 
24	people to even delay a discharge if necessary in those 
25	instances.  The infants are sent home with zidovudine; 

			205 1	appropriate referrals for care; and then the woman is also
	2	referred for additional services and needs that may occur as 
	3	the result of the testing. 
	4		[Slide] 
	5		If you look at the projected utilization of 
	6	expedited HIV testing in New York State and, again, with
	7	about 250,000 births per year statewide seroprevalence is 

	8	about 0.4 percent.  We have about 1000 HIV-positive women 
	9	giving birth each year for the last several years.  In the 
10	last several months, since expedited testing began, the 
11	number of women who are tested during pregnancy has gone up
12	dramatically so that now about 90 percent of all pregnant 
13	women are tested during pregnancy or are known positive.  
14	For HIV-positive women that number is somewhat lower and it 
15	is around 80-82 percent who are actually tested during the 
16	current pregnancy or know their status.  That leads to about
17	25,000 pregnant women who are eligible for expedited 
18	testing, and approximately 120-200 of these women will be 
19	HIV positive each year. 
20		[Slide] 
21		We do continue with the universal newborn
22	screening program.  In a way, it is kind of a check on the 
23	system to be absolutely sure that somebody hasn't been 

24	incorrectly diagnosed.  So, all infants are still tested for 
25	HIV.  In the postpartum period, all women will be counseled 

			206 1	about the universal HIV testing in the newborn screening

	2	program so that they can expect to see that test result 
	3	return. 
	4		[Slide] 
	5		If you look at the predictive value positive of 
	6	our currently available tests, SUDS and EIA, SUDS performs
	7	less well than some of the standard EIAs and, again, it 

	8	really is largely dependent on the seroprevalence of the 
	9	hospitals.  I think if you look in some of the rural areas 
10	of the state, the predictive value is down in the 18 percent 
11	range, whereas in some of the high seroprevalence areas the
12	predictive value of a positive test is up in the 90-some 

13	percent range and EIA is, again, better.  Hospitals have 
14	been advised to choose an algorithm.  We have given them a 
15	suggested algorithm, either SUDS or EIA.  If the test is 
16	positive they repeat it in duplicate.  If that is positive
17	they are advised to ideally use an alternate test method.  
18	So, again, ideally if you had a positive SUDS you would 
19	follow it by a STAT ELISA and in a few hours have a 
20	confirmed test. 

21		[Slide]
22		In the testing program from 10/99, over this six- 
23	month period, among HIV-positive women there were 484 
24	births; 59 percent were tested during pregnancy; 29 percent 
25	tested prior to pregnancy; and 13 percent, or 61, required 

			207 1	expedited testing.  Of those, 45, or 75 percent of them, had
	2	expedited testing done and there were 16 missed 
	3	opportunities, or about a quarter. 
	4		The data on actual expedited testing among the 
	5	negative women is not as clear.  We require that any 
	6	positive expedited test result be reported to the state so
	7	that we are able to track what happens and try to get a 
	8	handle on false positives. 
	9		[Slide] 
10		Then, if you look at preliminary positive test 
11	results, to date we have had 58 positive expedited screening
12	test results come in.  Eight of those were from previously 
13	known positive women, and if a woman doesn't have 
14	documentation of the test then sometimes the hospital would 
15	go ahead and do a rapid test also, and 38 of those, or 66 

16	percent, were confirmed positives; 18 of them were EIAs and
17	20 were SUDS.  There were 17 false positives, 3 among the 
18	EIA and 14 among the SUDS.  Then, there is a number that is 
19	pending and one was an indeterminate Western Blot.  These 

20	data are really still quite preliminary as we are continuing 
21	to pull them in.

22		[Slide] 
23		On this slide I really just wanted to point out 
24	the change in the testing during the current pregnancy.  

25	This is all women in New York State, and back in '97 it was 

			208 1	around 50 percent, by August of '99, when the expedited
	2	program started, it was  around 70-75 percent and it is now 
	3	up around 90 percent.  For HIV-positive women the level is 
	4	about 80-85 percent of women being tested during the current 
	5	pregnancy. 
	6		[Slide]
	7		I think the conclusions are that antiretroviral 
	8	therapy during labor or soon after birth presents about a 50 
	9	percent decline in mother to child HIV transmission.  It is 
10	certainly not as good as the full regimen but it is a good 
11	option.
12		About 10-15 percent of HIV-infected pregnant women 
13	are diagnosed at labor only with the use of rapid tests.  In 
14	fact, that number may be closer to 20 percent. 
15		In New York State alone approximately 50 HIV 
16	infections in infants each year can be prevented by
17	expedited testing and timely antiretroviral therapy.  The 
18	use of more than one rapid test would prevent the 
19	unnecessary treatment of 30-40 percent of the infants whose 
20	initial rapid test is false positive and, obviously, the 
21	anguish that goes along with that.  I think, finally,
22	additional approved rapid tests are really urgently needed.  
23		I don't know if the committee wants me to take 
24	questions. 
25		DR. HOLLINGER:  Any questions for Dr. Wade right 

			209 1	now?  Yes, Dr. Nelson:
	2		DR. NELSON:  Are there any circumstances in which 
	3	a woman had a history of being tested but was tested again 

	4	at the time of delivery? 
	5		DR. WADE:  We have documentation of at least a 
	6	couple of women who have seroconverted during their
	7	pregnancy.  They were negative early in pregnancy, that 
	8	didn't have a rapid test, but the baby was picked up 
	9	subsequently on newborn screening.  We recommend if it is a 
10	high risk situation that people consider testing later.  It 
11	is not part of regulation but I am aware of at least two
12	instances of that happening. 
13		DR. HOLLINGER:  Yes, Jeanne? 
14		DR. LINDEN:  Since you were talking about using 
15	the second test to avoid unnecessary treatment, presumably 
16	you are using the formula of both tests would have to be

17	positive to be considered positive.  That is, you are 
18	sacrificing sensitivity for the sake of specificity. 

19		DR. WADE:  Currently, we are not requiring that 
20	they do two tests.  If they have simply a SUDS available at 
21	their facility, then that is what they are working from so
22	their chances of a false positive are much higher.  If we 
23	had available other rapid tests, then we would move forward 

24	with that.  Any positive test, obviously, is tested by ELISA 
25	and Western Blot but there is a lag before that gets done.  

			210 1	Not everybody is able to do them in a few hours.  It is more
	2	commonly a day or two before that is completed. 
	3		DR. HOLLINGER:  Thank you, Dr. Wade.  I think, Dr. 
	4	Janssen, you have another presentation? 
	5		Presentation by Robert S. Janssen, M.D. 
	6		DR. JANSSEN:  Yes, thank you.  When you have the
	7	opportunity to give two talks you can remember something you 
	8	didn't give in your first talk and add it to the second one. 
	9		[Slide] 
10		I wanted to start by just mentioning that one of 
11	the very important reasons for rapid tests that we see is

12	that we have recently begun an HIV prevention strategic 
13	planning process.  One of the goals of that process is 

14	within five years to increase the proportion of HIV-infected 
15	people who know their serostatus to 95 percent from the 
16	current estimated 70 percent.
17		Nancy Wade stayed on the perinatal -- a very 
18	important use of these tests.  Nationally, in 1998, less 
19	than 250 babies were infected perinatally by their mothers.  
20	The majority of that transmission occurred from mothers who 
21	did not receive antenatal care.  So, being able to use rapid
22	tests at the time of delivery I think will be crucial, based 
23	on the data that presented from the short course AZT data 

24	and from the New York State data as well and the Nevirapine 
25	data. 

			211 1		[Slide]
	2		What I want to talk about now is some of the 
	3	challenges to public health.  I think you have seen this 
	4	slide before so I won't dwell on it.  The point clearly is 

	5	that when you have one test, as prevalence goes down your 
	6	predictive value positive also goes down and your false-
	7	positive rate goes up. 
	8		This is an example of what happens in that 
	9	situation.  These are data from New York, as Nancy Wade 
10	presented.  Twenty-four percent had children who would have 
11	been diagnosed only at birth.  They had not had any
12	antenatal care.  There was no diagnosis prior to birth.  At 
13	Charity Hospital, in New Orleans, 20 percent.  The 
14	difference here is the prevalence, 0.3 percent in New York; 
15	over 3 percent in New Orleans.  This is the real-world 
16	example of that table before, where 40 percent of the HIV
17	tests in New York were false positives based on the single 
18	SUDS test and only 17 percent in Charity, and it is purely 
19	based on prevalence.  Predictive value, 60 percent in New 
20	York; 83 percent at Charity and very similar to that 
21	predicted based on the performance of the assay.
22		[Slide] 
23		So, we can do better and there is a need for 
24	several rapid tests.  There is only one currently licensed, 
25	as you know, and the use of two could increase sensitivity 

			212 1	and specificity and predictive value to nearly 100 percent.
	2		[Slide] 
	3		In fact, these tests are being used in other 
	4	countries.  This is a study that Harrison Stetler, from CDC, 
	5	published in Honduras.  I believe there are other co-authors 
	6	in the audience, actually.  Basically, this was using a
	7	combination of tests, a variety of rapid tests, and 
	8	basically what you can see in both low prevalence and high 
	9	prevalence settings is very good or excellent predictive 
10	positive and predictive negative values. 
11		[Slide]
12		This is another example of use internationally of 
13	these tests.  Again, we can't do this here yet but we look 
14	forward to it.  This is an example of an agglutination test, 
15	the Capillus test, which has some trouble with specificity, 
16	but this has been used in Uganda in 1997 on 35,000 people. 
17	Now, there were over 7800 HIV positives who then got tested 
18	with Serocard.  Those that were HIV negative on Serocard -- 
19	there was a tie breaker with Multispot.  What is interesting 
20	is that 862 out of those 7800 initially HIV positive on 
21	Capillus test turned out to be false positive.  But these
22	tests are being used successfully in international settings. 
23		[Slide] 
24		So, to turn to CDC's efforts about the 
25	availability of rapid tests and what we have been trying to 

			213 1	do to make rapid tests available in this country, we have
	2	been trying to encourage manufacturers to commercialize 
	3	rapid tests.  We are conducting clinical trials to establish 
	4	test performance in settings of intended care, and I will 
	5	show you some of those data in a minute.  Data also that we 
	6	would anticipate would be provided for PMA applications to
	7	speed FDA approval.  Finally, I will show some data in which 
	8	we are evaluating the use of specific combinations of rapid 
	9	tests to increase predictive value. 
10		[Slide] 
11		Our clinical trials that are necessary for
12	prospective tests were really focusing on our intended uses, 
13	that is, the public health intended uses of rapid tests, 
14	those particularly that we would be funding and these are in 
15	both high and low prevalence settings.  The low prevalence 
16	setting has been talked about already, and that is the
17	antenatal care setting.  But high prevalence settings abound 
18	in the work that we do, particularly STD clinics and 
19	outreach. 
20		In addition, these settings are key to us.  I said 
21	CDC but the military -- we don't do those.  You have heard

22	about those and then also the combination test algorithms. 
23		[Slide] 
24		You have seen these pictures so I will go through 
25	these quickly.  Fortunately, Hassan has shown a bunch of 

			214 1	pictures that I have so I can just go through them quickly. 
	2	This is SUDS. 
	3		[Slide] 
	4		The idea behind this is that SUDS, although a 

	5	rapid test, is not a simple test.  It requires multiple 
	6	reagents --
	7		[Slide] 
	8		-- centrifugation, several reagent steps -- 
	9		[Slide] 
10		-- and also a blue color that apparently can be 
11	somewhat difficult to read.
12		[Slide] 
13		The selection criteria for the tests that we have 
14	involved in our studies are listed here, the first being 
15	availability of clinical performance data from the 
16	manufacturers and preclinical data.  Then, what we wanted to
17	look specifically at was user-friendly performance 
18	characteristics, those that are easy to use, with clear 
19	interpretations, minimal technical requirements, and are 
20	suitable for use in field settings, particularly on whole, 
21	blood finger-stick specimens or on oral secretions.
22		[Slide] 
23		You have seen these.  This is the Determine test. 
24		[Slide] 
25		Determine tests can be done multiply, and are 

			215 1	suitable for multiple tests being run at one time.
	2		[Slide] 
	3		You have seen these.  This is Hemastrip, which is 
	4	a finger-stick blood specimen. 
	5		[Slide] 
	6		And, the results can be read in about 15 minutes. 
	7		[Slide] 
	8		You have seen similar pictures to most of these. 
	9		[Slide] 
10		That is UniGold. 
11		[Slide]
12		Then, MedMira, which is done a little differently.  
13	It is a flow-through device. 
14		[Slide] 
15		The results can be read immediately. 
16		[Slide]
17		There is a reader, for example, with this test 
18	which allows one to reduce subjective interpretation of the 
19	result. 
20		[Slide] 
21		And, an ability to store the results for the
22	medical record. 

23		[Slide] 
24		The OraQuick test that you have seen -- 
25		[Slide] 

			216 1		-- in which the results can be available within 20
	2	minutes. 
	3		[Slide] 
	4		The last one is Quix. 
	5		[Slide] 
	6		So, what did we do?  We did some lab evaluation
	7	based on 400 stored samples.  These are bank CDC repository 
	8	specimens that were used, and then a clinical study, 900 
	9	persons with known HIV status who came in to establish 

10	performance using whole blood and finger-stick specimens. 
11	These were matched specimens.  So, people gave both
12	specimens at the same time.  Then, there was the larger 
13	clinical study of 6000 persons with unknown HIV status to 

14	determine sensitivity, specificity and predictive value of 
15	combination tests. 

16		[Slide]
17		So, the test results are here.  This is the first 
18	group, sensitivity and specificity on serum.  These are the 
19	repository specimens.  You can see all the tests performed, 
20	both in terms of sensitivity and specificity, very well, as 
21	good as or better than those tests that are currently
22	licensed. 
23		[Slide] 
24		These tests weren't available when we did the 

25	first test.  So, this group is done with a second set of 

			217 1	repository specimens but, again, this is serum-based on
	2	frozen specimens. 

	3		[Slide] 
	4		The next two slides will show the comparison of 
	5	the performance on plasma and on whole blood in a 
	6	prospective study in Los Angeles, which has been performed
	7	in a series of clinics as well as a mobile van.  In these, 

	8	again, you can see excellent sensitivity and specificity for 
	9	all the tests that we have been looking at. 
10		[Slide] 
11		This is the whole blood test.  I think, again, you
12	can see good performance on all of these, but perhaps the 

13	UniGold test here does not seem to perform as well as some 
14	of these other tests but, again, the numbers in these 
15	studies are small. 

16		[Slide]
17		Also, we have done some evaluations of Multispot. 
18	Many of these are historical and were done overseas -- 
19	studies in the Bahamas and, again, if you look here under 
20	sensitivity and specificity, very consistently high with 

21	studies done in a variety of places -- the Bahamas and
22	Trinidad and Honduras and, not quite an international 
23	location, Bronx Lebanon Hospital in the South Bronx. 
24		[Slide] 
25		Then, New York State has also done Multispot 

			218 1	evaluations and is using the Confirm HIV-2.  Again, here you
	2	see the same thing with very high sensitivities and 
	3	specificities, including in the expedited newborn testing 
	4	and then in a prospective evaluation as well. 
	5		[Slide] 
	6		This shows basically a similar slide to what
	7	Hassan showed, which is extremely difficult to read, but it 
	8	basically shows that these tests, when they pick up or miss 
	9	something they tend to be different.  So, a combination of 
10	these tests is likely to pick up something -- one test is 
11	likely to pick up a specimen that another one is not.
12		[Slide] 
13		So, lessons from our international studies are, 

14	first, and most importantly I think, rapid tests have been 
15	used internationally at least for the last four to four and 
16	a half years in a number of studies that we have done,

17	including clinical use and supporting clinical use in 
18	countries, particularly in Uganda most recently and Malawi.  
19	Both clients and staff prefer same day results.  Quality 
20	counseling can be provided in these circumstances.  
21	Combination test algorithms yield accurate results, and same
22	day results help clients to receive immediate referrals and 
23	services that they need. 
24		[Slide] 
25		Looking at our international experience, this are 

			219 1	the algorithms that we have been using internationally. 
	2	These are sequential algorithms, done in four countries, 
	3	South Africa and Malawi.  On the next slide I will show you 
	4	the other results.  You see the sensitivity and specificity 
	5	in the combination of the tests.  This is each one by itself 
	6	and then combined in the algorithm.  What you are seeing is,
	7	again, excellent sensitivity and specificity.  They weren't 
	8	missing many and in some cases missed different ones. 
	9		[Slide] 
10		The same thing with Botswana and Uganda, with very 
11	high sensitivities and specificities, again, in combination
12	algorithms. 
13		[Slide] 
14		In summary, rapid tests are essential for early 
15	access to prevention care and support services.  The 
16	currently approved rapid test doesn't really meet the needs
17	that we have and I think I made that pretty clear before.  
18	We really need a test that we can move out of the laboratory 
19	if at all possible to be able to begin to achieve our goal 
20	of an increase in the proportion of people who know they are 
21	infected.

22	*	Rapid testing with quality counseling is feasible.  
23	It can help staff provide immediate care and support.  There 
24	are numerous accurate rapid tests that exist, many of them 

25	being used overseas today, and the need to approve simple 

			220 1	rapid tests really is urgent in our opinion.
	2		[Slide] 
	3		Where do we go from here?  We concur on the 
	4	clinical trial requirements for HIV screening indication.   
	5	The reduction in the size of clinical trials should speed 
	6	clinical trials and should speed approval of tests.
	7		We are encouraging the submission of PMA 
	8	applications with available U.S. as well as foreign clinical 
	9	trial data.  We are supporting and are willing to support 

10	any necessary additional trials that are needed.  Finally, 
11	we recommend also that consideration be given for post-

12	approval requirements for other indications.  In this 
13	country HIV-2 and group O are of interest, primarily 

14	academic interest.  They are certainly not a public health 
15	interest.  We have recently pretty much given up our HIV-2 
16	surveillance.  We haven't completely but we are doing much

17	less of it because of the 675,000 people who are infected in 
18	this country, it seems there are about 100-150 who are 
19	infected with HIV-2.  So, we would actually recommend that 
20	approval for these kinds of claims be done post-approval 
21	rather than a requirement for getting these tests on the
22	market if they are going to delay getting these tests on the 
23	market.  Thank you.  Questions? 
24		DR. HOLLINGER:  Thank you.  Yes, Dr. Katz? 
25		DR. KATZ:  I am just interested in your 

			221 1	sensitivity and specificity numbers.  Those all look like

	2	point estimates to me and I am wondering if you have the 
	3	numbers, or can give us a feeling for how they would fit 

	4	into the FDA's intention to talk about a lower bound of a 95 
	5	percent confidence interval at 98 percent. 
	6		DR. JANSSEN:  I want to acknowledge Bernie Branson
	7	who has really been the major push on rapid tests and has 
	8	provided a massive amount of work, including all these data.  
	9	Bernie, do you want to address that?  Bernie is intimately 
10	familiar with these data. 
11		DR. BRANSON:  Those data were used to generate the
12	FDA's state-of-the-art estimates so that those tests 
13	basically would all meet the recommended standards that the 
14	FDA has presented today. 
15		DR. HOLLINGER:  Yes, Dr. Nelson? 
16		DR. NELSON:  I know that one population has not
17	been considered for rapid tests for discussion, and I think 
18	it is probably appropriate given that we are talking about 

19	the United States.  But, I think worldwide blood donors are 
20	a very important group and only half or so of the blood 

21	donors in the world are even tested but of those that are
22	tested, even with high quality tests in places like Thailand 
23	where there is a delay in the results -- the problem is that 
24	when we have tried to notify people of their results, the 

25	positives, we were able to notify about 70 percent because 

					222 1	there aren't phones; you have to try to find the people.
	2		I think a rapid test in the setting of a blood 
	3	bank where the prevalence in the donor population is fairly 
	4	high is an important use because these are people mostly who 
	5	are healthy, who come in often, populations with a large 
	6	heterosexual epidemic.  Knowing at least presumptively that
	7	somebody is positive when they are in the blood bank, where 
	8	they can be counseled, is critical.  Yet, you know, this 
	9	wasn't mentioned here.  I am not suggesting necessarily that 
10	the current algorithm in the U.S. donor population should be 
11	replaced or modified, but I think if we are thinking about
12	the global AIDS epidemic, this is a very important 
13	population. 
14		DR. HOLLINGER:  Yes, Dr. Mitchell? 
15		DR. MITCHELL:  I have a question on the algorithm 
16	for the four countries.  When you talked about the tests,
17	were they repeated? 
18		DR. JANSSEN:  They were repeated. 
19		DR. MITCHELL:  Each was repeated, and then in 
20	combination they were also repeated? 
21		DR. JANSSEN:  Yes.
22		DR. MITCHELL:  One time? 

23		DR. JANSSEN:  One time. 
24		DR. HOLLINGER:  Just a couple of questions, Dr. 
25	Janssen.  Some have to do with the testing as it is looked 

			223 1	at, and I would like to get your feeling about this, but one
	2	of the reasons would be, as you said, first of all, to 
	3	decide who would take advantage of these rapid tests here, 
	4	in the United States.  Presumably, people who don't have the 
	5	funds to maybe go somewhere else, and there may be other 
	6	reasons for it.
	7		So, one of the questions is what is the social 
	8	responsibility of the individuals who might come in and do 
	9	this who may be given an answer that they are positive in 
10	terms of their preventing transmission to other people 
11	anyway?  Are these the individuals in general who might come
12	in and want to test, who can't afford it otherwise, who may 
13	then go out and ignore the very advice you are going to give 
14	them in terms of transmission?  That is one question. 
15		The other is that you mentioned that many people 
16	don't know they are even infected.  I guess then the
17	question is why would they come in anyway if they don't know 
18	they are infected, or are not sure that they might be 
19	infected?  They probably would not come in anyway to get 
20	tested. 
21		Then, the third thing is, if it is for treatment,
22	many patients are not able to afford the HAART treatment and 
23	so on, and there are not funds in the public sector to even 
24	treat these people, or perhaps provide them certainly with 
25	HAART treatment at least in the indigent population.  So, 

			224 1	could you sort of take a stab at those?
	2		DR. JANSSEN:  First of all, I assume you are 
	3	talking about what is currently licensed with the single 
	4	provisional test result. 
	5		DR. HOLLINGER:  No, I want to talk about even a 
	6	little further with the tests we are talking about now, as
	7	they become licensed and could be utilized. 
	8		DR. JANSSEN:  One of the things in the process of 
	9	right now is modifying CDC's counseling testing guidelines.  
10	One of the parts of those guidelines that will not be 
11	modified is post-test counseling, particularly risk
12	reduction, prevention counseling for people who are found to 
13	be HIV positive.  So, there will be prevention intervention 
14	at the time of provision of the test result. 
15		Beyond that, then people who continue -- and I 

16	think the idea behind SAFE is that a very important part of
17	it is supporting HIV-infected people in adopting and 
18	supporting safe behavior.  One of those ways is through 

19	something we call prevention case management, which is 
20	essentially case management with a counseling or prevention 
21	component to it.  Those people, for example, who are HIV-

22	infected and come in repeatedly with sexually transmitted 
23	diseases would be people we would want to get into 
24	prevention case management or other prevention interventions 
25	to try to get them to reduce their risk behavior. 

			225 1		It is a concern.  I think you might have had a
	2	question that was sort of leaning towards intentional 
	3	transmission.  That clearly happens; it seems to be a fairly 
	4	rare event.  The vast majority of infected people reduce 
	5	their risk behavior. 
	6		You asked me three questions --
	7		DR. HOLLINGER:  The treatment issue. 
	8		DR. JANSSEN:  The treatment issue is one which we 
	9	have thought a lot about.  The question is do you wait for 
10	the services and then encourage testing and getting people 
11	into treatment, or do you get people to learn their status

12	and push for the services?  The decision we have made is 
13	that if we wait the services will never be there.  But if 
14	there is more and more demand on the services, then more 
15	services will come about. 
16		DR. HOLLINGER:  Yes?
17		DR. OHENE-FREMPONG:  I am trying to imagine the 
18	various settings in which we encounter patients in whom we 
19	want to know their HIV status.  The sort of sensitive 

20	counseling that would be required if you receive the results 
21	-- if somebody is in the emergency department, they are

22	planning to be there for a few hours and they will be 
23	leaving, not like, say, CBC where you get results and what 
24	you say about it is not that sensitive and there are not 
25	often long-term consequences -- I just wonder who will be 

			226 1	the counselors who will follow up on that?
	2		DR. JANSSEN:  The idea is not for the ER doc. to 

	3	spend an hour counseling someone because that is not going 
	4	to be practical in an emergency room, but to actually 
	5	provide counseling through other people.  During the day it 
	6	would be easy to refer someone to a service that is ongoing
	7	in a hospital.  At night I think it would be more 

	8	complicated and at a very high prevalence hospital, like the 
	9	Grady Hospital in Atlanta, you would want counseling 
10	services available 24 hours a day to be able to deal with 
11	this, depending on what the rate would be at which you would
12	be identifying people. 
13		You are right, this is not like a CBC result; it 
14	is not like a lot of test results, and you do need someone 
15	to sit down and talk to people when they initially learn the 
16	results.
17		DR. OHENE-FREMPONG:  I know it is very important 
18	but in any of the clinical trials has the follow up also 

19	been looked at? 
20		DR. JANSSEN:  Yes, we are looking at how do you 
21	implement these tests in this setting.  Although I
22	personally am convinced, and part of it is based on my 

23	experience in hospitals at some work I did at University 
24	Hospital in Newark about eight years ago.  There were no 
25	rapid tests then but routine testing in their emergency 

			227 1	room, and did it successfully.  But we are looking now at
	2	what are all the factors that would make this a successful 
	3	strategy.  It is not a strategy to implement in every 
	4	emergency room.  It is a strategy to target toward those 
	5	hospitals with high prevalence of HIV. 
	6		DR. HOLLINGER:  I will tell you what I would like
	7	to do, we are going to take about a 20-minute break and then 
	8	we are going to come back and we will have the open public 

	9	sessions.  I would like those who are going to present to 
10	limit their talks to about 5-7 minutes each.  Then we will 
11	go into the other questions with the committee and so on. 
12	So, it is now about 3:55.  So, at 4:15 we will meet again. 
13		[Brief recess] 
14		DR. HOLLINGER:  Somebody said what we ought to do 
15	is have each of the manufacturers start their test and then 
16	just speak for the time limit of their test.  When their
17	test became positive they could sit down. 
18		[Laughter] 
19		Actually, I had a colleague who used to do that.  

20	When he got up to speak he would take a Lifesaver and put it 
21	in his mouth, and he timed it just perfectly so that when
22	the Lifesaver was all dissolved, then he was over his talk.  
23	He never spoke over that until one day he reached in his 
24	pocket and pulled out a dime and talked too long. 
25		[Laughter] 

			228 1		Dr. Wade had another comment she wanted to make. 
	2	Is she here? 
	3		DR. WADE:  This actually falls under public 
	4	comment as opposed to my other role here, and it is just a 

	5	very brief comment.  In New York State, I think there is an 
	6	urgent need for additional rapid HIV tests for use in the
	7	labor, delivery and newborn setting. 
	8		The New York State Department of Health is 

	9	actively pursuing an application with the CDC for a 
10	treatment use IDE for access to three rapid HIV tests.  FDA 
11	has recommended the treatment IDE mechanism to meet New
12	York's urgent need for rapid tests in the perinatal setting, 
13	however, the treatment IDE is a research mechanism that 
14	invokes another set of requirements to be met by each of the 
15	160 birth facilities in New York State, including IRB 

16	approval and single-project assurances.  This will be
17	exceedingly cumbersome and will likely delay implementation 
18	for more than a year.  It would delay identification of as 
19	many as 200 HIV positive women, and the lack of two rapid 
20	tests would result in the unnecessary treatment of as many 
21	as 50 infants who would be false positive on the single test
22	now available. 
23		We feel that available data support the 
24	sensitivity and specificity of these tests, and have 

25	confidence in their use when used in combination.  All rapid 

			229 1	tests performed during labor and deliver in New York would
	2	still be confirmed by ELISA and Western Blot.  We feel that 
	3	the tests should be approved, and could be approved in the 

	4	same time frame that the treatment IDE could be implemented.  
	5	Our Health Commissioner, Dr. Antonio Novello, has submitted 

	6	two letters to the FDA, encouraging them to accelerate their
	7	approval process, and I just wanted to take a moment to kind 
	8	of reiterate that. 
	9		DR. HOLLINGER:  Thank you, Dr. Wade.  Dr. 
10	Chamberland? 
11		DR. CHAMBERLAND:  Actually, Blaine, I am just
12	checking up on you.  You asked Rob Janssen three questions 
13	and I believe he answered two of the three, and I actually 
14	wanted to ask him if he would elaborate a little bit on the 
15	second question.  If I can paraphrase your question, it went 
16	along the lines of just because rapid tests might be

17	licensed, what would cause us to believe that the 
18	approximately 200,000 infected individuals in this country 
19	who do not know their status would then seek to be tested?  
20	My understanding, and Rob can amplify on this, is that the 
21	rapid assay is only one component of a much larger strategy
22	that would allow public health agencies to be much more 

23	proactive in trying to go out and find these individuals. 
24		DR. JANSSEN:  The idea behind the use of rapid 

25	testing -- I think there are a couple of things behind it.  

			230 1	One, in studies we have done, asking people about getting

	2	testing in publicly funded facilities, they prefer rapid 
	3	testing, which will probably increase the acceptance of 
	4	rapid testing in those facilities. 

	5		But I think what we really see is expanding the 
	6	availability of testing, and that expansion is through the
	7	use of these of tests in mobile vans, for example, by 

	8	community-based organizations, at Gay Pride parades, in bath 
	9	houses, in places where people at high risk for HIV 
10	congregate, in addition to which I had mentioned routine 
11	screening, routine voluntary testing in emergency rooms, and
12	high prevalence hospitals, and other high prevalence medical 
13	settings.  Those are settings where people are going in for 
14	some other problem. 
15		Again to use the New York University Hospital 
16	emergency room, a high proportion of the neighborhood
17	injecting drug users get their primary care in that 
18	emergency room, and men go to that emergency room at least 
19	once every 18 months; women use it about, I think, twice a 
20	year.  It is a real opportunity if you offered routinely to 
21	everybody coming through the door an HIV test.  There is
22	going to be a number of people whom you are going to 
23	identify as positive who didn't know they were at risk. 
24		We have a couple of studies, and Bernie and I were 
25	just talking about them also -- we have a couple of studies 

			231 1	looking at this.  Carlo del Rio is doing it at Grady
	2	Hospital where he has increased from 4 percent to 35 percent 
	3	the acceptance of HIV rapid testing at Grady.  They have 
	4	doubled the number of HIV-infected people they have 
	5	identified.  It is only from 4 to 8; it is a small pilot 
	6	project but they are identifying more people.  We are doing
	7	a similar type of study. 
	8		The other is to work with correctional facilities.  
	9	Again, it is difficult by voluntary testing, increased 
10	voluntary testing in correctional facilities where you are 
11	likely to find a large proportion of infected people who
12	don't know their status. 
13		So, it is really not just living within the 
14	current publicly funded counseling testing system, it is 
15	really expanding that and going way beyond it. 
16		DR. HOLLINGER:  Are you looking at something like
17	this in the future like a home test kit as well, or if 
18	somebody is going to have sex with something else they are 

19	going to look at this and do this test on their own to find 
20	out if their partner may be infected?  Is this where this is 
21	going?
22		[Laughter] 
23		DR. JANSSEN:  Can I give my personal opinion?  

24	This is not a CDC opinion, this is a personal opinion.  
25	There are some data that Vina Verghesi and our group at CDC 

			232 1	has been looking at and modeling, looking at risk behavior,
	2	whether the partner is infected, the different sexual 
	3	behaviors and condom use, and which of these are the most 
	4	important in predicting transmission of HIV, what increases 
	5	the probability of transmission of HIV in any sex act.  It 
	6	is clear the thing that drives it the most is serostatus. 
	7	So, if somebody tests negative or is recently negative, then 
	8	the sexual behavior or condom use becomes less important in  
	9	those circumstances. 
10		I think this is an area that we are beginning to 
11	talk about.  I think it is going to require a lot of hard
12	thinking.  It is going to require some very sophisticated 
13	prevention messages.  Whether or not this is where we need 
14	to go, I don't know.  I think there is potential benefit to 
15	it, but I think there are also some real potential dangers 
16	as well that I think really need to be explored very
17	carefully.  I mean, these tests offer that opportunity but 
18	whether it will go there, I don't know. 
19		DR. HOLLINGER:  Thank you for your candid 
20	comments.  Yes, Dr. Epstein? 
21		DR. EPSTEIN:  On the same question, Blaine, the
22	issue of whether FDA would approve a home-use test was first 
23	raised in the late '80s.  Initially there were policies 
24	promulgated which required professional use tests in medical 
25	settings, venipuncture samples etc.  This was a Federal 

		233 1	Register notice in 1989.  Then, as the technology for blood
	2	spots emerged, we ultimately relaxed that policy and 
	3	permitted the home sample collection test system with mail 
	4	order testing, performed in clinical laboratories and, 

	5	although the results were provided confidentially and 
	6	anonymously, they were provided with counseling by a live
	7	individual. 
	8	          There is, to my knowledge, no formal policy 
	9	position by the FDA that would preclude a home-use test.  
10	However, we do have policies that have been published, 

11	guidances from the Center for Devices and Radiological
12	Health which generally review the considerations applicable 
13	to an OTC, or over-the-counter, diagnostic test, medical 
14	diagnostic.  It shouldn't surprise anyone that these 
15	guidances suggest that there ought to be a very high level 
16	of concern both about the accuracy of lay use and also the
17	ability to properly handle the medical information, 
18	including limitations to the ability to be referred to the 
19	medical system. 
20	          So, think that these would be very serious 
21	concerns.  I agree with Rob that the technologies, in and of
22	themselves, could potentially permit this as the methods 

23	become simpler and simpler.  But, one has to look very 
24	critically about the circumstances of use and ask whether it 
25	is or isn't in the larger public health interest to enable 

			234 1	people to test themselves and get results in the home or, I
	2	should say, in the workplace without the benefit of any 
	3	medical interface whether at the laboratory control level, 
	4	whether at the operator training level, or whether at the 
	5	counseling and referral level, and I think that those would 
	6	all be matters for very serious scrutiny.
	7		DR. HOLLINGER:  Yes, Dr. Schmidt? 
	8		DR. SCHMIDT:  We have on our list an FDA position 
	9	on labeling.  The first ELISA test was labeled, as I 
10	remember it, for blood donor use only and, of course, people 
11	used it for many other things.  So, if there is a position
12	on labeling, if these rapid tests come into being would they 
13	be labeled not for blood bank use or not for home use?  That 
14	is one question. 
15		The other question is if they are so good, why 
16	wouldn't they be allowed for blood bank use?
17		DR. EPSTEIN:  First of all, would they be labeled 
18	restrictively?  They would be labeled for intended use in 

19	healthcare settings by properly trained individuals.  In 
20	other words, they would not be labeled as over-the-counter 
21	products.  They would not be available for sale over-the-

22	counter.  In other words, they would have to be distributed 
23	through medical distribution channels analogous to other 

24	medical devices, and there would be oversight that they 
25	would be used with properly trained individuals.  In other 

			235 1	words, the operators would have to meet some kind of
	2	training criteria as established by the product sponsors. 
	3		Now, on the question of whether they could or 
	4	should be labeled as donor screens, that depends on whether 
	5	the sponsor seeks that label.  If the sponsor seeks that 
	6	label, then the FDA's response would be that that test needs
	7	to show equivalence to previously licensed donor screens, 

	8	and we would hold it to a higher performance standard than 
	9	what we have proposed for approval as general medical 
10	diagnostics. 
11		So, it is not that the FDA is saying that they
12	can't be so labeled.  Indeed, some of these products 
13	potentially could perform sufficiently well to be donor 

14	screens.  But, we do think that they should then meet a 
15	standard of comparability. 
16		Now, having said that, it is not just the
17	performance characteristics that enables a test to be a 
18	routine donor screen.  It also has to be capable of very 
19	high throughput and with an objective readout.  In other 
20	words, we don't want to promote in the routine donor 
21	screening environment systems that can't handle, you know,

22	thousands of samples and don't produce hard, objective data 
23	as the readout. 
24		So, the way we have labeled rapid tests when used 
25	for blood donor screening is that they are suitable for use 

			236 1	only when the routine ELISA is either unavailable or
	2	impractical.  That is the label that was put both on the 
	3	Murex SUDS and the Cambridge Bioscience Recombigen.  Use in 
	4	that manner has occurred but has been infrequent, as might 

	5	be expected. 
	6		DR. HOLLINGER:  Miss Knowles?
	7		MS. KNOWLES:  Getting back to your question, 
	8	Blaine, about other potential uses in terms of a home-test 
	9	kit, I am going to say that I really think what Jay just 
10	said about training by providers of this test, even 

11	expanding to the potential SUDS that Dr. Janssen is
12	suggesting, you still have to have trained people to do it. 
13		Further, federal rules of 1997 require partner 
14	notification of all HIV-positive people.  So, in our current 
15	setting right now, counselors have to encourage; they have 
16	to help make sure -- they don't have to actually do follow-
17	up but they have to make sure that that person who is HIV 

18	positive is actually willing to go, seek and find and 
19	disclose.  How can you follow that up in a home-test kit?  
20	It is very difficult. 
21		DR. HOLLINGER:  Thank you.  I am going to move to
22	the rest of the public hearing today.  We have about three 
23	or four companies who want to talk.  The first one is from 
24	Abbott Laboratories, and this is Bill Murray. 

25		    Open Public Hearing (Continued) 

			237 1		MR. MURRAY:  Thank you very much.
	2		[Slide] 
	3		I am Bill Murray.  I am the product manager for 
	4	Determine, and we have been asked by the FDA to come, speak 
	5	to the committee today to outline our rapid HIV device, 
	6	which is currently sold outside of the U.S., called
	7	Determine. 
	8		[Slide] 
	9		In coming here today, the real goal was to be able 
10	to provide a general overview of what the product is all 
11	about and how it is being used in various countries around
12	the world.  When we set out to build Determine, and we 
13	launched the product in 1998, we spent a great deal of time 
14	meeting with potential customers and in different healthcare 
15	settings around the world, with the simple goal of building 
16	a product that would provide HIV results to more people
17	faster.  With that basic premise under way, we wanted to 
18	make sure that we had a product that would certainly fit the 
19	needs in places that we would consider to be developing, but 
20	certainly that would offer a quality product that people 
21	could feel comfortable with the results.
22		[Slide] 
23		So, these are some of the very basic things that 
24	we set out to do and that Determine offers.  We have a 
25	product that does detect HIV-1 and 2 and subtype O, that is 

			238 1	flexible and it is sample typed, especially including whole
	2	blood and that can be done with finger sticks, as some of 
	3	the previous presentations outlined today.  Ease of use and 
	4	fast results, as we would determine them, were something 
	5	that we wanted to make sure we could deliver in a product. 
	6		One of the other interestingly important things
	7	that we found was the stability of the product to be used in 
	8	various settings around the world.  We find that the product 
	9	is used a great deal in very extreme environmental 
10	conditions where temperature is a real issue.  So, we are 

11	shipping product now that is stable for up to 15 months, and
12	in some cases more, with some pretty extreme environmental 
13	conditions. 
14		But one of the other things we did not want to 
15	lose sight of is to make sure that the product did perform 
16	as well as those methods that were used in settings around
17	the world, both in a rapid format in some cases as well as 
18	ELISA tests that were used in certain parts of the world. 
19		So, as I said, the product was launched in	1998.  
20	It is being used in approximately 100 countries around the 
21	world, and this would be both in what we would consider

22	developing as well as industrialized nations around the 
23	world, which would include Germany, France, Brazil, Japan 
24	etc.  So, the product has turned out to be a product that 
25	really exceeded our expectations from a performance 

			239 1	standpoint, and it has been very well received by
	2	industrialized nations around the world. 
	3		It is being used in a number of cases with UNAIDS 
	4	and UNICEF, and a number of other international relief 
	5	organization that we continue to work with on an ongoing 
	6	basis.  The bottom point is that we have recently started to
	7	sort of look at how many tests are being used around the 
	8	world, and we have had well over ten million of these tests 
	9	used in diagnostic settings around the world.  So, just 
10	looking at the sheer numbers that have been used, it has 
11	gotten quite a good reception in its use.
12		[Slide] 
13		I wanted to just sort of pool some data from 
14	published studies that have been done.  By no means is this 
15	inclusive and you have seen a number of other pieces of data 
16	from Determine that were presented earlier today, but I

17	wanted to pool the published studies that really lend 
18	themselves to fresh sample testing.  We have spent a lot of 
19	time and effort in making sure that we optimized Determine 
20	for fresh whole blood testing, which was really the goal of 
21	the product.  If we couldn't deliver a whole blood result,
22	that really defeats the purpose of rapid testing.  So, we 
23	wanted to make sure that, no matter what we did, we had a 
24	product that could do that very well, and to speak to some 
25	of the data that you have seen on Determine. 

			240 1		I think it is important to remember that, at least
	2	in this kit's case, fresh sample testing is very important.  
	3	When you start looking at stored samples and things that 
	4	have been freeze-thawed more than a few times, you do start 
	5	to defeat the purpose of your rapid kit.  So, we have 
	6	clearly optimized it for running fresh whole blood.
	7		As you can see, I have put up what we have as the 
	8	current package insert for the kit that is sold outside the 
	9	U.S.  We did the studies in Vietnam and Thailand.  We wanted 
10	to go to those places where we would be selling the kit and 
11	we wanted to make sure it was in the field, using samples
12	that would ultimately be run on the test, once approved. 
13		So, as you can see, we had very good performance 
14	on whole blood which, again, was our primary goal.  I have 
15	also put up the World Health Organization recommendation -- 
16	Determine now appears in the WHO book -- and corresponds to
17	the CDC study done in Malawi. 
18		[Slide] 
19		Additional studies highlight the use of whole 
20	blood and its performance versus serum plasma.  As you can 
21	see, I have focused on the studies that were primarily done
22	outside the U.S. exclusively.  I think you have seen enough 
23	CDC numbers to show that the product is being used in their 
24	studies within the U.S.  But the people who are actively 
25	using the product outside the U.S. are seeing the same sorts 

				241 1	of results.  As you can see, they are very, very good.  So,
	2	we are very proud of the test. 
	3		That is it.  Are there any questions for me at 
	4	this point? 
	5		DR. HOLLINGER:  Any questions? 
	6		[No response]
	7		MR. MURRAY:  Thank you. 
	8		DR. HOLLINGER:  Thank you.  The next speaker is 
	9	from Bio-Rad Laboratories, Scott Dennis. 
10		MR. DENNIS:  Good afternoon.  My name is Scott 
11	Dennis, and I am manager of regulatory and quality assurance
12	for Bio-Rad, formerly Genetic Systems Corp.  We currently 

13	manufacture and distribute HIV-1, HIV-2, HIV 1/2 and 
14	hepatitis B surface antigen licensed test kits.  And, we 
15	appreciate the invitation from FDA to speak today, and to 

16	present a brief overview of the Multispot HIV-1, HIV-2 rapid
17	test kit. 
18		[Slide] 
19		This test kit is a membrane-based enzyme 
20	immunoassay for the detection and differentiation of HIV-1 
21	and HIV-2 antibodies in human serum or plasma.  This rapid

22	HIV test kit was initially developed by Dr. Patrick Coleman, 
23	in the 1990s, under the name of Genie.  The Genie rapid test 
24	kit as extensively studied by CDC and other groups both 
25	within the U.S. and other parts of the world.  The 

			242 1	technology was then transferred to Sanofe Diagnostics
	2	Pasteur, now also Bio-Rad, facilities in France, where it 
	3	continues to be manufactured and distributed to various 
	4	countries around the world under the name Multispot. 
	5		[Slide] 
	6		The principles of the Multispot test kit are as
	7	follows: microscopic particles are individually coded with 

	8	antigens specific for HIV-1 and HIV-2.  The microparticles 
	9	are adsorbed onto the reaction membrane of the test 
10	cartridge to form test spots.  That is during the 
11	manufacturing process of course.  Then, for running the
12	test, the patient's sample is diluted in specimen diluent 
13	and added to the test cartridge.  HIV antibodies present in 
14	the sample will bind to the antigens on the membrane. 
15		[Slide] 
16		Then conjugate is added to the test cartridge and
17	will bind to antigen antibody complexes on the membrane.  A 
18	development reagent is added, and purpose color develops on 
19	the test spots and control spot where antibody has bound.  

20	The appearance and location of colored test spots determines 
21	if the sample is reactive for HIV-1, HIV-2, both HIV-1 and
22	HIV-2 or neither. 

23		[Slide] 
24		This slide shows the Multispot membrane 
25	configuration.  You can see that spot 1 is designed as the 

			243 1	reactive control spot.  Spot 2, in the lower left, contains

	2	an HIV-2 peptide.  Spot 3 contains an HIV-1 recombinant.  
	3	Spot 4 contains an HIV-1 peptide. 
	4		[Slide] 
	5		A little more detail on the spots themselves -- 
	6	spot 1, the reactive control spot consists of an anti-human
	7	IgG from goat source.  Spot 2 consists of a synthetic 

	8	peptide which mimics the immunodominant epitope of the HIV-2 
	9	GP36 transmembrane glycoprotein.  Spot 3 consists of an HIV- 
10	1 enveloped glycoprotein expressed from E. coli, GP41.  
11	Finally, spot 4 consists of a synthetic peptide which mimics
12	the immunodominant epitope of the HIV-1 GP41 transmembrane 
13	glycoprotein.  As noted earlier, each of these four 

14	biological materials are bound to the test cartridge 
15	membrane during the manufacturing process. 
16		[Slide]
17		Quickly, the Multispot procedure -- in step one, 
18	serum or plasma specimen is pre-diluted in a sample diluent 
19	and added to the test cartridge.  Notice that the specimen 
20	is added through a prefilter which is effective in 
21	minimizing specimen flow problems.  At that point, the
22	sample is incubated for two minutes at room temperature. 

23		Step two, the prefilter is removed and 1 ml of 
24	wash buffer is added.  In step 3, 3 drops of conjugate are 
25	added and a second 2-minute room temperature incubation is 

			244 1	performed.
	2		[Slide] 
	3		Step 4 includes a 2 ml wash which involves simply 
	4	filling the cartridge reservoir twice with the wash solution 
	5	that is provided with the kit.  Step 5 requires the addition 
	6	of the development reagent, followed by a 5-minute room
	7	temperature incubation.  Finally, in step 6 the reaction is 
	8	stopped by the addition of 1 ml of stop solution, at which 

	9	point the test result may be read.  It should be noted that 
10	all liquids, including specimen and the kit components, are 
11	absorbed by a pad contained in the cartridge, thereby
12	allowing for easy decontamination and disposal. 
13		[Slide] 
14		Getting on to the Multispot assay interpretation 
15	of results, you will recall that spot 1, the spot in the 

16	upper left corner of the cartridge must show color in order
17	for the assay run to be considered valid.  Therefore, the 
18	negative result shown here reflects control spot and no 

19	color in either the HIV-1 spot or the HIV-2 spot.  An 
20	invalid result, shown down here, will have no color in spot 
21	1.  Similarly, any other test result which might show color
22	in any or all of the HIV-1 or HIV-2 spots but no color in 
23	the control spot would similarly be invalid. 
24		This slide also shows the positive results, 
25	including HIV only positives which show color in either or 

			245 1	both HIV-1 spots; the HIV-2 positive which shows color in
	2	the single HIV-2 spot; and finally the HIV 1/2 positive 
	3	results which show reactivity in either or both of the HIV-1 
	4	spots and the HIV-2 spot. 
	5		[Slide] 
	6		The Multispot kit design has been designed to
	7	allow for testing and differentiation of HIV-1 and HIV-2 
	8	through the application of separate HIV-1 and HIV-2 
	9	biologicals to the test cartridge membrane and, as noted 
10	earlier, the reactive control spot provides an indication of 
11	assay validity for every test run.
12		[Slide] 
13		Additional kit design features include a total 
14	incubation time of nine minutes.  The test was also designed 
15	to avoid the requirement for any special equipment such as 
16	incubators and, as noted earlier, the test cartridge
17	contains a prefilter to eliminate specimen flow problems. 

18		Finally, as Bio-Rad does intend to submit a PMA 
19	application to CBER for this product, I wanted to briefly 
20	describe the manufacturing strategy that is employed 
21	currently for Multispot, and let you know that we intend to
22	continue this strategy, initially at least, following PMA 
23	approval. 

24		Again, the HIV biologicals are manufactured in the 
25	licensed Bio-Rad, formerly Genetic Systems Corporation, 

			246 1	facility in Redmond, under the quality systems employed for
	2	our licensed test kits.  The cartridges and other kit 
	3	reagents are manufactured by Bio-Rad in Les Ulis, France.  
	4	This Les Ulis facility holds an FDA license for the 
	5	manufacture of blood typing reagents and has, to date, 

	6	undergone multiple FDA CBER inspections.  So, we would
	7	intend that the final kit would be tested and released at 
	8	that facility. 
	9		In summary, Bio-Rad intends to submit a PMA to 

10	CBER to obtain approval to market Multispot as a diagnostic 
11	test kit in the U.S.  Our PMA will include all relevant
12	chemistry manufacturing and control information, and also 
13	data from previous European studies, as well as data from 
14	studies conducted by multiple U.S. sites will be submitted 
15	in support of approval. 
16		[Slide]

17		I briefly have some data -- you have seen a lot of 
18	data done by CDC people, the Army people, but we also 

19	submitted this product in France, and here is a brief 
20	summary of some seroconverted panels.  As you can see, the 
21	number in each case represents the number of days from the
22	first bleed at which the sample was first detected as 

23	positive by each test.  Just for your information, the 
24	Genelavia test refers to an indirect ELISA which was 

25	approved for blood screening in France at the time of the 

				247 1	study, and the Western Blot data are taken from the
	2	seroconversion panel data from the manufacturers.  
	3	Basically, you can see at this point basic equivalence 
	4	between Multispot and the ELISA. 
	5		[Slide] 
	6		Finally, we also have some specificity data in a
	7	European study, 4230 normal donors.  Fresh and frozen plasma 
	8	and serum.  Six were initial and repeat reactive, for a 
	9	specificity of 99.85.  We also did other medical conditions 
10	for cross-reactivity, 144 samples from a variety of non-HIV 
11	medical conditions and zero reactive.  Thank you very much.
12		DR. HOLLINGER:  Thank you, Mr. Dennis. Any 
13	questions?  Yes, Miss Knowles? 
14		MS. KNOWLES:  What year were those studies 
15	conducted, please? 
16		MR. DENNIS:  I believe 1994.
17		DR. HOLLINGER:  Thank you.  The next speaker is 
18	for MedMira, Debrah Lynch and Hermes Chan. 
19		MR. CHAN:  Good afternoon.  I am definitely Hermes 
20	Chan, not Debrah Lynch.  I am a representative for MedMira. 
21		[Slide]
22		I would first like to thank FDA for inviting us to 
23	such an important meeting.  First of all, MedMira is a 
24	Canadian public company.  We are the first and only rapid 

25	HIV test approved by Health Canada for the detection of HIV 

			248 1	type 1, 2 and group O antibodies in laboratory settings.  We
	2	have submitted a full PMA for FDA approval for serum and 
	3	plasma applications, and we have initiated discussions with 
	4	FDA regarding whole blood HIV testing. 
	5		My central point of the presentation today is to 
	6	share the excitement we have about the fact that we have
	7	developed a novel approach to overcome some of the 
	8	limitations of a rapid diagnostic test. 
	9		[Slide] 
10		Obviously, our rapid HIV test shares similar 
11	features with other manufacturers, as you have seen before. 
12	However, to ensure the excellent performance of our test we 
13	have done over 20,000 tests in Canada alone and also over 
14	10,000 tests in the United States to achieve sensitivity and 
15	specificity of over 99.5 percent. 
16		What I would like to share briefly with you is
17	some of the procedures that we have.  This is for our serum 
18	and plasma test.  Basically, we are using a colloidal gold 
19	conjugate which can increase the stability of the test, and 
20	with a few simple steps we can achieve a test showing a 

21	positive with a single dot and a negative with a clear
22	background within less than three minutes. 
23		[Slide] 
24		The second one that I want to share with you is 
25	our whole blood test kit.  The whole blood test kit is very 

			249 1	similar to the serum plasma kit, except that we have a
	2	prefilter system whereby, within a few seconds time, we can 
	3	separate the cells from the serum or plasma. 
	4		[Slide] 
	5		In the past year we have done clinical trials in 

	6	three different locations, and they were all very successful
	7	and I want to share with you some of the results.  We have 
	8	done it in Nova Scotia, in Canada, with 154 real-time 

	9	patients whole blood specimens, with matching plasma, and we 
10	have shown sensitivity of 100 percent. 
11		[Slide]
12		The second studies were done with Newfoundland 

13	Public Health Lab, again in Canada.  Here, we have 145 
14	routine specimens for HIV screening, out of those there are 
15	96 positive specimens, again with matched plasma, and 49 
16	negative.  The same as before, we have an overall agreement
17	with the reference test of 100 percent. 
18		[Slide] 
19		The last one happened in the Bahamas while we are 
20	doing our serum plasma test.  We happened to have 15 in- 
21	hospital patients and again we saw 100 percent sensitivity.
22		[Slide] 
23		You have heard so much about all the wonderful 
24	things concerning rapid HIV tests today, and you can't help 
25	but wonder about what the catch is.  It is too good to be 

			250 1	true, isn't it?  This is a comparison of the routine ELISA

	2	system versus rapid assays.  A rapid assay does provide a 
	3	very unique advantage over the ELISA system in the time 

	4	required to perform the test, as well as the portability 
	5	compared to the ELISA system.  However, there are two 
	6	disadvantages of rapid assays.  One is that it does only
	7	have a subjective readout.  Secondly, it does not have 

	8	computer data storage. 
	9		[Slide] 
10		From MedMira's point of view, this is not a home 
11	test.  Because of this, data storage as well as results and
12	interpretation are a very important features when tests are 
13	not done in a routine, controlled environment such as 
14	clinical laboratories.  As a result, MedMira does not just 
15	introduce a point of care rapid test, we give you a rapid 
16	HIV point of care testing system, and this is what our
17	system looks like.  It is a portable reader that can read 

18	out the result of a rapid test.  The test itself takes about 
19	two minutes to do, and the result to be interpreted by the 
20	reader takes only about two seconds. 
21		[Slide]
22		The interesting thing about this rapid reader 
23	system is that it does have the possibility of including all 
24	the patient information which the software can adapt to the 
25	clinical laboratory so that we can get all the information 

			251 1	directly.
	2		[Slide] 
	3		Negative specimens take about two minutes and does 
	4	offer a graphic interpretation saying it is a negative 
	5	result.  It also gives you numerical values as well as 
	6	written, whether it is positive or negative.
	7		[Slide] 
	8		On top of it, it also is able to provide you with 
	9	the actual image of the test result which is stored in the 
10	database and you can retrieve it any time. 
11		[Slide]
12		With a positive result, it gives you a similar 
13	thing except that now we have a positive graphic 
14	interpretation as well as numerical.  On the right-hand side 
15	we also have the statistical data that you can use for any 
16	statistical analysis.
17		[Slide] 
18		When we look at the comparison using the ELISA 

19	system as well as our Rapid Reader 2000 systems, again we 
20	can see the advantage of the rapid test, as has been shown, 
21	and also we can store our data in the computer, as well as
22	having the test image stored on the hard disc. 
23		[Slide] 
24		I would like to conclude my presentation with the 
25	comment that Dr. Spencer Lee, the Director of Virology, 

			252 1	Public Health Lab of Halifax, Nova Scotia.  He said that the
	2	MedMira rapid test and the rapid readers 2000 have all the 

	3	testing performance characteristics of a test acceptable in 
	4	point of care testing.  I thank you for your patience. 
	5		DR. HOLLINGER:  Thank you.  any questions?  If 

	6	not, we will move on.  The final person who has asked to
	7	speak is Mr. Raymond Smith, for the National Alliance of 
	8	State and Territorial AIDS Directors. 
	9		MR. SMITH:  Hello, and thank you.  I have no 
10	slides and this will be brief.  I am with the National 

11	Alliance of State and Territorial AIDS Directors.  For those
12	of you who are not familiar with us, we represent the heads 
13	of the HIV and AIDS programs in all the U.S. states and 
14	jurisdictions, and that is both in terms of care and 
15	prevention. 
16		On May 18 of this year, we sent a letter from
17	Wendy Craytor, who is the Chair of NASTAD and the AIDS 
18	director from the State of Alaska, and Julie Scofield, who 
19	is the executive director of NASTAD, to the Office of Blood 
20	Research and Review.  We have received a very gracious 
21	reply, and I understand that there is a copy of this letter
22	in the packets that were distributed to the committee.  So, 
23	I will just very briefly read a couple of excerpts which 

24	highlight the position of NASTAD on the question of rapid 
25	tests. 

		253 1	          On behalf of the National Alliance of State and
	2	Territorial AIDS Directors, NASTAD, we are writing to 
	3	request expedited approval of rapid HIV antibody tests by 
	4	the U.S. Food and Drug Administration.  Public health 
	5	agencies and their community partners must have available to 
	6	them a range of testing technologies and approaches to
	7	maximize the number and proportion of clients who are tested 
	8	for HIV and who receive their test results in a timely 
	9	manner.  Rapid testing technologies, in particular, would 
10	contribute to the provision of high quality HIV/AIDS 
11	services responsive to the needs of consumers and providers.
12	          As representatives of the front-line HIV/AIDS 

13	programs in the jurisdictions directly funded by the CDC, 
14	NASTAD members are deeply involved with the full range of 
15	testing issues.  We have been anticipating the availability 
16	of rapid HIV antibody testing for quite some time, and

17	expect that it will have an important positive effect on our 
18	ability to deliver effective HIV counseling, testing and 
19	referral services.  Although we recognize that rapid testing 
20	will require modifications to the existing systems of HIV 

21	counseling and testing, including providing assurances of
22	appropriate confirmatory testing, we believe that it would 
23	not be problematic for us and other providers to implement 
24	such modifications in a relatively short time span.  Given 
25	the demonstrated benefits of early medical intervention in 

		254 1	promoting health and delaying disease progression, as well
	2	as the key role that HIV antibody testing plays in a 
	3	comprehensive approach to HIV prevention, it is critical 
	4	that rapid testing be made available in the U.S. as soon as 
	5	possible.  NASTAD strongly encourages the FDA to expedite 
	6	review and approval of these tests.  Thank you.
	7	          DR. HOLLINGER:  Are there any questions for the 
	8	companies with regard to their tests? 
	9	          I have just a couple of questions and I think this 
10	has probably been done, but I would like to know about a 

11	couple of issues about the various tests, and maybe the
12	companies individually can remark about this.  There are 
13	several things which might cause a false-positive test or 

14	even a false-negative test, and I would like to know if they 
15	have been looked at.  For example, patients who are on 
16	heparin, where there is a very marked charged particle
17	present, has this caused any problems in there.  I would 
18	like to know about jaundice patients.  I would like to know 
19	about hemolyzed samples, patients with hemolytic anemia or 
20	even cirrhotics who have cells which are quite fragile, and 
21	any other charged particles where they might be taking
22	drugs, like the heparin.  I think some of them have looked 
23	at lipids.  But could each one of you at least let me know 
24	if you have looked at all of these things, and whether there 
25	are any problems associated with these particular aspects of 

				255 1	your tests?
	2		MR. BERNSTEIN:  Dave Bernstein, from Guardian 
	3	Scientific.  The Quix test has a prefilter.  Badly hemolyzed 
	4	samples, no problem.  Icteric samples, no problem.  Also all 
	5	the anticoagulants -- we have looked at heparin, EDTA, ACD, 
	6	no problem.  The test is very versatile in terms of samples.
	7		MR. MURRAY:  Bill Murray, with Abbott.  Concerning 
	8	the Determine test, a couple of things -- we recommend EDTA 
	9	in our package insert as an anticoagulant although we have 
10	had studies done to support other anticoagulants.  Our 
11	clinical studies within the package insert show a full array
12	of patient samples that we used, including hematocrit, etc.  
13	We looked at a battery of different sorts of potential 
14	interferences.  So, we did include that and we can certainly 
15	make that available to the committee. 
16		DR. HOLLINGER:  Heparin?
17		MR. MURRAY:  The samples do work using heparin, 
18	yes. 
19		DR. HOLLINGER:  All right.  Yes? 
20		LT. ZAHWA:  Lt. Zahwa, from Walter Reed.  
21	Regarding the comments on hemolyzed samples, in most of the
22	lateral flow devices, the color that develops is a reddish 
23	color and that is the interference substances there such as 
24	the red color in the hemolyzed sample will mask the view of 
25	the reader from that distinct line that might be present.  

				256 1	Some companies have done extensive studies on the hemolysis

	2	effect on the results of the test but the question remains 
	3	whether that reddish background can be distinguished from 
	4	the clear line that the individual reader is looking for. 
	5		DR. HOLLINGER:  Yes, please? 
	6		DR. COLEMAN:  My name is Patrick Coleman.  I am
	7	from Bio-Rad, representing the same test that Scott Dennis 
	8	talked about.  The Multispot test, previously known as 
	9	Genie, has been actually studied around the world for more 
10	than ten years.  It has been very well evaluated with the 
11	same anticoagulants that the other gentleman mentioned --

12	heparin, ACP and other major anticoagulants, EDTA.  Because 
13	it is a flow-through device and not a lateral device, most 
14	anything that is in solution will really not be impacting 
15	the test.  It will go right through the membrane and into 
16	the absorbent cartridge.  So, it will not reside with the

17	test itself. 
18		DR. HOLLINGER:  Thank you.  Yes? 
19		MR. GEORGE:  I am Richard George, from Epitope.  
20	We didn't make a presentation but some data has been 
21	presented about our test.  I would just like to say that we
22	have looked, as I think most people have, at all the 
23	anticoagulants that are frequently used in collecting 
24	samples.  They don't interfere with the test, the OraQuick 
25	test that was presented. 

				257 1		In response to what Lt. Zahwa just said about
	2	hemolysis, our strategy for doing whole blood is that we 
	3	actually lyse the blood but we only add 5 mcl of blood and 
	4	it does not affect the test at all, and the color that is 
	5	generated from the lysing of the blood is really not visible 
	6	on the strip.
	7		DR. HOLLINGER:  Yes, please? 
	8		MR. CHAN:  My name is Chan, from MedMira.  I just 
	9	want to point out that with our product we have extensively 
10	studied the interference, and anticoagulants and everything 
11	is no problem.  However, as with any flow-through device,
12	the only samples that will cause some sort of a problem will 
13	be heavily lipemic specimens.  If there are heavy lipemic 

14	specimens the samples will not filter through the membranes.  
15	That is why the filter system that we put in does help to 
16	improve the sensitivity in that way.
17		       Open Committee Discussion 

18		      Questions for the Committee 
19		DR. HOLLINGER:  Thank you.  We have some questions 
20	but I want to just see if there are any other burning 
21	comments that anybody from the committee would like to make
22	about anything.  If not, why don't we see the questions that 
23	have been put before us?  There are two of them. 
24		The first question is does the committee agree 

25	with the FDA criteria for approval of a rapid test for use 

			258 1	in a diagnostic setting?  Yes, Paul?
	2		DR. SCHMIDT:  It is not really clear to me what 
	3	the question is.  We haven't heard what the problem is, if 
	4	any, with the FDA standards for approval.  What is the issue 
	5	here? 
	6		DR. HOLLINGER:  Paul, are you asking about what
	7	are the FDA criteria for approval? 
	8		DR. SCHMIDT:  Why do they create a problem for the 
	9	licensing of what we have heard about today? 
10		DR. POFFENBERGER:  I want to switch over to the 
11	overhead slide because then I can present to you what we are
12	proposing. 
13		[Slide] 
14		What is happening today is we are proposing to use 
15	a standard that is different from a standard previously used 
16	for licensing of blood screening tests.  We are proposing to
17	allow a test to be approved if it can show that it can meet 
18	the 98 percent sensitivity and specificity standard, which 
19	is that the lower bound of the 95 percent confidence 
20	interval must be at least 98 percent.  For sensitivity, in 
21	addition, we are asking that the test be able to detect 11

22	out of the 11 positive samples on the FDA HIV-1 panel. 
23		So, the difference is a different standard for 
24	sensitivity and specificity.  Now, as you have seen some 

25	data shown today, a lot of these tests, we think, are going 

				259 1	to be able to meet or come very close to the same
	2	sensitivity and specificity that is already out there for 
	3	tests that are licensed.  However, at this point in time we 
	4	don't have a lot of data in U.S. populations.  So, we have 
	5	chosen this point based on the preliminary data that the CDC 
	6	has obtained in studies that they are performing.
	7		Our goal here really is to try and include as many 
	8	of the assays as possible, to do it on a rational basis, 
	9	because we don't know, for instance, with multiple test 
10	algorithms which combinations might prove to be very 
11	beneficial.  So, we felt that based on the data available
12	this would be a reasonable standard for rapid tests. 
13		DR. HOLLINGER:  Yes, Dr. Nelson? 
14		DR. NELSON:  I am not clear about what the 
15	licensure would mean.  In other words, would it mean that 
16	two rapid tests would then preclude the need for a
17	confirmatory assay, or does this mean it would be a rapid 
18	screening test which would then be followed by a 
19	confirmatory assay?  I am not sure what the licensure would 
20	mean. 
21		DR. POFFENBERGER:  That is a good thing to ask
22	about.  Approval, as I said before, will mean the test can 
23	be used in the intended sites.  The users there will be able 
24	to choose how to use it.  Approval will mean we say that 
25	this test meets the standards, is able to be made 

				260 1	consistently.  At this time -- now we are sort of getting
	2	into the second question with your question here, and maybe 
	3	we would want to separate it out.  So, maybe we ought to 
	4	postpone that discussion.  Okay? 
	5		Right now, for this question, we are specifically 
	6	asking does the committee feel that this 98 percent lower
	7	bound is acceptable for these tests for diagnostic use 
	8	settings. 
	9		DR. HOLLINGER:  Based also on the number that are 
10	required for the testing. 
11		DR. POFFENBERGER:  Yes, based upon the sample
12	populations and sizes that are requested. 
13		DR. HOLLINGER:  Yes, Jeanne? 
14		DR. LINDEN:  Other the decrease in the number of 
15	samples that have to be tested, what is the other change 
16	from the present requirement for diagnostic testing for
17	sensitivity and specificity?  You are talking about lowering 
18	the standard? 
19		DR. POFFENBERGER:  The current blood screening 

20	tests, the lowest one for sensitivity out there has a 99.2 
21	percent but the ones that are commonly used are typically
22	performed at 99.9 percent levels. 
23		DR. HOLLINGER:  Is that a requirement?  I think 
24	maybe what Dr. Linden was asking is, is that a requirement 
25	now for licensure of those particular tests which are 

			261 1	currently out there, that they be at least 99 percent, or
	2	are the same -- 
	3		DR. POFFENBERGER:  No, we are not changing any 
	4	standards for licensing of screening tests.  This pertains 
	5	only to approving, under the PMA setup, diagnostic use tests 
	6	-- if that is the question.
	7		DR. HOLLINGER:  Yes, Dr. Epstein? 
	8		DR. EPSTEIN:  If I could also clarify, part of the 
	9	issue is operational because we approve new donor screening 
10	tests by requiring that in clinical trials they be shown to 
11	be equivalent.  The statistical equivalency standard is a

12	more rigorous standard and it drives the requirement for 
13	larger trials.  Additionally, we have had a more stringent 
14	requirement for showing geographical distribution of the 
15	samples.  We have placed more emphasis on prospective 

16	studies under clinical use conditions, and we have had
17	requirements for HIV-2 sensitivity.  We have also requested 
18	that tests meet standards for HIV-1 group O sensitivity, 

19	although that is evolving for the donor screens.  So, we 
20	have also eliminated all of those requirements except if a 
21	product sponsor wishes to make a specific claim for HIV-2

22	sensitivity or group O sensitivity.  So, we waived that as a 
23	trial requirement or validation requirement. 
24		Additionally, coming back to Paul Schmidt's basic 
25	question, why is there an issue here; why are we bringing 

			262 1	this?  Of course, we hope there is not much at issue in your
	2	minds and you will concur.  But the reason we are bringing 
	3	this is because there are those who have stated that FDA has 
	4	set the bar too high and that we are, therefore, impeding 
	5	the development of these technologies for use in the United 
	6	States.  We don't believe we have set the bar too high.  We
	7	believe that we have asked for the least burdensome 
	8	validation consistent with tests that we think will be 
	9	sufficiently accurate for the proposed use.  But the 
10	underlying question is has the FDA set the bar too high? 
11		DR. HOLLINGER:  Yes, Col. Fitzpatrick?
12		COL. FITZPATRICK:  I guess maybe I am being a 
13	little dense this afternoon but I don't understand, relative 
14	to sensitivity and specificity in paragraph (b) there, in 

15	relationship to Jay's last comments where is the bar now?  
16	You said tests are functioning at 99.9 percent but what is
17	the bar? 
18		DR. HOLLINGER:  I guess I would say the same 

19	thing, if a test came in today to be licensed for donor 
20	screening and fit these criteria, would it be licensed -- 
21		DR. EPSTEIN:  No, but the strategy for getting
22	there isn't the same.  See, in this case we have said the 
23	standard is a sensitivity and specificity determined from 
24	the point estimate of the clinical trial plus statistical 
25	analysis.  For the donor screens the standard is defined 

				263 1	operationally.  We are saying do a head-to-head trial with a
	2	licensed test and prove that it is equivalent -- not even 
	3	not inferior; it has to be proven equivalent with 
	4	statistical rigor.  John is nodding because he knows what I 
	5	am saying statistically.  It is not the same standard.  Now, 
	6	if you ask me what is the statistical statement of the
	7	operational standard, it would be higher than this.  I mean, 
	8	I haven't computed it so I can't answer the question but it 
	9	would be higher than this. 
10		DR. HOLLINGER:  Thank you.  Any other questions 
11	before we vote?  Yes, Dr. Mitchell?
12		DR. MITCHELL:  Again, when you are talking about 
13	the sensitivity and specificity of the standard, that is for 
14	one test, is it not? 
15		DR. POFFENBERGER:  That is for each individual 
16	test to be approved, yes.
17		DR. MITCHELL:  So, that, again, makes it much 
18	higher than if you are repeating it twice or three times -- 
19	repeating it once or twice. 
20		DR. POFFENBERGER:  It is possible that it could 

21	be.  It would depend on the data from doing repeat testing
22	but, yes, maybe. 
23		DR. HOLLINGER:  In fact, that is a good point.  I 
24	guess the question is, is this based on repeatedly positive 
25	tests or just based on a single one? 

			264 1		DR. POFFENBERGER:  The use of the test is
	2	primarily under the trials and what has been proposed, that 
	3	I have been aware of, for testing by individual rapid test - 
	4	- it is a single use; a single result.  There are instances 
	5	where a secondary or repeat result is recommended. 
	6		DR. HOLLINGER:  So, it depends on how they come in
	7	and ask for it, but if they come in and they say these are 
	8	based upon a single test -- 
	9		DR. POFFENBERGER:  If the clinical data will show 
10	that it meets the standard, then we are proposing that they 
11	can be approved.
12		DR. HOLLINGER:  All right.  Thank you.  All right, 
13	if that is the case, then we will vote on the question.  
14	Based on these criteria, does the committee agree with the 
15	FDA criteria for approval of a rapid test for use in a 
16	diagnostic setting, as described herein?
17		All those that agree with that and vote yes, raise 
18	your hand. 
19		[Show of hands] 
20		All those opposed, voting no? 
21		[No response]

22		Abstaining? 
23		[One hand raised] 
24		And, Mrs. Knowles? 
25		MS. KNOWLES:  Yes. 

				265 1		DR. HOLLINGER:  And, Dr. Simon?
	2		DR. SIMON:  Yes. 
	3		DR. SMALLWOOD:  The results of voting for question 
	4	number one, there were 14 "yes" votes.  There were no "no" 
	5	votes; one abstention.  Both the consumer and industry 
	6	representative agreed with the "yes" votes.  There are 15
	7	members that are qualified to vote on this issue. 
	8		DR. HOLLINGER:  Thank you.  Now we will go to the 
	9	second question.  Again, I think we will probably have to 
10	have some additional information, if we could.  Does the 

11	committee agree with the FDA approach to labeling rapid
12	tests?  Would you like to go ahead and tell us what the 
13	approach is that you have up there? 

14		DR. POFFENBERGER:  What you are seeing in front of 
15	you is the proposed labeling.  The first statement, for use 
16	as an aid in diagnosis, is what is our current practice. 
17	The second statement is really what we are looking for input 
18	on, which is that this test may be used as part of a 
19	multiple test algorithm.  What we are proposing is that when 
20	a test is approved, based on its individual merits, meeting 
21	that 98 percent sensitivity and specificity standard, we
22	will also be putting the statement in the labeling that will 
23	in specific testing settings allow the use of the test in 
24	multiple rapid test algorithms. 
25		DR. HOLLINGER:  So, Dr. Poffenberger, what you are 

			266 1	asking from the FDA standpoint is that where these other
	2	tests are not feasible, supplemental tests, confirmatory 
	3	tests, you could use it but in a multiple algorithm of some 
	4	sort. 
	5		DR. POFFENBERGER:  Yes, that is correct. 
	6		DR. HOLLINGER:  Dr. Boyle?
	7		DR. BOYLE:  My question is related to the last 
	8	part of the second labeling, which says in settings with the 
	9	use of an approved supplemental test for HIV antibodies is 
10	impractical or infeasible prior to patient counseling.  My 
11	question is are people going to interpret that the same way? 
12	I mean, is one emergency room going to say yes and another 
13	no?  I mean, what exactly -- I know what you are intending 
14	it to say, but what does it say? 
15		DR. POFFENBERGER:  Well, I think you are probably 
16	correct, it won't be interpreted in quite the same way by
17	everyone.  What we are trying to do is open the door to meet 
18	the needs that you heard of before.  We are trying to do 

19	that without imposing a lot of burdensome requirements for 
20	submission of data that is going to become exponential as 
21	the different tests overlap.  We want to allow individuals
22	at testing sites to be able to design their algorithms. 

23		We are hoping, and I believe it is being planned, 
24	that recommendations will be issued, Public Health 
25	recommendations will be issued on the basis of studies, and 

			267 1	that these recommendations would be then available to the

	2	users in the settings that you have heard described.  So, 
	3	that is sort of the approach. 
	4		DR. HOLLINGER:  Dr. Poffenberger, I am a little 
	5	confused about this in some respect because, in the first 
	6	place, I thought the object was that when you saw somebody

	7	for the first time in a setting and you do this test, you do 
	8	it while they are there so you could counsel them.  But now 
	9	what this essentially is indicating, at least to me, is that 
10	it requires a supplemental test before you can do the 
11	counseling.  It says "prior to patient counseling" which
12	would mean you would then have to either do two tests to get 
13	to that point or you would have to have another supplemental 
14	test, or do something to get to that point. 
15		DR. POFFENBERGER:  It is not intended to mean 
16	that.  What it is intended to do is to allow the use of the
17	algorithm to increase the accuracy.  With the overlapping 

18	test algorithms you might be able to tweak your specificity 
19	up a good bit higher so that when you do give the results 

20	there on site, you can essentially counsel them that this is 
21	your serostatus.  At this point in time, the current
22	recommendations for the sample to be further tested by the 
23	Western Blot as a confirmatory will still remain in place.  
24	These recommendations are still in place. 
25		DR. HOLLINGER:  Yes, Dr. Chamberland? 

			268 1		DR. CHAMBERLAND:  I guess that is my question
	2	somewhat, and maybe I could ask Rob Janssen or others to 

	3	elaborate on this, if in a clinical setting you are using 
	4	only one of these rapid assays and it is positive, is the 
	5	individual then going to be counseled or should there be a 
	6	supplemental test performed, a Western Blot supplemental
	7	test performed? 
	8		DR. JANSSEN:  [Comment away from microphone; 
	9	inaudible.] 
10		DR. CHAMBERLAND:  But in the same clinical 
11	setting, if there are data that have been developed that

12	demonstrate that two or more of these rapid assays are as 
13	good as an EIA and a Western Blot, or better, then you would 
14	still have to proceed to a traditional Western Blot, or does 
15	this labeling allow you to eliminate the need for a Western 
16	Blot?  I just wanted some clarification on that.  Rob, you

17	indicated that CDC is developing these revised testing and 
18	counseling guidelines that are trying to incorporate the 
19	probability of rapid assays being available. 

20		DR. JANSSEN:  The way we have looked at the rapid 
21	test algorithms is as a replacement for Western Blot, as a
22	replacement for EIA and Western.  In terms of this, I think 
23	it is incumbent upon the Public Health Service to develop 
24	those algorithms and publish guidance for those algorithms, 
25	as we have done in the past. 

			269 1		DR. HOLLINGER:  Dr. Epstein?
	2		DR. EPSTEIN:  Yes, it is not really an FDA 
	3	question.  When we approve a test as a diagnostic, that test 
	4	approval doesn't imply what you do next.  The recommendation 
	5	for performance of supplemental testing prior to counseling 
	6	is a PHS recommendation, which I think has been on the books
	7	since about 1989.  I think that the concept of validating 

	8	the preliminary test result remains necessary.  In other 
	9	words, nobody really wants unconfirmed results reported. 

10		The distinction that is being made here is between 
11	confirmation through supplemental testing and, if you will,
12	improvement of accuracy on a statistical basis by performing 
13	multiple tests with essentially similar technology.  When we 
14	have approved supplemental tests, the concept has always 
15	been that there is what is called an orthogonal method.  In 
16	other words, the nature of the signal is different than what
17	you did with the first test.  Those differences can arise 

18	because of differences in format or differences in the 
19	underlying principle of the test.  For example, the Western 
20	Blot operates on a different principle than the EIA because 
21	it separates the antigen and enables you to see the signal
22	independent of the surround.  So, the concept of 
23	confirmation through supplemental testing is that on each 
24	and every individual sample tested it yields a definitive 
25	result, whether it is a true positive or a false positive. 

			270 1		Now, the concept that is being put forward here is
	2	a little bit different.  The concept is that the accuracy 
	3	can be increased on the basis of test concordance which is, 
	4	therefore, a statistical validation of accuracy.  What has 

	5	been argued, based on experience and mainly the studies in 
	6	Africa, is that the two test method using rapid diagnostics
	7	can produce in the end results that are, on average, as 

	8	accurate as with confirmatory testing.  But that would never 
	9	be known with the same degree of certainty as if one had 
10	come back and tested with an orthogonal method. 
11		So, what we are saying here is we are faced with a
12	situation in which we believe, based on the available data, 
13	that the accuracy of reported results can be significantly 
14	increased by using multiple independent diagnostics, each of 
15	which is, as it were, a preliminary test or a screening 

16	tool, although we don't label it for screening because by
17	that we mean donor screening. 
18		So, it is a rapid diagnostic.  No one of them is 
19	definitive in its own right.  Because it is useful to 
20	combine them, we think we should move in that direction.  
21	But we don't want to find ourselves in the position where we
22	don't allow it without sending manufacturers out to 
23	collaborate with each other, or having clinical 
24	investigators study all the possible test combinations and 
25	then bring the data to the FDA.  FDA thinks that if we can 

			271 1	set a high enough standard for the individual tests, then we
	2	shouldn't have to entertain applications for all the 
	3	possible combinations. 
	4		So, what we are asking the committee is do you 
	5	concur that if we have put the approval standard is place, 
	6	we can then let the tests be labeled as suitable for use in
	7	multiple testing algorithms without the FDA reviewing trials 
	8	for those combination algorithms?  We do envision that such 
	9	trials will be done, and we do envision that guidance will 
10	be published by the Public Health Service on optimal 
11	combinations, such as choice of the test sequence; such as,
12	you know, true hits; is it positive or best out of three; or 
13	test sequence proposals, particular test followed by a 

14	particular test.  We do think that guidance of that sort 
15	will be necessary.  We just don't think it should rise to 
16	the level of FDA approving every such combination and every
17	such algorithm.  So, we are asking whether you concur with 

18	generically labeling the tests as suitable to be combined to 
19	improve accuracy on a statistical basis. 
20		DR. HOLLINGER:  Yes, go ahead, Paul. 
21		DR. SCHMIDT:  Unless this is defined some place

22	else, to me, a multiple test doesn't necessarily mean use 
23	two different reagents.  It could mean you do the same test 
24	twice.  Is that defined some place else, what a multiple 
25	test algorithm is?  Is it really two different manufactured 

					272 1	products?
	2		DR. HOLLINGER:  There was data, I think, presented 
	3	in the material that was handed out that did suggest that if 
	4	you combine the test and you use as your first test the most 
	5	sensitive test, and then combined it with a more specific 
	6	test at the end, that this would be comparable to or close
	7	to perhaps the EIA and the Western Blot -- 
	8		DR. SCHMIDT:  I agree, but the requirement doesn't 
	9	say that. 
10		DR. HOLLINGER:  No, it doesn't. 
11		DR. SCHMIDT:  So, is that the right label?
12		DR. HOLLINGER:  If I understood what you said, Dr. 
13	Epstein, you said that you may not require -- and I agree 
14	with you, we don't want to get into should you combine this 
15	test with that test; I don't think that is what we should be 
16	talking about, but I do think there needs to be some
17	requirement because someone could combine a less sensitive 
18	test with another test and end up with some erroneous 
19	results on that basis.  Yes, Dr. Simon? 
20		DR. SIMON:  I think we need to keep in mind the 

21	difference between licensing a test and approval process as
22	a diagnostic.  When a test is licensed, licensed 
23	organizations like blood and plasma organizations have to 
24	follow exactly the instructions.  But as I understand it, 
25	this test will have labeling that will indicate something 

			273 1	but once it gets out in the public health arena it will be
	2	used as directed by appropriate physicians and 
	3	professionals.  So, I think that the agency is trying to 

	4	give the flexibility that the public health professionals 
	5	have requested to be able to use these rapid tests in a 
	6	situation that would be helpful to them.
	7		DR. HOLLINGER:  Yes, Dr. McCurdy? 
	8		DR. MCCURDY:  My question is why does the label 
	9	have to say anything about multiple tests?  Why can't it 
10	just say for use as an aid in diagnosis and let the 
11	guidelines that are in preparation, I guess, deal with how
12	you should use them? 
13		DR. HOLLINGER:  Dr. Macik? 
14		DR. MACIK:  I had the same question, and I would 

15	like to ask currently, do the tests that are being used for 
16	diagnosis have on their labeling that you have to do the

17	second supplemental test?  Or, is that being done only as 
18	part of the guidelines from the Public Health Service? 
19		DR. POFFENBERGER:  It is being performed as part 
20	of the guideline for the Public Health Service but most, if 
21	not all, of the licensed tests also include language to
22	recommend that a positive test proceed on to a supplemental 
23	test.  So, it is really in both places. 
24		DR. MACIK:  So, it would be similar to having this 
25	labeling on it?  I mean, are we going to be labeling the 

			274 1	Point of Care test in a manner different than the current
	2	test that is being labeled? 
	3		DR. POFFENBERGER:  Yes, this will be a difference 
	4	in labeling, but it is a difference that is necessary really 
	5	because of where it is going to be used and how the test is 
	6	going to come to market, that is, as an approval.
	7		DR. MACIK:  Then it kind of gets back to the 
	8	question again, when Jay started off he said determining 
	9	whether you need a supplemental test was not done by FDA; 
10	that is guidelines, Public Health Service.  Then, in a way, 
11	by putting this label on there it looks like the FDA is
12	saying that you have to do something. 
13		DR. EPSTEIN:  In the setting of blood screening, 
14	FDA does have standards to recommend and/or require 
15	supplemental tests.  Currently, they are only required under 
16	HIV lookback regulations, and not for all tests.  We
17	published a proposed rule on testing last year which would 
18	create a regulatory requirement to follow all screens with 
19	licensed supplemental tests whenever available.  So, in the 
20	donor screening setting it is either already required or to 
21	be required.  In the medical diagnostic setting there is no
22	such requirement.  However, there are PHS recommendations 

23	which are long-standing, which call for the performance of 
24	confirmation, by whatever means, before notification.  That 
25	is why if you, as a physician, order an HIV test you always 

			275 1	get it back both with the screen and confirmatory.  You get
	2	back the ELISA and the Western Blot.  The reason is because 
	3	the clinical laboratory is complying with the PHS guideline, 
	4	or should be. 
	5		Now, what we are trying to do here is address the 
	6	fact that we have existing guidance which calls for
	7	supplemental testing, but we are going to permit algorithms 
	8	that don't use those tests.  So, what we are trying to do is 
	9	indicate in the test label how you might comply with the 
10	available guidance. 
11		Now, you know, I would agree that we could drop it
12	from the test label but I am not sure that that would add 
13	any help for users.  Whereas, putting it in the test label 
14	suggests that, you know, you are not done as a clinical 
15	laboratory, and we still do want that message. 
16		DR. HOLLINGER:  Dr. Boyle?
17		DR. BOYLE:  Since I started picking on the thing, 
18	I would like to come full circle and say, although I think I 
19	can wordsmith it better, the intent I think is reasonable.  
20	The fact that there is going to be follow-up guidance on 

21	exactly what is meant by some of the phraseology where we
22	basically said, beyond the use and diagnosis, is that it 

23	could be used in a multiple test algorithm and we don't have 
24	to go through a new approval process to get that added to 
25	the label.  Since that will simplify everybody's lives, I am 

				276 1	willing to forget what I said earlier and just -- you know,
	2	I think it works pretty well with follow-up guidance. 
	3		DR. HOLLINGER:  I certainly agree with that, and 
	4	maybe you can help me out of this, Jay.  The problem I have 
	5	with this is, I mean, the whole idea with the rapid test was 
	6	that you could talk to people and give them information
	7	before they left a clinical setting somewhere.  And, then we 
	8	are hit with a label that says you have to have this other 
	9	possible thing, a supplemental test prior to patient 
10	counseling.  Am I missing something? 
11		DR. EPSTEIN:  Yes.
12		DR. HOLLINGER:  Well, then help me. 
13		DR. FINLAYSON:  Let me say something because this 
14	is almost instant replay.  I had the same problem when I 

15	first encountered this, and my reaction was, well, you can 
16	do the first test in three minutes or five minutes or seven
17	minutes, and then you are going to make them wait for a 
18	Western Blot?  The answer is what Dr. Poffenberger is 
19	proposing that you have another test there which will also 
20	take only five minutes, or seven minutes, or ten minutes.  
21	So, in a span of about 25 minutes you can get your answer
22	with enhanced accuracy.  Maybe Dr. Poffenberger would like 

23	to show that slide again in which she showed the worst case.  
24	If you combine two tests together, the worst that you could 
25	ever come out, in as much as you have already voted on 

				277 1	question one and said both sensitivity and specificity must
	2	be at least 98 percent -- the worst you could ever come out 
	3	with is 98 percent/96 percent, or 96 percent/98 percent. 
	4		DR. HOLLINGER:  John, I don't have a problem with 
	5	that.  I mean, I totally agree with you but then essentially 
	6	what it is asking us to do, or me as I view it, is to vote
	7	that there is a requirement for these multiple tests.  I 
	8	don't have a problem with that either, but that is basically 
	9	what it is saying because, you are right, you do one test 
10	and then you do another test and then you can do patient 

11	counseling.  But that is basically what it would say, that
12	we are not going to license a test just for a single test 
13	only and then follow up with patient counseling.  It is 
14	saying you are really going to have to do both of these 

15	tests and you are going to have to have another test.  That 
16	is what I am having a problem with.
17		DR. FINLAYSON:  I don't work in this area so, see, 
18	I have the overwhelming advantage of consummate naivete when 
19	it comes to HIV test kits.  But I read this as saying this 
20	test may be used.  It is not a requirement; it is a 
21	recommendation, and it is not an FDA specific

22	recommendation; it is a Public Health Service 
23	recommendation.  And, this is saying this may be used this 
24	way to fulfill that overall recommendation. 
25		DR. HOLLINGER:  I just wanted you to say that.  

			278 1	Yes, Dr. Macik?
	2		DR. MACIK:  I guess that is what I am kind of 
	3	getting back to.  I understand Jay saying you want to get 

	4	across to them that you are not finished.  But, how do we 
	5	want to put that?  And, I think putting something like it 
	6	should be recognized that this diagnostic test must be used

	7	in a way consistent with current Public Health, or whatever, 
	8	recommendations for validating the test before you counsel a 
	9	patient, or something like that -- in other words, still get 
10	the message across that this test by itself doesn't end but 
11	without bringing up the exact -- leaving it open to whatever
12	the reigning guidance is from the appropriate authorities 

13	that this test should be used in concordance with that 
14	guidance. 
15		COL. FITZPATRICK:  I am having the same problem 
16	you are,  Dr. Hollinger, with some of that, and that is

17	helping but is it feasible to drop the "prior to patient 
18	counseling" part, and that fixes it? 
19		DR. HOLLINGER:  Well, that is basically what I 
20	wanted to do, just take that last portion out.  I guess we 
21	could vote on it, and if the committee doesn't want to do

22	it, then they can decide not to.  So, I will propose that we 
23	modify or revise this -- that for the purposes of the vote 
24	we revise this by taking out "prior to patient counseling" 
25	and then vote on that.  So, I would like to propose that as 

			279 1	a revision and if there is not a second we can go on from t
	2	there.  Is there a second to that motion? 
	3		COL. FITZPATRICK:  Second. 
	4		DR. HOLLINGER:  So we will vote on that.  The vote 
	5	is to remove from this approach "prior to patient 
	6	counseling."  Dr. McCurdy?
	7		DR. MCCURDY:  Blaine, I am continuing to have the 
	8	problem that I mentioned before, and I am not really sure 
	9	that helps.  My suggestion is to split question two into 
10	2(a) and 2(b), and 2(a) would be labeling for use as an aid 
11	in diagnosis, which I think is pretty common for all
12	diagnostic test kits.  The second one would then say you 
13	should use some other kind of test.  I think at one time it 
14	was fairly common to use more than one liver function test, 
15	but I doubt if the labeling of the kit said this may be used 
16	as part of a multi-test algorithm.  And, I think this is
17	basically clinical medicine and PHS guidelines, if they are 
18	not too far delayed, would take care of this. 
19		DR. HOLLINGER:  Dr. Simon? 
20		DR. SIMON:  I a thinking that the FDA was trying 
21	to be permissive and helpful to the public health sector
22	with this wording.  Is that true?  Because, if that is the 
23	case, then I would want to be supportive and vote for the 

24	wording. 
25		DR. CHAMBERLAND:  I agree with you, although I 

		280 1	think we need to hear from the folks at CDC who have been

	2	working in this.  This document that is in process about 
	3	testing and counseling, as I see it, I mean, again maybe 

	4	there would be words to wordsmith this a little bit better 
	5	but I see that second statement basically as saying that 
	6	this test can be used either as a single test where the
	7	confirmatory test would be a Western Blot, and there may be 
	8	settings -- and other people in this room may know that 
	9	there may be settings where it is a better sequence to do a 
10	rapid assay and do a Western Blot as the supplemental 
11	confirmatory test, or it can be used as one of a series of
12	multiple rapid assays. 
13	          Maybe what people are reacting to is that there is 
14	a sense that the first part of that is missing, that if you 
15	use this as the sole rapid assay you need to have a 
16	supplemental confirmatory test performed, the traditional

17	Western Blot or whatever.  Are people feeling that this 
18	somehow is missing that element?  Because I don't feel as 
19	strongly as others do on the committee about the need to 

20	delete the language.  I certainly would have no problem with 
21	FDA or others maybe rethinking the language, and I don't
22	think we need to think that this is the final, final version 
23	of the language.  It seems like it is up for discussion, and 
24	I think what they are trying to do is tell us what their 
25	intent is, and maybe the feedback we are giving them is you 

					281 1	might need to work on the wordsmithing a little bit better
	2	because it is not as clear as we would like. 
	3		DR. POFFENBERGER:  I think you have really 
	4	captured what we were intending.  We were intending to make 
	5	it an "or" situation.  That is, you can either use it as a 
	6	single, initial rapid screening test or you may use it in a
	7	combination.  The recommendations, if it is used as a single 
	8	test, would still be in place.  That is, the site would be 
	9	under Public Health recommendations to go on and do a 

10	confirmatory Western Blot.  So, what we are trying to do 
11	here is be flexible and offer the option, and let it be up

12	to the testing site and the health professional running that 
13	site as to which path they are going to choose. 
14		DR. HOLLINGER:  Which would mean that they could 
15	counsel patients before they do that other confirmatory 
16	test.
17		DR. POFFENBERGER:  Yes, they can counsel the 

18	patients but those recommendations are part of the PHS 
19	recommendations.  So, they would be following that and 

20	presumably following the counseling recommended by the CDC. 
21		DR. HOLLINGER:  Well, with that understanding, I
22	would withdraw my -- if Col. Fitzpatrick will withdraw his 
23	second. 
24		COL. FITZPATRICK:  I will certainly do that, yes. 
25		DR. HOLLINGER:  Let's vote on the intent of this 

				282 1	question.  Does the committee agree with the FDA approach to
	2	labeling the rapid tests?  All those that favor that 
	3	question and are voting yes, raise your hand. 
	4		[Show of hands] 
	5		All those opposed, or voting no? 
	6		[No response]

	7		Abstaining? 
	8		[No response] 
	9		Consumer representative?  Mrs. Knowles? 
10		MS. KNOWLES:  Yes. 
11		DR. HOLLINGER:  And Dr. Simon?
12		DR. SIMON:  Yes. 
13		DR. HOLLINGER:  Thank you. 
14		DR. SMALLWOOD:  Results of voting for question 
15	two, unanimous "yes" votes.  The consumer and industry 
16	representative both agreed with the "yes" vote.

17		DR. HOLLINGER:  Thank you.  This concludes today, 
18	but let me just mention about tomorrow.  Tomorrow we start 
19	at 9:00. The first three updates are going to take a little 
20	bit of time, so I am hoping we are going to get out at 12:30 
21	but it may be 1:00.  So, you need to know that.  So, we will
22	see you all tomorrow morning. 
23		[Whereupon, at 5:45 p.m., the proceedings were 
24	recessed, to reconvene at 9:00 a.m., Friday, June 16, 2000.] 
25			 - - -