DEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

BLOOD PRODUCTS ADVISORY COMMITTEE

62ND MEETING

This transcript has not been edited or corrected, but appears as received from the commercial transcribing service.  Accordingly the Food and Drug Administration makes no representation as to its accuracy.

Thursday, March 25, 1999

8:15 a.m.

Bethesda Ramada Inn

8400 Wisconsin Avenue
Bethesda, Maryland

PARTICIPANTS

Blaine E. Hollinger, M.D., Chairperson
Linda Smallwood, Ph.D., Executive Secretary

MEMBERS

John M. Boyle, Ph.D.
Corey S. Dubin
Norig Ellison, M.D.
Rima F. Khabbaz, M.D.
Marion A. Koerper, M.D.
Jeanne V. Linden, M.D.
Gail B. Macik, M.D.
Mark A. Mitchell, MD.
Kenrad E. Nelson, M.D.
David F. Stroncek, M.D.

NON‑VOTING INDUSTRY REPRESENTATIVE

Donald H. Buchholz, M.D.

TEMPORARY VOTING MEMBERS

Paul R. McCurdy, M.D.
Jane A. Piliavin, Ph.D. (Session III)

CONSULTANT

Michael G. Fitzpatrick, Ph.D.

C O N T E N T S

Statement of Conflict of Interest
Linda A. Smallwood, Ph.D.	5

Welcome and Opening Remarks
Blaine F. Hollinger, M.D.	9

Committee Updates

HCV Lookback Guidance
Paul Mied, Ph.D.	10

Transmissible Spongiform Encephalopathies Advisory
Committee Meeting Summary
Mary Elizabeth Jacobs, Ph.D.	22

Current Policy Regarding CJD and Blood Donors
Dorothy Scott, M.D.	28

Group O Sensitivity in Rapid Tests
Bernard Branson, Ph.D.	42
Paul Mied, Ph.D.	47

I. NUCLEIC ACID TESTING OF WHOLE BLOOD‑‑INFORMATIONAL

Introduction and Background
Indira Hewlett, Ph.D.	54

High‑Throughput Assay for the Simultaneous
Detection of HIV‑1 and HCV RNAs
Christina Giachetti, Ph.D.	60

American Red Cross
Susan Stramer, Ph.D.	67

Blood Centers of the Pacific, Irwin Center
Michael Busch, M.D., Ph.D.	78

Association of Independent Blood Centers
Richard Gammon, M.D.	88

Roche Molecular Systems
Mr. Alex Weslowski	97

Open Public Hearing
Dr. Andrew Conrad, National Genetics Institute	107
Dr. Susan Cushing, Baxter Healthcare	111
Dr. Charles Watson, Centeon	116
Dr. Steven H. Kleinman, AABB	120
Dr. David Pittman, Hospital IRB Committee 	129
Dr. James Linder, American Association of Clinical 	133
  Pathologists (by Dr. Hollinger)
Dr. Jerry Schochetman, M.D., Abbott Laboratories	135

C O N T E N T S   (Continued)

Committee Discussion 	137

II. HIV p24 ANTIGEN TESTING: POTENTIAL CRITERIA FOR
    DISCONTINUATION
Introduction and Background
Indira Hewlett, Ph.D.	170

American Red Cross
Sue Stramer, Ph.D.	174

Alpha Therapeutics
Ms. Sue Preston	182

Blood Centers of the Pacific, Irwin Center
Michael Busch, M.D., Ph.D.	189

Abbott Labs
Gerald Schochetman, M.D.	201

Open Public Hearing

Dr. Steven H. Kleinman, AABB	206

Committee Discussion	213

III. VALIDATION OF DONOR HISTORY QUESTIONS

Introduction
Capt. Mary Gustafson	221

Presentation
Alan Williams, M.D., AABB	232

Presentation
Celso Bianco, NYBC	251

Open Public Hearing
Dr. Paul Cumming	261

Committee Discussion 	268

P R O C E E D I N G S
Statement of Conflict of Interest
DR. SMALLWOOD:  Good morning.  Welcome to the 62nd Meeting of the Drug Products Advisory Committee.  I am Linda Smallwood, the Executive Secretary.  At this time, I will read the conflict of interest statement that applies to this meeting.
This announcement is made a part of the record at this meeting of the Blood Products Advisory Committee on March 25 and 26, 1999.  Pursuant to the authority granted under the Committee charter, the Director of the FDA Center for Biologics Evaluation and Research has appointed the following consultants as temporary voting members: Dr. McCurdy for all committee discussion and Dr. Jane Piliavin for the discussions on validation of donor history questions.
Based on the agenda made available and on relevant data reported by participating members and consultants, it has been determined that all financial interest in firms regulated by the Center for Biologics Evaluation and Research that may be affected by the committee's discussions have been considered.
No waivers under Section 208 were necessary.  In regard to FDA's invited guests, the agency has determined that the service of these guests is essential.  There are reported interests which are being made public to allow meeting participants to objectively evaluate any presentation and/or comments made by the participants.
The interests are as follows: Dr. Michael Busch reported that he has a grant from the National Heart Lung and Blood Institute to study nucleic‑acid testing in which Roche and Gen‑Probe are collaborators.  He also has a grant reported by Roche to develop PCR assays.  In addition, Dr. Busch is a member of the Gen‑Probe Scientific Advisory Group.
Dr. Christina Giachetti is employed by Gen‑Probe.  Ms. Sue Preston is employed by Alpha Therapeutics Corporation.  Alpha has contacted firms that could be affected by the discussions of p24 antigen test kits.  Dr. Susan Stramer has a financial interest in Abbott Laboratories.
The topics that Drs. Celso Bianco and Jane Piliavin and Alan Williams are commenting on are not subject to conflict of interest.  In the event that the discussion involves specific products or firms not on the agenda for which FDA participants have a financial interest, the participants are aware of the need to exclude themselves from such involvement and their exclusion will be noted for the public record.
Screenings were conducted to prevent any appearance, real or apparent, of conflict of interest in the committee discussion.  With respect to all other meeting participants, we ask, in the interest of fairness, that they address any current or previous financial involvement with any firm whose products they wish to comment upon.
At this time, are there any further declarations to be made by any of the advisory committee members or the participants?
Hearing none, I would just like to announce to all assembled here that the environment in which we are having this meeting is obviously a little different than what we have had in the past.
We are trying to be accommodating in terms of making it as comfortable as possible and we are working on the audio system.  I hope that you will be patient with us.  We do have a full agenda and we would like to proceed.  But, just to let you know, we are trying to do the best that we can and, if there are any inconveniences, please let me know very gently.
At this time, I would like to introduce to you the members of the Blood Products Advisory Committee.  We also have two new individuals that are serving on the committee with us today.
First, I would like to introduce Dr. Blaine Hollinger, who is our Chairperson.  Dr. Gail Macik.  Dr. Macik is new to the Blood Products Advisory Committee.  She is a hematologist and she is with the University of Virginia.  Dr. Mark Mitchell.  Dr. David Stroncek.  Dr. Michael Fitzpatrick is from the Department of Defense.  He is new with us now.
Dr. Kenrad Nelson.  Dr. Donald Buchholz.  Dr. Marion Koerper.  Dr. Norig Ellison.  Mr. Corey Dubin.  Dr. Rima Khabbaz.  Dr. John Boyle.  Dr. Paul McCurdy.  Dr. Jeanne Linden.
Our members absent today are Dr. Richard Kagan, Dr. Kwaku Ohene‑Frempong and Dr. Joel Verter.  Dr. Jane Piliavin will join us later this afternoon.
Also, if Dr. Epstein would like to come forward and introduce our new members on our staff, our new Deputy Director.
DR. EPSTEIN:  If I could just ask Richard Lewis to stand and to, perhaps, come a little bit forward so you are visible.  Richard was appointed new Deputy for the Office of Blood Research and Review.  We welcome him aboard in this new role.  Let me not delay our meeting, but let me also send a personal welcome to our new members on the committee.  As always, we have a very full agenda and look forward to full participation of the group.
DR. SMALLWOOD:  Thank you.  At this time, we will proceed with the agenda and I will turn the proceedings of this meeting over to our chairman, Dr. Blaine Hollinger.
Welcome and Opening Remarks
DR. HOLLINGER:  Thank you, Linda.  While Linda was saying this, I remember a few years ago standing up at a conference giving a talk and I asked the same thing Linda did.  I said, "Can you hear me in the back?"  And some people said, "No; I don't think so, not very much."  And two or three people in the front row got up and went to the back.  So I don't do that anymore.
Just so that the committee members know, these mikes have a push button on and off.  So when you see this little red thing here on top, that means your mike is on and live.
The last time we met in December, there were impeachment trials going on.  This time, there is a NATO operation.  So I am not sure we should have another one in June.  But this is an interesting meeting today.  I saw somebody from the Pentagon today say something like, "There is nothing such as a risk‑free military operation."  I think, obviously, we can say the same thing.  There is nothing such as a risk‑free blood transfusion.
But I will tell you, it is getting to the point where we are getting extremely good, safe blood.  A lot of the things that we are doing now are looking for ways in which we can reduce the number of operations that need to take place such as in donor histories, such as looking for ways to reduce, perhaps, some of the testing that was done in the past.  All of these things are going to go on over the next, I think, several months to a year to try and find out if we can reduce those operations, make the blood even safer.
Most of the operations that are being introduced are actually not going to change the safety of the blood except to make it safer.  It is not going to make it less safe.  I think that is a real plus.
So, today, we do have several items and I think we need to get started.  The first thing we start on is committee updates, not so much for discussion but more to give us an idea of some of the issues that are before us.  The first one is on the HCV lookback guidance.  Paul Mied is going to talk about this.
Committee Updates
HCV Lookback Guidance
DR. MIED:  Good morning.  Thank you, Dr. Hollinger.
[Slide.]
This morning, I will provide the committee with an update on HCV lookback.  Specifically, I will summarize the actions of the Public Health Service and the blood industry to implement HCV lookback and the current status of the lookback effort.  I will review the resolutions on HCV lookback approved by the Advisory Committee on Blood Safety and availability on January 28, 1999 and I will conclude by discussing the upcoming draft FDA revised guidance for industry document with a review of the recommended time frames for implementation of HCV lookback by the industry.
The current PHS initiative and industry effort for identifying transfusion recipients at risk for HCV infection includes direct notification of recipients of blood from donors who had subsequently tested repeatedly reactive on a multiantigen screening test‑‑that is, the EIA 2.0 or 3.0‑‑ with a reactive supplemental test result and general notification of all persons transfused before July, 1992.
[Slide.]
The current status of the implementation of HCV lookback may be summarized as follows.  The blood organizations report that blood establishments have implemented HCV lookback programs prospectively, or based on current donor testing and retrospectively, or based on review of records of historical donations tested using EIA 2.0 or EIA 3.0.
They have established written SOPs for lookback based on current and historical donations.  They have diligently conducted record searches to identify prior collections from donors who were reactive on multiantigen screening and supplemental tests and they have been performing additional tests on stored samples or, in some cases, on fresh donor samples.
As I reported in my December update to this committee, some blood banks have already begun doing lookback based on EIA 1.0.  The Chiron RIBA 3.0 supplement test was licensed in February and it is useful for resolution of donor‑infectivity status to minimize false notifications of recipients.
Blood establishments have begun to notify consignees.  The deadline for this consigning notification was specified as March 23, 1999 in the FDA guidance document issued last September 23.  Blood establishments will need to complete consignee notifications by March 23, 2000.  In coordination with the public education and physician efforts of the CDC, transfusion services have begun to notify recipients.
The Advisory Committee on Blood Safety and Availability met on January 28, 1999 in Washington, D.C. to consider options for implementing the November 24, 1998 recommendation of the advisory committee to expand the current targeted HCV lookback program to include recipients of blood from donors subsequently identified as repeatedly reactive by the single‑antigen enzyme immunoassay, EIA 1.0, screening test of HCV infection that was licensed in 1990.
Now, it would be necessary for lookback based on EIA 1.0 to include unconfirmed as well as confirmed EIA 1.0 tests because about 80 percent of the EIA 1.0 repeatedly reactive donations had been culled by EIA 1.0 screening before the first confirmatory test became available.
The committee considered that it might be reasonable to limit the lookback for EIA 1.0 based on the signal‑to‑cutoff ratio of the screening test in cases where supplemental testing had not been done.  In other words, it may be optimal to perform lookback on a subset of the EIA 1.0 repeat reactives to capture the vast majority of the true positives and minimize the unnecessary false‑recipient notifications.
Data were presented at that meeting to support the use of the signal‑to‑cutoff ratio as an estimate of what the result of a RIBA 2.0 test would have been if the RIBA 2.0 test had been available and performed on the donor sample.
[Slide.]
In a study of HCV EIA 1.0 data from four regionally diverse blood centers, Tobler and Busch and several other colleagues found a highly significant correlation between the signal‑to‑cutoff ratio and RIBA 2.0 positive or negative results.
Dr. Busch discussed the choice of a signal‑to‑cutoff ratio that would optimally distinguish an uninfected from an infected donor using the expected results of a RIBA 2.0 test as the gold standard.  A signal‑to‑cutoff value of greater than 2.5 yielded an 89 percent sensitivity for RIBA 2.0 positives.
In other words, if a signal‑to‑cutoff value of 2.5 is taken as the trigger for lookback, 89 percent of recipients from repeatedly reactive donors who would be RIBA 2.0 positive would be notified.  For a signal‑to‑cutoff value of greater than 2.0, 91 percent of recipients from donors who would be RIBA 2.0 positive would be notified.
For a signal‑to‑cutoff of greater than or equal to 1.5, 95 percent of recipients from donors who would be RIBA 2.0 positive would be notified.  However, for a signal‑to‑cutoff value of greater than 2.5, of the 11 percent of repeatedly reactive donors who would be RIBA 2.0 positive for whom recipients would not be notified, only 48 percent of those donors would have been HCV RNA positive.
So, in effect, of 100 people who would have been notified simply on the basis of EIA 1.0 repeatedly reactive results, if the signal‑to‑cutoff value of greater than 2.5 is taken as the trigger to lookback, there would be only five at‑risk individuals who would not be notified since their donors had signal‑to‑cutoff values of less than 2.5 or an EIA of 1.0.
The flip side of this is that as you approach a signal‑to‑cutoff value of 1.0, the specificity drops off rapidly.  However, for a signal‑to‑cutoff value of greater than 2.5, 87 percent of recipients from donors who would be RIBA 2.0 negative would not be notified.
In other words, if the signal‑to‑cutoff value of greater than 2.0 is taken as the trigger to lookback, we would not be notifying 87 percent of those individuals who are not at risk who would have been notified on the basis of their donor being EIA 1.0 repeatedly reactive.
[Slide.]
Now, Dr. Busch estimated that if direct notification was to be based on a signal‑to‑cutoff ratio of 2.5 or above, about 100,000 notifications would be triggered.  About 10 percent of these individuals would be alive and be traced by the notification effort; that is, 10,000 of those individuals.
About half of those, or 5,000 individuals, would have been previously unaware of their potential HCV infection.  Dr. Busch estimated that using a signal‑to‑cutoff ratio of 2.5 to trigger direct notification as opposed to simply using an EIA 1.0 repeatedly reactive test to trigger direct notification would prevent about 452 false‑positive notifications.  For every true‑positive notification that would not occur.
[Slide.]
Having taken the signal‑to‑cutoff value of 2.5 as being the optimal ratio for triggering lookback for EIA 1.0, the Advisory Committee on Blood Safety and Availability unanimously approved the following recommendations at its January 28, 1999 meeting.
One, the advisory committee recommends that targeted lookback should be initiated based on the repeatedly reactive EIA 1.0 test result on a repeat donor unless a supplemental test result was performed and did not indicate significant risk of HCV infection, no supplement test result is available, but the signal‑to‑cutoff ratio of the repeatedly reactive EIA 1.0 test was less than 2.5 or follow‑up testing from the same blood donor is negative.
[Slide.]
Two, the advisory committee believes that, in light of the scope of the hepatitis‑C epidemic, current funding is inadequate for notification, testing, counseling, education and therapy.  We urge the secretary to take immediate measures to increase funding to meet this major public‑health challenge.
We further urge the Public Health Service to work with professional and private organizations to promulgate appropriate recommendations for testing, counseling and therapy and to secure additional resources for these purposes.
[Slide.]
Three, the advisory committee urges the Secretary to consider providing appropriate support and resources for blood centers and hospitals, both public and private, to conduct HCV lookback activities.
In accordance with these recommendations, FDA intends to issue a revised guidance for industry document that will replace the guidance issued on September 23, 1998.  This revised guidance, which will be issued for implementation and comment, will include recommendations for implementation of targeted lookback based on a repeatedly reactive EIA 1.0 test result on a repeat donor except in the cases listed in recommendation 1 of the advisory committee.
[Slide.]
With respect to the time frames for implementation of the retrospective HCV lookback by industry, the current September 23, 1998 guidance document recommended that blood establishments should begin notification of consignees‑‑that is for EIA 2.0 and 3.0‑‑within six months of the date of issuance of the September 23 guidance‑‑that is, by MarchÊ23, 1999.
As I mentioned earlier, this deadline has passed and blood establishments have begun this notification of consignees.  In addition, blood establishments should complete all notifications of consignees within eighteen months of the date of issuance of the September 23 guidance‑‑that is, by March 23, 2000.
FDA anticipates that the new revised guidance will issue in May, 1999.  In this revised guidance, due to concerns raised by the blood organizations with respect to having adequate time for implementation of retrospective HCV lookback pertaining to EIA 1.0, FDA is considering recommending that blood establishments should begin notification of consignees for EIA 1.0 as soon as feasible and within six months of the date of issuance of the upcoming revised guidance expected in May‑‑that is, by November of 1999.
However, blood establishments should complete all notifications of consignees for EIA 1.0 by the same date as that for completing all consignee notifications for EIA 2.0 and 3.0‑‑that is, by March 23, 2000.
Thus, FDA intends to recommend that this date for completion of all consignee notifications be unchanged from that in the current September 23 guidance document.
[Slide.]
The other target dates will remain the same.  A transfusion service should begin notification of the recipient when notified by the blood establishment and should complete all notifications of recipients within one year following receipt of notification from the blood establishment‑‑that is, by March 23, 2001 for the last of the notifications received.
Thank you.
DR. HOLLINGER:  Thank you, Paul.  Any burning questions for Paul from the committee on this issue?
MR. DUBIN:  It is a question, but I need to precede with some comments so we know where we are.  The Committee of Ten Thousand, which has been involved in calling for this lookback for a number of years supports the targeting lookback as was designed and the recommendations at the Blood Safety and Availability Committee.
We have raised the issue of pre‑1989‑88, because if we are going back in terms of donor and donor records that are in pretty good shape until 1990, we will get to recipients in the 1988‑89 range.  Our concern is that the majority of potential exposures identified by the Subcommittee on Human Resources, the Sherman Chase Committee, the figure he gave is $1 million.
Two‑thirds of that $1 million will fall outside of this targeted lookback.  We are concerned if they are left as part of the overall CDC general campaign on the hepatitis C epidemic that two things will happen.  The connection between that campaign, their transfusion or usage of blood products or blood components, that hepatitis C will not be very direct and the unique relationship between consumer and manufacturer of plasma derivative or consumer and blood bank will be lost.
What we suggested at the advisory committee and what we continue to suggest, and when I asked FDA staff about‑‑we believe that what should occur is the "Dear Resident" letter a la what Surgeon General Koop did in the 1980s a la HIV and that that should go to every home in America, something to the effect that, "If you were transfused or received blood, blood components, blood products, you should be antibody tested for hepatitis C."
This, we believe, is the only way to reach the entire potential exposed population.  So I wonder how FDA has looked at that and if FDA supports, at a staff level, the issuance of a "Dear Resident" letter.
Thanks.
DR. MIED:  Corey, I don't know.  We were both at the same meeting.  That concern was raised.  That point was made.  Frankly, I don't know if any action will be taken to that end regarding a letter.
DR. EPSTEIN:  You highlight an important issue.  There are really two different points here.  With respect to a mailer to all households, that is under discussion at the CDC.  There is an issue of finding the funds to do it, but, generally, the concept is well endorsed and we are looking at feasibility.  That lies with CDC.
As far as whether the records search for the targeted lookback could be extended prior to 1988, the key issue there is a practical one which is the state of the records.  Many transfusion services, and, indeed, blood‑collection centers, were not computerized at that point in time.  Some of them were, but, in many cases, the records are paper records, index‑card records.
They are sitting in boxes.  They are deep‑sinked in warehouses.  It becomes impractical to think that they can be searched.  What FDA is doing is considering where we can draw the line.  We will come forward with some practical recommendation based on a feasible search of records as far back as can be done.
But there is a practical constraint and we are just going to have to live with it.
DR. HOLLINGER:  Who is paying for the‑‑people who are notified and they come in, are they supposed to come into blood banks primarily, and the blood banks are taking care of the testing?
DR. EPSTEIN:  For the most part, the answer is yes.  And it is my understanding that there is a statement recently out of HCFA that Medicare will reimburse recipient testing based on targeted lookback.  Now, that, of course, will not affect all recipients, but the majority of blood recipients living today are over age 65 and are Medicare‑eligible so it will go a long way toward providing funding for lookback testing.
DR. HOLLINGER:  But increased funding was not provided, or has not been provided through the Health Department.
DR. EPSTEIN:  I don't believe it has.  Perhaps, Rima knows the answer.  But I don't think that there have been any earmarked funds for this; no.
DR. MIED:  HCFA Memo 804 talks about funding a little bit.  It was just released over the past week.
DR. HOLLINGER:  I think we will move forward, then, to the next update.  Dr. Mary Jacobs is going to give us an update on the Transmissible Spongiform Encephalopathies Advisory Committee meeting.  I guess this was the one in December.
DR. JACOBS:  Yes; that's correct.
Transmissible Spongiform Encephalopathies Advisory
Committee Meeting Summary
DR. JACOBS:  Thank you, Dr. Hollinger.
[Slide.]
My presentation is a brief summary of the December 18, 1998 meeting of the Transmissible Spongiform Encephalopathies Advisory Committee which we usually call TSEAC which was asked to make recommendations to FDA concerning new deferral criteria for blood donors to attempt to reduce the theoretical risk of new‑variant CJD from possible food‑borne exposure to the agent of bovine spongiform encephalopathy, or BSE.
[Slide.]
First, what is the current status.  There have been no cases of BSE or of new‑variant CJD in the U.S.  As an aside, the March 20 paper in Lancet by Dr. Robert Will reported that, as of the first quarter of 1999 with incomplete data for that quarter, there have been 39Êdeaths from new‑variant CJD.
Although there have been no cases in the U.S., we are well aware of precautionary measures taken in the U.K. including implementation of universal leukoreduction and also not using U.K. source plasma.
We brought the question of potential deferral to the TSE Advisory Committee and asked them to consider the questions in the light of potential shortages.  In order to have continuity with BPAC, Drs. Hollinger and Nelson were temporary voting members of the committee as was Dr. Lightman of NIH.
In addition, Dr. Gilcher of the PHS Blood Safety and Availability Committee served as a guest.  Drs. Katz and Sayers, former chairs of this committee, were guests as well bringing blood‑banking experience and took part in the deliberations.
The complete transcript is available on FDA's website as shown on the overhead.  I think you might find it interesting to read.
[Slide.]
The agenda addressed the issues which are relevant to the questions of the safety of blood, blood products and plasma derivatives.  First, the scientific presentations included Dr. Robert Will who had first described new‑variant CJD in U.K. patients, who described the characteristics of the disease and its demographics.
Dr. Robert Rohwer discussed experimental studies in animals using infected blood.
[Slide.]
Dr. Adriano Aguzzi discussed the role of circulating lymphocytes.  Next we turned to the time course of the BSE epidemic which was discussed by Dr. Ferguson of the U.S. Department of Agriculture.
[Slide.]
Because we had asked the committee to talk about shortages, we then went first to the topics of donor‑deferral policies.  Captain Gustafson, who is Division Director for Blood Applications in our office, talked about U.S. donor deferral policies.  Dr. Alan Williams, who is here today, of the Red Cross, talked about results from the REDS study, Retrovirus Epidemiology Donor Study, which were relevant to this question.  Dr. Mark Weinstein, Director of our Division of Hematology, talked about withdrawal and recall policies and their relationship to the supply of plasma derivatives in the U.S.
To talk about policies, we had Dr. Jeremy Metters who is Deputy Chief Medical Office of the U.K. and is their senior spokesperson on this issue, and Dr. Douglas Kennedy of Canada.
[Slide.]
Turning to their recommendations; first, we asked them should FDA recommend new deferral criteria for blood donors to attempt to reduce the theoretical risk for transmitting new‑variant Creutzfeldt‑Jacov disease by excluding donors potentially exposed to the agent of BSE.  The committee voted nine yes, six no.
[Slide.]
In the next question, they were asked whether this recommendation should apply to those who had resided in the U.K. or other BSE countries.  As you can see, they decided to restrict the considerations to the U.K.  Secondly, because of the results from the REDS donor survey, we showed that 11 percent of U.S. donors had to travel in the U.K or resided there between 1984 and 1990.
They decided that, before they went to the more detailed questions which we will come to in a minute, that they would like to see the results of a survey giving them more specific data about times of residence.  The committee voted 12 to 1 in favor of a survey.
[Slide.]
Before we go to the remaining questions, let's look at the planned survey.  It is a joint survey by the American Red Cross, the American Association of Blood Banks, America's Blood Centers and the National Heart, Lung and Blood Institute.  The principle investigator is Dr. Williams who also has head the REDS study.
It is going to be an anonymous mail survey using eight blood centers from the 1998 REDS survey and four ARCNET sites which are part of the Red Cross system for collecting data.  It will include questions on BSE countries which could be useful in the future.
[Slide.]
These survey results can be used for the other questions which we had asked the committee to address which they are going to address at a later date.  Those include, should FDA recommend distinguishing between donors who were resident in BSE countries during periods of higher or lower risk of exposure because of the time course of the BSE epidemic and, secondly, should we recommend exclusion of donors who had less intense exposure to beef products based on limited travel to the BSE country.
That time period will be addressed in the survey.
[Slide.]
The committee did go on to address, based on the information presented to them in their deliberations, additional questions, however.  In the case of recommendation of withdrawal for blood components, based on donor‑deferral criteria, they have voted 7 yes and 5 no.  In the case of withdrawal for plasma derivatives based on these criteria, they voted 11 no, 1 yes.
[Slide.]
We also discussed with them that we plan to refer possible cases of new‑variant CJD to the CDC for investigation.  Considering precautionary withdrawal for possible new‑variant CJD, we asked, "Should we recommend precautionary quarantine or withdrawal for plasma derivatives to which a possible new‑variant CJD donor contributed, pending confirmation?"
They voted 8 yes, 1 no, 1 abstaining and asked to have the question of definitions of possible brought back to them at the next meeting.
[Slide.]
We also asked whether or not a tonsil biopsy negative for PRP would be sufficient to make product withdrawals unnecessary.  They voted 3 abstaining, 6 no.
[Slide.]
What is the planned follow up?  We expect that the survey results will be ready for the next meeting of the advisory committee which is scheduled for June 2, 1999.  We will then consider their recommendations within FDA.  We will consult with other PHS agencies in the Department.  We may discuss it at the PHS Advisory Committee on Blood Safety and Availability and then there will be an announcement of policy through revised guidance.
DR. HOLLINGER:  Thank you, Dr. Jacobs.
Any questions for Dr. Jacobs from the committee?  If not, then we will go to the next update on current policy regarding CJD and blood donors by Dr. Dorothy Scott.
Current Policy Regarding CJD and Blood Donors
DR. SCOTT:  Good morning.
[Slide.]
I am going to provide you with a summary of recent events and current considerations regarding CJD and blood donors.  First, I want to refamiliarize the audience with the previous recommendations regarding CJD and blood products.
These recommendations were formalized in a guidance in August of 1995 and this guidance was revised on December 11, 1996.  Basically, the recommendations were to defer all donors who had CJD risk factors, of course, or CJD and the CJD risk factors included a family history, pituitary‑growth‑hormone recipients and dura‑mater‑graft recipients.
In addition, it was recommended to withdraw all plasma derivatives, all products, if a donor developed CJD, had a strongly positive family history, was a pituitary‑growth‑hormone receipient or a dura‑mater recipient.
[Slide.]
These recommendations were revised.  This revision was announced on the Internet on September 9, 1998.  These revisions were based upon an extensive review of old and new epidemiologic and scientific evidence about the possible transmission of CJD through blood and blood products and also there were many discussions with advisory committees and the CDC.
So the revised recommendations are not to retrieve quarantine or destroy plasma derivatives if a donor has CJD risks, as outlined previously, or CJD.  However, it is still recommended to defer donors who have CJD risks or CJD.  In addition‑‑and of course, this is completely new because of the concern about possible new‑variant CJD‑‑it was recommended to retrieve quarantine and destroy any materials if the donor develops or is reported to have new‑variant CJD.
Obviously, new‑variant CJD is of particular concern because there is a lack of experimental data about blood infectivity with new‑variant CJD.  We don't know anything, really, about blood infectivity at this point and we don't know anything about partitioning of this new‑variant agent during the manufacturing of plasma derivatives.
In addition, we do know that new‑variant CJD is biologically different from classical CJD.  For example, in new‑variant CJD‑‑and there is a paper that came out in The Lancet in January of 1999‑‑it is clear that the patients have tonsillar expression of the prion protein, which is not seen in classical CJD cases.
Of course, this raised concerns that there might be more expression of the agent, or some expression of the agent, in blood.  Furthermore, we don't really know whether the new‑variant agent is more virulent or infective.  Finally, because it is an emerging agent and has only been around since the early '90's, or has only been identified since the early '90's, we lack the kind of epidemiologic data that might reassure us.
[Slide.]
How is new‑variant CJD diagnosed?  I will mention some of the biological features of new‑variant CJD, just very briefly.  These patients have what are called florid plaques.  They have spongiform changes that are common in certain parts of the brain but are not common in the cerebral cortex.  They tend to have a very high density of prion protein accumulation, especially in the cerebrum and cerebellum.
There may be a role now for tonsillar biopsy in the diagnosis of these patients.  In addition, they have been reported to have a unique glycoform of the prion protein.
[Slide.]
As you have seen from Dr. Jacobs' presentation just now, the TSE Advisory Committee has recommended quarantine and withdrawal of materials that come from a suspected new‑variant CJD patient.  And so we have been working with the CDC on a case definition for suspected new‑variant CJD.  The reason this can come about, obviously, is because there may be a patient who has characteristics of new‑variant CJD for which we do not have a brain biopsy or an autopsy.
Suspected cases, of course, would be patients with some form of dementia and some or all of the following characteristics; a young age of onset‑‑that is, age less than 55 years.  All the new‑variant patients have had sensory or psychiatric presentations so this would be a characteristics that would raise suspicion.
In addition, overt movement disorders such as chorea and myofungus are often delayed after the initial presentation of systems.  New‑variant patients tend to have a prolonged duration of illness, an average of fourteen months as compared with classical CJD patients.  Of course, if such as suspected patient arose, the index of suspicion would be greatly increased if they had been exposed to the BSE agent, obviously by travel and residence in the BSE country.
Again, suspected new‑variant case would be somebody who did not have another explanation for having a CJD‑like illness such as iatrogenic exposure and the other things that I have outlined here.
So this is a working definition.  It hasn't been finalized.
[Slide.]
I should mention that the CDC is investigating all such cases that are reported to it.  I think, to date, they have investigated about forty suspected cases and have not come up with a new‑variant case yet.
After September, 1998, we were almost immediately challenged with an unusual case of CJD which initially raised concerns about the possibility of new‑variant CJD in a plasma donor.  This person actually does have CJD.  The patient was a regular plasma donor since 1996 and made donations through August of 1998 and had obvious signs of mental decline as of May, 1998.
So there were a couple of unusual and unexpected aspects of this case as compared with other kinds of CJD‑donor reports that we have had in the past.  First of all, the donor was very young, 29 years of age, when its symptoms were first exhibited.  In addition, there were donations made during the symptomatic period.
So the initial manufacturer action, when they heard about this case, was one with which the FDA concurred and that was to place all products and intermediates under their control on hold.
[Slide.]
Further investigation occurred.  There was a brain biopsy and this patient actually had a biopsy that was consistent with classical CJD.  Prion glycoforms were also done and the glycoform was consistent with classical and not new‑variant CJD.  However, the manufacturer voluntarily did withdraw factor VIII and factor IX.
The FDA further recommended, along with advice from the Blood Safety Committee, that the manufacturer could distribute medically necessary products such as immune globulins, antithrombin III and alpha 1 protease inhibitors.  They were asked to limit albumin distribution to documented medical requests and also to notify vaccine manufacturers to avoid use of this albumin.
This was not really a safety issue, but this was to address concerns about public confidence in vaccines.  Finally, they were asked to find out whether any of the affected product lots were used to make non‑medically necessary products and, if so, to let us know.
[Slide.]
So, finally, this is just a summary of the ongoing CJD regulatory issues and FDA actions.  Of course, FDA continues to review epidemiologic and scientific studies of CJD transmissibility by blood and, naturally, this will include new‑variant CJD.
If there are other suspected new‑variant CJD cases, we will‑‑currently, at least, we are treating any products from such a donor on a case‑by‑case basis with CDC investigation.  So we are actually working through the CDC to investigate cases like that.
Labeling issues are planned to be addressed in terms of labeling plasma derivatives with a generic statement indicating that there is a theoretical risk of transmission of the CJD agent by blood.  As you have already heard, deferral of United Kingdom donors is under discussion and will be addressed at the June 2 TSE Advisory Committee meeting.
Finally, we are in the process of drafting new recommendations of formal guidance which will include criteria for suspected and new‑variant CJD and, obviously, will incorporate, in much greater detail, the recommendations made in September, 1998.
That's all.
DR. BOYLE:  On your list of regulatory issues, why isn't mandatory reporting on that list of issues being discussed?
DR. SCOTT:  The mandatory reporting of‑‑
DR. BOYLE:  Of CJD cases, new‑variant CJD cases.
DR. SCOTT:  I think that is a CDC issue.  In other words, that has to be‑‑that is not under our control.
DR. BOYLE:  I just noticed that your list of things included things of your work with CDC, in terms of the whole blood‑product safety issue.  I was wondering where that stands.
DR. KHABBAZ:  The authority for mandatory reporting lies with states and a number of states actually have made CJD a notifiable disease.  But some have not.
DR. BOYLE:  Does CDC recommend to the states things that should be under mandatory reporting?
DR. KHABBAZ:  We work with the Counsel of States and they are the ones making the recommendation.
MR. DUBIN:  Just a couple of issues.  Obviously, we would support the mandatory reporting question.  And the landscape seems to be changing out there with classical CJD over the last six or seven months, year, year and a half.  We have seen cases of classical CJD confirmed in people in the 27‑ to 31‑year‑old range.
We are aware of two confirmed.  We believe there are three.  And that would mean that something had changed in that equation.  And we are absolutely concerned about that.  We are concerned about the slowness in which the government is responding to the British donor question.  Obviously, action in Canada, Europe and the UK has been at a different pace.
I think all of these things indicate we still have a lot to learn about this and need to put the resources on the table in both the private sector and government to get answers at the most rapid pace possible.  In lieu of those answers, I think we need to be responding faster to questions like British donors.
DR. HOLLINGER:  Thank you, Dr. Scott.  Oh; Dr. Mitchell?
DR. MITCHELL:  I had a comment and then a question about your presentation.  First of all, I think that it is important that we get information about blood products that are under the jurisdiction of other committees.  So I am very happy to be able to receive the information on the deliberations and the recommendations of the SE committee and the other Blood Product Safety and Availability Committee.
The question that I had is that you said that the recommendation was changed to not retrieve or quarantine people who are known to have CJD.  Could you talk about why that was done?
DR. SCOTT:  That is actually a talk in itself, but I think that I can summarize for you that there was a lot of reassuring epidemiologic data.  Quite a bit of that has been new since 1995 which suggested, for example, through case‑control studies, that transfusion did not infer a risk of CJD.
In addition to that, we have access to lookback studies.  The largest one, I think, is by Marian Sullivan where people did receive blood components from donors who came down with CJD or, I think even, in a few cases, actually had some symptoms of CJD.  These people have been followed, now, for up to, I think, it is twelve to fifteen years and have not come down with CJD.
There is experimental evidence which also suggests, in animals, that the titer of the CJD agent in endogenous infection is very low and that transmissibility through blood is extremely difficult unless you do a blood‑to‑brain injection.
In addition, in the last several years, we have had a lot more information about partitioning of the CJD agent in plasma derivatives and so I would refer you to Paul Brown's article in Transfusion in 1998 where he did spiking and endogenous experiments and showed that the processing of plasma derivatives just to‑‑the early fractions diminish the titer of the CJD agent.
In addition, we have access to unpublished information from manufacturers.  Some of these experiments are extremely well done which also show that the manufacturing procedures, many of them cause log reductions in titers of the CJD agent in spiking experiments.
We also, of course, have not heard of any case reports of transmissions through blood.  There is a cryoprecipitate study in Seattle where people also receive a great deal of cryoprecipitate and are now being followed, and haven't come down with CJD.
There is also some surveillance of the hemophilia community, both active now and also there was a brain‑autopsy study of hemophilia people who had died of neurologic disease.  None of those have shown evidence of CJD‑like illness.
In addition, the CDC went back and searched death records for the concurrence diagnosis of CJD and other diagnoses which would cause people to receive a lot of blood products such as hemophilia A, hemophilia B, thallasemia, and sickle‑cell anemia.
They also found now CJD cases, and there were more than 4,000 for the period that they had studied.  They had found no cases where the person also had that co‑diagnosis of one of those blood disorders.  So there was sort of a massive accumulating reassuring epidemiologic data.  In addition, there was the laboratory data.
It is the scientific weight of that.  Also, in the context of shortage of many products that has caused or precipitated this change.  I think the Blood Safety and Availability Committee also recommended that we relax our CJD criteria because of shortage but, really, it was the scientific and epidemiologic evidence that has been pushing this.
DR. HOLLINGER:  I think the problem is, though‑‑and just a comment‑‑that there is a massive and overwhelming group of scientific evidence that CJD, not the NV CJD data right now, but the CJD, does appear to be‑‑that the safety issue seems to be clear.
On the other hand, when one has a recommendation and then you remove or quarantine products under these things, I don't think that allays public fear.  I think it just, perhaps, points out to the public that you may not have the convictions that you do of this scientific data.  So I think there is a real problem here when manufacturers then remove products when the recommendations are made that it seems to be safe.
DR. EPSTEIN:  I just wanted to comment, in follow up to Mr. Dubin's remark.  Everyone, of course, is concerned about the question whether cases at a young age are increasing in frequency.  But, to the best of my knowledge, they are not.  About 95 percent of cases have always been over age 55.
There is more attention being paid to these very young cases for two reasons.  One is because of the known association of new‑variant CJD at a young age and, therefore, the need to make sure that young cases in the U.S. do not represent the appearance of new‑variant in this country.
The second is because it is known that, of the young cases that have been reported, the majority are associated with exogenous exposure.  So when you have young cases, you want to be sure you are not dealing with some form of novel, exogenous exposure.  But it is well known that, among sporadic CJD cases, 95 percent are over age 55.  That has not changed, to my knowledge.
The second point about how quickly one can proceed about considering deferral of donors with potential BSE exposure due to food consumption in endemic countries, particular of the U.K., the problem that we face is that we can't ignore the impact on the blood supply.
What we learned, to our astonishment and, as Dr. Jacobs pointed out, 11 percent of U.S. donors have resided in or traveled in the U.K.  We simply can't dispense with 11Êpercent of the blood supply.  So it is going to take us some time to find out what the impact of a deferral criterion would be and how to craft it sensibly.
I believe that is the responsible course.
MR. DUBIN:  Jay, we, of all people, wouldn't suggest for a moment that you dispense with 11 percent of your potential donors.  That has not been suggested.  We still believe, within the context of responsible action, we are not moving fast enough.  There are questions about youth.  I don't have the numbers with me.  I will get them to you.  They are in our office.  I don't have them with me.
But there has been no concept, on our part, of dumping 11 percent in an irresponsible way.  We could begin to talk about other issues as well, about the way we conceptualize the donor pool in this country, the smallness of our conceptualization.  There are a lot of issues that relate to this that have come up, and to narrow it in like that and suggest that we would make a suggestion like that, doesn't work for us, Jay.  Not at all.
DR. HOLLINGER:  Thank you, Corey.
We will move on, then, to the last committee update.  It is on Group O sensitivity in rapid test.
Group O Sensitivity in Rapid Test
DR. MIED:  We will hear from Dr. Bernard Branson of CDC who will present a CDC recommendation on this issue.  Then I will return to give the update.
DR. BRANSON:  When the first case of HIV‑1 Group O infection was detected in 1996, when CBER, on the recommendation from the Blood Products Advisory Committee, asked manufacturers of approved HIV tests to revise their currently approved products to include a consensus antigen for Group O.
CBER also instituted a requirement which specified that any new HIV‑1 test must demonstrate the ability to detect Group O in order to be considered for approval.  Several developments since that time have led CDC to conclude that, in posing this requirement, on rapid HIV tests intended for diagnostic use only, represents a major missed opportunity for public health because this requirement presents a barrier to manufacturers seeking licensure for such tests.
First, CDC's system for sentinel surveillance has allayed initial concerns about the extent and spread of Group O infection in the United States.  Only one additional case of Group O has been identified in the three years since the first case was detected in 1996.  Thus, the requirement for Group O sensitivity appears unnecessary.
HIV‑2 has been detected more frequently than GroupÊO but, because it is still rare, CDC does not recommend routine diagnostic testing for HIV‑2 unless it is warranted by epidemiologic circumstances.  Although HIV‑2 and HIV‑2 combination tests are FDA approved, a recent survey indicates that 88 percent of public‑health laboratories use HIV‑1‑only tests when testing for purposes other than blood donation.
Second, the need for rapid HIV tests that detect Group M infection, the strain observed in almost all HIV‑infected persons in the United States, has become increasingly acute.  CDC's data from clinics at publicly funded testing sites consistently demonstrate that persons do not return to receive about a quarter of positive test results.
This problem could be virtually eliminated by the use of rapid tests from which results could be provided immediately.  Thus, the use of rapid test would, each year, allow approximately 8,000 more positive test results to be provided to persons at publicly funded testing sites at the time they are tested.
Numerous studies have demonstrated that many HIV infections go undetected in persons seeking health services in emergency rooms, clinics and hospitals because they are not tested.  Since 1993, CDC has recommended that testing be routinely offered to persons in areas with high HIV prevalence when they access healthcare.
This recommendation has rarely been implemented because the logistics of testing with the convention EIA Western Blot makes this impractical.  Studies have shown that when HIV testing is offered in these venues, many tested persons do not make the routine visit required to learn their results.
Many institutions do not conduct the recommended testing because they lack the resources necessary to locate and notify the infected persons who do not return.  Using rapid tests for screening in such settings would solve many of these logistical problems and could help to identify a substantial number of HIV‑infected person who are unaware of their infection.
A study published in the February, 1999 issue of Annals of Emergency Medicine by researchers at Johns Hopkins compared standard and rapid tests among emergency department patients and found that the use of a rapid test for emergency departments was well accepted and detected a number of new HIV infections.
Even when the standard EIA test was performed immediately, persons who received the rapid test were less likely to leave before receiving their test results and more likely to keep their follow‑up appointments.
Rapid test also promises to substantially boost efforts to eliminate perinatal HIV transmission.  Data from New York State described in the November 1998 New England Journal of Medicine revealed that initiating antiretroviral therapy for infants born to HIV‑infected mothers who were not identified during pregnancy reduced transmission by 50 percent.
This prompted the State of New York to require that HIV test results for infants be available within 48Êhours of birth and also led New York to formally request FDA to expedite the approval of rapid HIV tests.
The only FDA‑approved rapid test currently available for use in the United States, SUDS, the single‑use diagnostic system for HIV‑1, is insufficient to address these needs.  Although relatively rapid, the SUDS test poses its own logistical problems in that it is cumbersome to perform and somewhat difficult to interpret.
More importantly, two recent evaluations using stored sera found a low specificity for SUDS, 75Êpercent in the WHO performance evaluation and 77 percent in the study by the neurology lab of the Walter Reed Army Institute of Research.
Even if SUDS specificity approached the 99.6Êpercent observed in the clinical trial submitted with the PMA application, there remains the problem of the low predictive value when using a single screening test in a low prevalence population.  This is of particular concern for the screening of intrapartum mothers and neonates.  A two rapid‑test algorithm will provide a much better predictive value in such populations.
Since CDC's March, 1998 recommendation for the expanded use of rapid HIV tests, several manufacturers of tests in use outside this country have indicated intentions to commercialize these tests for use in the United States.  CDC and Walter Reed have evaluated several of these tests and found their sensitivity and specificity to be excellent and a clinical trial evaluating for such tests under field conditions is currently under way in Los Angeles.
Although several of these tests, marketed outside the U.S., detect both HIV‑2 and Group O, rights for the use of these antigens are subject to complicated cross‑licensing agreements.  The requirement for Group‑O sensitivity threatens to impede or preclude their availability in this country.
Based on these observations, and in view of the urgent public‑health needs for additional rapid tests in the United States, CDC considers it prudent for CBER to suspend the requirement for inclusion of a specific Group‑O antigen in HIV tests not intended for blood screening.
CDC will maintain active surveillance for HIV subtypes and will advise CBER and the Blood Products Advisory Committee immediately of any increase in Group‑O infection that might warrant such a requirement in the future.
Thank you.
DR. MIED:  Thank you.
[Slide.]
In 1996, following the discovery of the first HIV‑1 Group‑O case in the United States, FDA sent letters to kit manufacturers alerting them to the need to move rapidly to develop new tests or to modify existing tests to detect individuals infected with HIV‑1 Group O.  This request applied to both screening and supplemental assays.
Specifically, a letter to IND holders notified them of the requirement that all new tests be able to detect Group O in order to obtain licensure for their test.  Manufacturers who had a product‑license application under review at CBER for a test which was close to licensure were requested to modify the test as soon as possible after licensure.  Manufacturers of licensed tests were requested to modify their tests as soon as possible.
[Slide.]
In the letters to kit manufacturers, FDA indicated that the modified kits should contain some portion of an HIV‑1 Group O virus.  It was stipulated that a claim of sensitivity for Group O will be permitted if the modifications to their test include the incorporation of either a Group O consensus antigen in the test‑‑that is, a published Los Alamos‑type consensus antigen‑‑or the manufacturer's own composite consensus antigen derived from reactivity data for various sequences or, a sequence from a prototype isolate that is highly representative of Group O as a whole.
Secondly, it was necessary for manufacturers to show best effort in obtaining Group‑O sera and to demonstrate reactivity of all Group‑O sera they run on their modified test.
Thirdly, it was essential for them to demonstrate that sensitivity of the test for antibodies to the Group‑M viruses had not been compromised; that is, they would need to perform an equivalency study to demonstrate that their modified kit retains its previous sensitivity for HIV‑1 Group M.
Although manufacturers have been diligently addressing this issue and making the necessary modifications to their kits, at the present time, there are no licensed tests that are labeled with a specific claim of sensitivity for Group O.  FDA is aware that the policy of requiring all new tests for HIV to be sensitive for Group O by meeting these criteria, especially the inclusion of a Group‑O antigen in the kit may be a barrier for manufacturers who wish to submit new rapid tests to FDA for approval and introduction into the U.S. marketplace.
In June of 1998, FDA brought to the Blood Products Advisory Committee the question of whether to retain the requirement of sensitivity for Group O in rapid tests for use in diagnostic settings.  The committee voted 12 to 1 that FDA should continue to require Group‑O sensitivity in all new HIV tests to be used in a diagnostic setting.
[Slide.]
However, FDA had reconsidered this issue for several reasons.  As Dr. Branson had indicated, there have been only two HIV‑1 Group‑O cases identified in the United States.  These two cases, which were discovered by CDC's ongoing surveillance for HIV variance represent an extremely low incidence of Group O infection.
A CDC study showed that the currently licensed blood‑screening or diagnostic kits, including the licensed rapid test, detect most Group‑O sera due to cross reactivity with the Group M antigens in the kits.
In recent studies conducted by Dr. Neil Constantine using a panel of 24 Group‑O sera, five out of eight unlicensed internationally available rapid tests detected 100 percent of the samples while three of the tests detected 89 percent to 96 percent of the Group‑O samples.  It is of note that four of the five tests that detected all 24Êsamples did not contain a Group‑O antigen.
[Slide.]
The major reason for the FDA reconsidering its policy on Group‑O sensitivity in rapid tests is that of the public‑health benefit that would result from the approval of additional rapid tests.  In the March, 1998 MMWR on expanded use of rapid tests, CDC estimated that, in 1995, over 8,000 more infected individuals would have learned of their infection if a rapid test were used.
In the MMWR, the Public Health Service advocated providing preliminary positive results from a rapid test to the patient at the time of their first visit to the clinic.  In settings with a high prevalence of HIV infection where the rate of patient return for test results is low, this would be a clear public‑health benefit.
However, of the two rapid tests which have been licensed by FDA, only one remains commercially available, the Murex SUDS test.  Use of the Murex test alone carries the disadvantage of having more than 8,000 additional preliminary false positives per year.
When FDA approves another rapid test, that test could be used concurrently with the Murex test to minimize preliminary false‑positive notifications.  It is for this reason that the World Health Organization currently recommends that combinations of rapid tests be run.
With the approval of another rapid test, the Public Health Service could recommend a diagnostic algorithm governing the concurrent use of two rapid tests to improve the predictive value of a positive test result.  So, to help achieve this public‑health benefit, FDA would like to facilitate the submission and approval of applications for rapid diagnostic tests.
Inclusion of Group‑O sensitivity is a clear barrier to market for manufacturers of rapid tests so, in accordance with CDC's position statement on this issue as presented by Dr. Branson, FDA, therefore, has suspended the requirement of inclusion of a specific Group‑O antigen in rapid tests for HIV‑1 antibody for use in a diagnostic setting.
[Slide.]
For approval, the manufacturer of a rapid test that does not include a specific Group‑O antigen will be required to demonstrate a level of sensitivity for Group‑O sera based on cross‑reactivity with the current Group‑M antigens in the test that is comparable to that of the currently licensed non‑rapid EIA tests for HIV antibodies.
In addition, FDA may require labeling for Group‑O cross‑reactivity based on a panel of sera.  This approach was useful in the past to address cross‑reactivity for HIV‑2 and HTLV‑2 without creating a false claim for kits that lacked the specific antigens.
In addition, for approval of a rapid test, the manufacturer will be required to make an explicit commitment to file a PMA amendment within two years of initial approval to modify the test to obtain a specific claim for sensitivity for Group O.  This amendment would include the incorporation of the Group‑O antigen in the test an clinical‑trial results that demonstrate Group‑O detectability as well as retention of sensitivity for HIV‑1 Group M.
I should emphasize that this policy does not affect the current requirement that new tests licensed for use in blood screening include a Group‑O antigen in the test and be labeled with a claim for sensitivity for HIV‑1 GroupÊO.
We welcome feedback from the committee on FDA's current policy which suspends the requirement for inclusion of a specific Group‑O antigen in rapid diagnostic tests.
DR. HOLLINGER:  Any comments?  Any questions?
DR. LINDEN:  I have two questions.  One; when is, or was, this effective?
DR. MIED:  We are making it effective now.  The suspension of the requirement for inclusion of a Group‑O antigen in a rapid test.
DR. LINDEN:  Do you have any feedback from any potential sponsors as for how many this might make a change that will cause them to apply?
DR. MIED:  We think it will help most of the manufacturers because there are difficulties with obtaining patent positions and licensure of the rights to using specific Group‑O sequences in the United States.  It is a very difficult matter for them and that alone, is a major part of the reason why it represents a barrier to inclusion of such antigens in a rapid test.
DR. LINDEN:  My last question is I assume that there is no change in terms of the product that is currently on the market; right?  I mean, they are approved and there is not a necessity for them to move to group O?
DR. MIED:  Are you referring to the Murex subtest?
DR. LINDEN:  Yes.
DR. MIED:  In the CDC study that I talked about a little earlier, I believe the Murex subtest, although the numbers are low, did detect seven of eight Group‑O sera in that evaluation.  So it does well with Group‑O sensitivity as it is.
DR. LINDEN:  Thank you.
DR. HOLLINGER:  Thank you, Dr. Meid.  This concludes the committee updates.  We are now going to move into the first open session.  The session, at this point, is on nucleic acid testing of whole blood.  It is informational, primarily.  The committee does not have any questions to respond to.  It is mostly for discussion later on.
I want to remind the speakers that the time allotment that is given to you is ten minutes.  We will hold you to that.
So the first person to discuss this is Dr. Hewlett who will give an introduction and background to the session.
Dr. Hewlett?
I. NUCLEIC ACID TESTING OF WHOLE BLOOD‑‑INFORMATIONAL
Introduction and Background
DR. HEWLETT:  Thank you, Dr. Hollinger and good morning, everyone.
[Slide.]
This morning, we are going to discuss the status of nucleic‑acid testing, or NAT, of whole‑blood donations by testing minipools of plasma.  I would like to also mention that this is an information session intended to provide the committee with an understanding of how NAT is being implemented and some of the issues surrounding this implementation.
[Slide.]
By way of background, the key measures in place to insure viral safety of blood and blood products are the screening of donations for the presence of viral antigens and antibodies and the use of viral inactivation methods to eliminate virus from products.
However, a small number of transmissions continue to occur, primarily from whole blood and transfusable components collected during the seronegative phase of infection.
[Slide.]
In September, 1994, FDA held a conference on the feasibility of genetic technology to close the HIV window in donor screening.  Data presented at this conference indicated that nucleic‑acid testing could reduce the infectious window period, particularly of HIV and HCV from several days to several weeks.
However, the techniques in development did not lend themselves to application for mass screening at that time.  As an interim measure, to further reduce the low risk in HIV transmission, p24‑antigen screening of blood and plasma was implemented.  The former Commissioner of our administration, Dr. David Kessler, had urged the plasma‑derivatives industry and the blood‑banking community at the time to purse the development and implementation of new technology that would improve the safety of the blood supply.
[Slide.]
Since then, industry, in collaboration with government, has been actively engaged in developing NAT for donor screening.  Due to the complex and labor‑intensive nature of this type of testing, there was considerable interest in screening small pools, or minipools, rather than single donations.
Also, testing minipools is a concept in process control to assure viral safety of fractionation pools.  By 1997, some countries in Europe had initiated voluntary screening of donations by testing pooled donations of plasma using a nucleic‑acid‑based method.
Also, a directive was issued by the European Union that HCV RNA testing would be required in Europe for all plasma for fractionation by July 1, 1999 and that HIV‑1 testing of such plasma would be required at some unspecified later date.
[Slide.]
This move on the part of the Europeans created an impetus in the U.S. to implement such testing for blood and plasma.  FDA discussed its position that pool testing would be considered a form of donor screening at the Blood Products Advisory Committee meeting in September, 1997.
FDA also developed guidance outlining regulatory approaches for implementing pool testing and discussed them at this meeting.  Briefly, FDA described possible approaches to implementing testing under the IND involving three potential scenarios for pool testing; one, a commercially provided test kit; two, a testing service; and, three, an in‑house test.
In addition, FDA developed and published draft guidance to industry for validation of nucleic‑acid tests.  At this time, virtually all source plasma‑‑that is, at the present time‑‑in the U.S. is being screened for HCV RNA by a nucleic‑acid‑based test and some source plasma is being tested in a similar manner for HIV‑1.  A significant portion of this testing is performed by a central testing laboratory or a testing service.
[Slide.]
The primary regulatory concerns for FDA in regard to pool testing by NAT include, but are not limited to, the manufacturing consistency of the test, pool size and its impact on test sensitivity, clinical and analytical sensitivity and specificity, reproducibility, validation of methods for tracing positive results back to the unit and the donor, and validation of instrument and software as well as lot‑release requirements for the test.
FDA also defined a proposed sensitivity limit of 100 copies per ml which is the analytic sensitivity of the pool test and is currently considering establishing a sensitivity limit of 5,000 copies per ml for the original donation.  Compliance with these limits will be monitored using reference materials and lot‑release panels developed by FDA in addition to clinical trials.
[Slide.]
The European directive spurred the development and implementation of pool testing for whole blood donations at a rapid pace.  Establishments involved in the collection of whole blood and transfusible components are currently implementing plasma pool testing nationwide under the IND.  Again, testing is being accomplished by the use of test kits or by centralized testing laboratories.
Due to the current technology limitations, NAT requires several days more than conventional tests and, consequently, some blood products‑‑example, platelets and some red cells‑‑are expected to be released on the basis of serology, basically.  This is necessary to prevent product shortages and harm caused due to lack of products.
This phase, which is expected to be of short duration, will be followed by a phase where all components are released on the basis of both NAT and serology.
[Slide.]
Other implementation issues are that donor testing in all cases is subject to informed consent and the necessary IRB approvals.  Issues such as donor notification and counseling, deferral and lookback, are consistent with the practice that has been developed for other viral marker tests.  Donors whose blood is confirmed as being NAT‑reactive are notified and counseled regarding their investigational test result.
Such donors are deferred until their status is resolved and are indefinitely deferred from donating after they have undergone seroconversion.  During the phase where products are released on the basis of serology only, a small number of recipients of labile components may be informed that they had received a product that was potentially at risk for HCV or HIV based on an experimental test on the donor.
Such recipients would be appropriately counseled and referred for follow up and medical care as well as follow‑up testing.  FDA allows local hospitals to decide whether the risk of such notification necessitates any special notice to patients prior to transfusion.  In the subsequent phase, when products are released on the basis of both serology and NAT, it is anticipated that this number will be reduced.
[Slide.]
In conclusion, NAT is being implement for whole blood via the IND mechanism.  NAT testing is expected to further reduce the low risk of viral transmission of HIV and HCV during the window period and the introduction of NAT is considered a major public‑health advancement in viral safety of blood and blood products.
So, with that, I will conclude my presentation.  I would just like to say that in the presentations that will follow, you will hear from various blood organizations and manufacturers of test kits about the strategies and approaches to implementing NAT in the blood‑bank setting.
Thank you.
DR. HOLLINGER:  Thank you, Dr. Hewlett.
The next speaker is from Gen‑Probe, Dr. Christina Giachetti.
High‑Throughput Assay for the Simultaneous
Detection of HIV‑1 and HCV RNAs
DR. GIACHETTI:  Thank you.
[Slide.]
I would like to thank the organizers for inviting me to give this talk.  I will present the Gen‑Probe high‑throughput assay for the simultaneous detection of HIV and HCV RNA.
Gen‑Probe's strategy is to develop a cost‑effective high‑throughput automated system named TIGRIS for the detection of HIV and HCV RNA for individual donor testing and, as an interim measure until TIGRIS is commercially available, to develop a semi‑automatic system, the TMA component system for plasma pool testing.
This test is currently used at the American Red Cross.
[Slide.]
Our assay objectives are shown here.  It is an analytical sensitivity of 100 copies per ml, detection of HCV and HIV subtypes, detection of infection before seroconversion, a specificity higher than 99.5Êpercent, incorporation of internal control.  The same reagent formulations will be applicable to both systems, the semi‑automatic and the fully‑automatic.  And we provide discriminatory assays for resolution of multiplex assays repetitive reactives.
[Slide.]
The assay protocol consists of three steps.  They are all hybridization based and they are all fully integrated.  The steps are sample processing followed by amplification and then detection.
[Slide.]
For the sample preparation, we use target capture and magnetic microparticle separation.  During these, the RNA target is hybridized to a capture probe with hybridization through a poly‑A‑tail to a poly‑DT‑tail which is present in magnetic microparticles.  Once hybridization occurs, the use of magnetic rods allows separation our or input target from all the rest of the specimens.
The system is very efficient and allows for batch processing of the samples and allows us to eliminate all potential inhibitory substances.
[Slide.]
Following sample processing, we do transcription‑mediated amplification to amplify our target.  The reaction uses two enzymes, reverse transcriptase and T7 polymerase.  It can be used to RNA or DNA targets.  It produces a RNA amplicon.  The system is very efficient.  In our reactions, we generate around 1012 molecules of HIV and HCV per copy input of target and the reaction is isothermal.
[Slide.]
Detection occurs with the hybridization protection assay.  During this assay, what you do is you utilize acridinium ester‑labeled probes which will hybridize to our target amplicon RNA.
[Slide.]
Hybridization of the probe to the RNA allows for protection of the A level so that addition of a selection reagent will only destroy the level on the non‑hybridized probe, and then the hybridized probe is passed to a detection step where chemiluminescence allows detective of our protected probe.
[Slide.]
Incorporation of the internal control requires the use of the dual kinetic analysis.  They use different acridinium ester labels with different kinetics.  We label our internal control with a probe with rapid kinetics which called a flasher probe and our target molecules are labeled with a glower probe with slow kinetics.  We use the exponential tail‑fit algorithm to be able to deconvolute the mixed signal and calculate the amount of internal control or target that we have in each sample.
[Slide.]
I will switch here to show some data for assay performance.  We tested analytical sensitivity, clinical sensitivity, subtype detection and specificity.  First, HIV sensitivity.  Here, I am showing this table which is analytical sensitivity for four different lots of reagents and manufacturers.
As you can see, in all the cases, we were able to obtain 100 percent detection at the 100 copies per ml level.  Also, sensitivity is still very good at 30 copies per ml where our lots have between 88 and 98 percent detection at 30 copies per ml.
To confirm these, we have tested different panels.  In this case, I am showing results from the CBER panel distributed in 1997.  As you can see, we can detect as positive signals all the positive panel members including the one which has just 25 copies per ml.
[Slide.]
We make it big effort to demonstrate detection of different subtypes.  Here is a summary in which I show which are the different subtypes which we have tested, subtypes from A to H belongs to Group M and also we tested subtypes that belonged to the new Group N as well as type Os.
As you can see, for type O, we tested a total of 39 different viral isolates and 19 different specimens.  In all the cases, are test is able to detect it even after very serial dilution of the viral isolates down to 10‑6 or 10‑8 dilution.
[Slide.]
We tested clinical sensitivity in seroconversion panels.  On an average, our test is able to detect infections 3.6 days before seroconversion and we are able to detect infection 7.5 days before the detection with p24 antigen.  If these samples are pool‑diluted, we still were able to have early detection with this test.
[Slide.]
Now to HCV sensitivity.
[Slide.]
Here, again, I am showing results from four different clinical lots.  In all the cases, we were able to have 100 percent detection in 100 copies per ml.  Sensitivity, at 30 copies per ml, is between 100 and 90Êpercent for our lot, showing very good sensitivity.
Again, we tested different panels.  Here is the HCV panel distributed lots here and we were able to detect HCV in all the panel members including the one that had just 5 genomic equivalents per ml.  In many cases, we were able to detect it after further dilution.
[Slide.]
Again, here we detect subtype from Group 1 to 5.  And, in all the cases, our test is positive for all the HCV subtypes.  Clinical sensitivity was tested with these seroconversion panels.  On average, we were able to detect HCV infections 83.8 days before seroconversion for undiluted samples.  For pool‑diluted samples, still we were able to detect 31.7 days before seroconversion.
[Slide.]
Specificity was tested in normal plasma as well as a variety of problematic samples.  I am just going to show the results from normal plasma.  Here we show specificity studies with four different lots of reagents that we have manufactured so far.  Overall, specificity, in terms of repetitive reactive rate is 0 percent.  This test has very good specificity.
Also, we monitor internal control as a measure of assay inhibition and our repetitive internal‑control failure rate is 0 percent confirming that our method removes all potential inhibitors.
[Slide.]
Conclusions regarding specificity; we haven't found any cross‑reactivity with other infectious agents or conditions of liver diseases.  No interfering substances have been found so far.  Our sample processing removes all interfering substances and we have an internal control that is very useful for confirmation of amplification performance.
Regarding sensitivity, we have 95 percent detection of 100 copies per ml and 50 percent detection at the 8Êcopies per ml letter.  For HCV, 95 percent detection at 100 genomic equivalents per ml and 50 percent detection at the 5 genomic equivalents per ml level.
We were able to detect virus before seroconversion on an average 16.3 days before antibody and 7.5 days before p24 antigen for HIV.
[Slide.]
For HCV, we were able to detect 32.8Êdays before seroconversion.  We were able to detect all different subtypes including type O and N as well as HCV subtypes.
[Slide.]
Finally, this process has been funded in part by federal funds from the National Institute of Heart, Lung and Blood.
Thank you very much.
DR. HOLLINGER:  Thank you.
The next speaker is from the American Red Cross, Dr. Susan Stramer.
American Red Cross
DR. STRAMER:  Thank you.  I am going to update the committee and others present on the progress that the American Red Cross has made for NAT testing for HIV and HCV.
[Slide.]
First, I need to go through a little bit of the history that the Red Cross has had with NAT.  In December of 1996, the Red Cross submitted an amendment to National Genetic Institute's IND using pool using sizes of 512 for HCV and HIV PCR testing.  That pooling and testing would have occurred at NGI.
Following that, myself and Roger Dodd met with members of NHLBI to solicit increased support for Gen‑Probe to pursue pool testing.  That occurred during September of '97.  That would allow pooling and testing within the blood center control.
Following that, the Red Cross submitted a two‑part IND with Gen‑Probe and that included using pool sizes of 128 on the test you just heard described, the multiplex HIV‑1 HCV transcription‑mediated amplification assay including discriminatory‑probe reagents; that is, when you get a multiplex reactivity, you then have the ability to distinguish HIV from HCV reactivity.  The Gen‑Probe submission went in on December 14.
[Slide.]
The Red Cross submission went in on 12‑23.  We received IND approval on January 21 and we initiated linked testing on March 3 of this year with collection starting from March 1.  This corresponded with AABB releases of the Association bulletins on NAT, 99.3 and 99.6.
[Slide.]
Our program objectives include to evaluate the feasibility, efficacy and performance characteristics of the Gen‑Probe test.  Regarding performance, what we are going to evaluate is sensitivity, specificity and reproducibility of both the multiplex and discriminatory reagents.  Under that, we must meet all international regulatory standards including those from Europe‑‑that is the CPMP requirement, which is a test requirement‑‑and, as you have heard from Dr. Hewlett, an FDA requirement per test and an FDA requirement per donation of 5,000 copies per ml.
As part of the feasibility and efficacy, we must implement NAT to testing to meet the European plasma requirements promulgated for July 1, 1999 with the eventual release of all products based on NAT.
[Slide.]
Other IND objectives are to define the meaning of the NAT‑reactive seronegative result; that is, to determine the yield and time‑to‑seroconversion for both HIV and HCV and through resolution by follow‑up testing which I will describe in more detail.
Also, as one goal which you will hear more about this afternoon, is to evaluate the replacement of p24 antigen testing.
[Slide.]
To go through our IND program in a little more detail, all 37 Red Cross regions collect samples in a dedicated tube which is a plasma preparation tube which is a plastic gel‑sep tube spray‑coated with EDTA which we find to be the anticoagulant of choice for the stability of RNA.  All regions will ship their tubes to a one centralized facility within the Red Cross referred to as the National Genome Testing Laboratory, NGTL.
At the NGTL, during our phase I, which I said has started on March 3, we will construct pools of 128 donations using the Tecan robot.  Anti‑HIV and anti‑HCV seroreactives will be removed prior to pooling.  In this program, management of donors and products will be based on a reactive single donor.  All products, except for plasma‑‑that is cellular products‑‑will be released during phase I based on serology.
Results will be available on it is actually daysÊ3 to 4 following collection and we anticipate, even with this turnaround, that 70 to 80 percent of red cells will still be in our control and available to quarantine if we get a NAT‑reactive result.
[Slide.]
The pooling scheme looks something like this.  We take 128 individual donations, put them into primary pools of 16‑‑and this is important because I will be focusing on primary pools.  All eight primary pools, then, are pooled by the robot into a 128‑member pool.
If a reactive pool occurs at the 128 level, the resolution scheme involves testing all eight primary pools containing sixteen donations each.  One reactive primary pool is identified and then the individual donations are tested.  We have one individual donation in our program donor and product management.
[Slide.]
Our phase II, which is projected to begin on July of '99, will involve pools of 16.  As I just showed you, we are already creating those pools by the Tecan.  They will include all seroreactives.  That is so we have simultaneous release of all products based on NAT and serology.  All donors that have a NAT test result in this case‑‑any seroreactive will have a NAT result as well which will aid in donor counseling.
The main part of this program is that all products then will be released based on NAT.  We will then add NAT testing to one or two of our national testing laboratories so we can really expedite turnaround time and, finally, we will pursue FDA licensure.
[Slide.]
Phase I program donor notification is based on the reactive donation, as I said, following the discriminatory results so we know if the donor is HIV or HCV reactive.  We will then follow up the TMA test by a confirmatory NAT test of a different type and that will be PCR testing at NGI.
Product withdrawal and recovery, as I said, will be based on the reactive donation.  Consignees then will be further notified as we find out the discriminatory test result that is HIV or HCV.  Previous collections from NAT‑reactive donations will be recovered for three months for HIV and twelve months for HCV‑‑that is, following the established FDA guidelines.
Lookback of previous donations‑‑that is, recipient tracing of previous donations‑‑will be performed only if a discriminatory test result is confirmed by a supplemental NAT test.
[Slide.]
Regarding our IRB issues for donor management, our study involves donors as the study subjects of the IND under informed consent.  HIV and HCV NAT‑reactive subjects following discriminatory testing will be enrolled in a follow‑up study to resolve the meaning of the NAT result.  HIV follow up will be for three months or until seroconversion occurs with weekly sampling.
Testing will include p24 antigen, HIV‑1,‑2 antibody and Western Blot if applicable; supplemental NAT test, again, at NGI which will include a quantitative test and genotyping.  For HCV, we will do twelve months or until seroconversion occurs with monthly sampling.  Testing for ALT, HCV antibody, RIBA is appropriate, supplemental NAT which will then include NGI PCR quantitative and genotyping.
[Slide.]
Recipient management; you heard a little bit about this from Indira.  Let me elaborate.  Recipients are outcome of this research.  However, they are not classified as research subjects of this IND.  During phase I, what our Red Cross IRB, has required us to do is notify hospitals of the program such that modification of transfusion consent can be determined by each hospital individually.
Recipients receiving NAT‑reactive units‑‑we hope them to be very few, if at all‑‑will be notified when the individual donation is identified followed by letting them know the discriminatory results‑‑that is HIV or HCV‑‑followed by any other supplemental testing information that we have on NAT and follow‑up information.
Let me just comment that these units would be transfused if we were not doing NAT testing so this does not decrease the safety of the blood supply.  This also enables early treatment as an option and knowledge regarding secondary transmission, if we inform these recipients.
It will be up to the primary‑care physician and the transfusion‑service medical director to determine if there is post‑exposure treatment.
[Slide.]
Our time line; phase I, I said, initiated on 3‑3‑99.  We are now up to 14 regions who are doing testing with all 37 blood‑collection regions testing by June 7.  Our phase‑I modifications, which are actually occurring now but will take full swing in the middle of April, will be shipped as we collect.  So, as we collect samples, they will be immediately shipped for testing.
Discriminatory testing will be moved up to the primary pool level so that as soon as we find a reactive donation, we also know, presumptively, if it is HIV or HCV.  We will base product quarantine on the reactive master pool‑‑that is, on the pool of 128‑‑and you will see that the specificity of this test is so good that it will allow that.  This will enable us to immediately take control of product either within Red Cross control or consignee control.
As I mentioned, our phase II project is targeted for July 1 and this, again, will involve all product‑release based on NAT and then we will file a PLA.
[Slide.]
Just to show you some data, before I get terminated, our sample storage‑requirement studies have been divided into two sections; whole blood and plasma.  This gives you these three bullets here.  We collected EDTA.  We will store for up to three days as whole blood at temperatures less than 10 degrees, less than or equal to 10Êdegrees.
EDTA plasma, the same temperature requirement.  But we have a prolonged storage time as plasma‑‑this was the time period, seven days, we did our studies at‑‑with no greater than 24 hours at room temperature.  Room temperature and time sitting on the cells is what destroys RNA from the studies that we have done.
[Slide.]
Look at specificity, the specificity of this test is, again, excellent.  We looked at three different master lots denoted by three different colors.  The population mean is all less than 0.3 which is really excellent for the test.  We have no reactive samples in our pre‑clinical feasibility study including almost 200,000 donations.
[Slide.]
Looking at sensitivity, briefly, this is a plasma seroconversion series.  You can see frequent sampling here.  Blue indicates for HCV when the donor became EIA reactive.  You can see a 46‑day window period if you look against quantitative PCR.  These were the data we generated with the National Genetics Institute under that IND.
[Slide.]
Then, adding the data from the TMA IND, the Gen‑Probe IND, you can see that if we do the testing either at a neat, undiluted or multiplex of 128 pool size, there is no difference.  So there is no difference between the dilution and undiluted sample.
[Slide.]
Looking at another seroconversion series for HCV, because this one is a little different, here you see a 32‑day window period reduction from the EIA‑‑that's serology anti‑HCV 3.0‑‑to the first reactive on the NAT test that is PCR, quantitative PCR.
[Slide.]
If you add the TMA data to that, interestingly enough, the multiplex test here, tested neat, was a little bit more sensitive, three days more sensitive than quantitative PCR but we lost seven days here based on the pooling of 128 dilution.
Interestingly enough, the sample that was not detected at a pool had 100,000 copies.  What we have seen reproducibly in our hands is HCV does aggregate and it does influence the efficacy of pooling if you are doing large pool sizes.  But it is really not an issue with pool sizes of 128 or lower, as I will show you.
[Slide.]
Looking at the reactivity of a neat‑‑that is, undiluted‑‑sample relative to a pool dilution of 128, and these are only the seronegative donations on this X‑Y plot‑‑shows you only those critical samples.  There are only two samples in this study of 117 total, actually from 22 individuals, that were not detected when diluted.
[Slide.]
These samples had this viral load, 100,000 and 90,000.  Here you can see the diluted S to CO and undiluted S to CO.
[Slide.]
So if we look at the analytical sensitivity studies that we did under IND, these were now not control samples as Indira talked about, but real seroconversion samples that we diluted to endpoint in which we did see aggregation.  We saw a mean endpoint titer of these samples at 95 percent confidence using Spearman‑Karber analysis of 4,395 copies per test.  That was the limit of detection.
If you multiply this by a pool size of 16, that would give us a theoretical cutoff of 70,000 copies and the two samples I showed you, those two of 117, had 90,000 and 100,000 copies per ml.  So, even under worst‑case conditions predicted by aggregation, we would detect those two samples at a 1 to 16 dilution.
So, in this case, HCV testing in a pool size of 16 is equivalent to single‑donation testing.
[Slide.]
Doing the same analysis for HIV, you see here the neat assay plotted on the X axis and the 128 dilution plotted on the Y axis.  There were eight such samples that fell below the cutoff at a pool dilution of 128.
[Slide.]
Looking at the viral load in these samples‑‑firstly, let me say they were all p24‑antigen negative.  This is the multiplex S to CO undilute.  This is the diluted S to CO at pools sizes of 128.  This is viral load.
[Slide.]
Doing the same type of analysis by Spearman‑Karber on seroconversion samples gave us a 95 percent endpoint detection by the test at 66 copies per ml.  Multiplied by 16 would give us a final copy number of 1,056.  So all eight samples that I showed you on the previous slide would not be detected at a pool size of 16.
So, interestingly enough, in this study for HIV, a pool size of 128 was equivalent to that of a pool size of 16.  However, if we use the p24 antigen yield to project how frequently we would see such individuals, they would occur once‑‑that is, one of these sample from seven different donors‑‑in every 2.68 years.
[Slide.]
So, in conclusion, we believe there is earlier detection for HIV and HCV.  By our pooled NAT program, we will decrease the possibility of a viremic window‑period donation.  I didn't go through all the means of this, but based on a viremic window period for HIV of six to ten days, pool testing, even in pools, in this case, as large as 500 would have cut the window period down by 30 to 50 percent.
For HCV, similarly, the viremic window period as defined in our studies at 41 to 57 days, would be cut by 50 to 98 percent doing pooled NAT testing.  All the unlinked studies we have done, including, now, linked studies of 86,016 donations, revealed no false‑positive results.  And, as an update, we have also had no true positives, either.
Thank you.
DR. HOLLINGER:  Thank you, Susan.
The next speaker, Dr. Michael Busch, is going to be talking for the America's Blood Centers.
Blood Centers of the Pacific, Irwin Center
DR. BUSCH:  I will presenting a summary of one of the two America's Blood Centers' NAT implementation programs.
[Slide.]
America's Blood Centers represents a consortium of the majority of the non‑Red‑Cross blood centers in the country representing approximately half the blood‑collection program.
America's Blood Centers have developed two relationships and is submitting two INDs.  One of these relationships is with Gen‑Probe Chiron and I will be presenting that program.  Then later we will hear the program that is a collaboration with Roche.
I will be summarizing each of these points with the exception of skipping a number of slides on test methodology because you have already seen a summary of that from the folks from Gen‑Probe.
[Slide.]
The program will consist of three testing laboratories.  The IND will actually has been submitted under the overall sponsorship of ADC with collaborators, a coordinating center, NCGS, and Gen‑Probe Chiron, the test manufacturer.  There will actually be a cross‑reference to the IND submitted by Gen‑Probe in the context of the Red Cross program.
So much of what we will be presenting in this talk will be built on the prior two presentations, the Chiron‑Gen‑Probe test system and the Red Cross strategy for many of the implementation processes.
There will be three testing laboratories; the Blood Centers of Southeast Wisconsin, Blood Systems in Scottsdale and the Florida Blood Services.  Overall, there will be approximately 60 different collection centers contributing specimens to these three laboratories and, overall, there are approximately 2.5 million donations which will tested annually by these three laboratories.
[Slide.]
We have gone through the appropriate process in terms of institutional review.  We have already obtained IRB approval using a central IRB.  The donors, like the Red Cross program, are considered the research subjects, not the recipients, and the donors will be required to consent.  Actually, the consent is built in to the routine donor informed consent with an extra information sheet apprising the donors of the full context of the NAT testing and potential follow‑up activities.
If the donors are found to be reactive, they then proceed through a more complete informed consent for follow up activities.  The participation in the study is a required event.  So, in other words, a donor cannot give blood, an allogeneic donor, without agreeing to participate in the NAT activities.
[Slide.]
The study, in terms of the IND formal study component, will really take place during the very brief period following implementation of NAT testing with continued testing after the initial phase under IND. But, in terms of generating the critical data to submit the FDA, that will be generated rather quickly and is really focused on a quick validation of the specificity of the test system, the reproducibility and sensitivity in the context of external standards, and then the logistical issues; can this program operate without significantly impacting blood availability.
[Slide.]
In terms of this initial phase specificity study, per FDA expectations, the initial phase will represent approximately 270,000 donations that will distributed in 11,000 pools.  This will actually be accomplished in the course of only about several months of initial phase testing.  We feel this will be an adequate period to define the specificity of the assay and to demonstrate the performance characteristics in the context of the sensitivity and logistical issues.
The committee handout can skip through the next about eight slides because they are really a repetition of the Gen‑Probe test platform.
[Slide.]
Some of the details in terms of samples and then a little bit of logistics.  We will be using EDTA anticoagulated specimens like the Red Cross although we will not be using the PPT special tubes.  We believe that the logistics and turnaround time we are able to accomplish will allow us to process the pooled specimens in time to meet the storage requirements.
The stability data that Gen‑Probe has generated, much of which is in collaboration with the Red Cross, we believe documents the current package‑insert stipulation that the samples need to be tested within 72 hours of holding at a reduced, below room‑temperature hold, of which no more than 24 hours would actually be at full‑fledged room temperature.
And then the residual period, up to five days after separation, complete separation off of the spun packed‑cell red‑cell pellet could be held‑‑the plasma could be held a further period of 2 to 10 degrees.  The samples will be transported from the point of collection through to the central laboratory and all subsequent downstream periods under validated shipping and storage conditions.
An important component of the ABC Gen‑Probe strategy is actually to try to demonstrate the potential to do a sorting strategy.  This involves sorting the donations into those that come from first‑time versus repeat donors.  Actually, within this single IND, two of the three testing sites will test all comers in parallel; in other words, seroreactive donations will be admixed with unscreened products.
Basically all products will go through NAT testing in parallel with serology whereas the larger testing site will sort donations into the 20 percent of donations that come from first‑time donors versus the 80 percent that come from repeat donors.
The strategy here is to take the 80 percent from repeat donors straight through the NAT testing in parallel with serology with results out almost at the same time as results are out currently releasing product hopefully within four to eight hours of current release, whereas the first‑time donors in which the vast majority of your seropositive specimens are represented will be held back.
Those donations will not be processed through for NAT testing until the serology is available and the seroreactive units removed.  The advantage of this is that dramatic reduction in the number of projected NAT‑positive pools by culling out what would be approximately 98 percent of seropositive specimens through this sort of the first‑time donors.
This will dramatically reduce, by about 50 percent, the number of repeat resolution tests performed, a substantial reduction of cost and labor and, most important, the potential for contamination of laboratories due to the representation of seroreactive units in the overall process.
[Slide.]
Our pooling strategy will consist of predominantly pooling donations into pools of 24.  Basically, at the end of runs, if there are less than 24 donations left that require testing, those specimens will be tested singly.  So we will either be testing pools of 24 or individual donations.
Like the Red Cross, we will be using a Tecan pipetting system to generate the pools, and all of the software has been established to link the pooled process with the final resolution in testing output data.  We are validating that every pool has been generated appropriately through weighing of the intermediate pools and the final pools to validate that all specimens were introduced as appropriate.
[Slide.]
Samples will be screened using the Gen‑Probe system with the initial pool tested by the multiplex HIV‑HCV assay.  The individual donations from reactive pools with be then tested again in singlicate by the multiplex assay and then further testing using the discriminatory HIV‑1 and HCV assays.
Product interdiction and donor deferral will be based on the individual reactive multiplex result.  In other words, at the point where an individual donation is determined to be reactive on the multiplex assay, it is at that point that we will defer the donors and trigger recall of products from that donation and any prior donations from that donor.
In terms of notification of the recipients, however, we will wait until we have determined which virus is responsible.  So we will wait until that next run‑through where we have discriminated is it HIV‑1 or HCV before we would notify recipients of the current donation, were they in phase I released.
In contrast further, prior recipients‑‑so lookback notification to prior recipients, we feel, should be further justified by even additional data confirming infection either by a supplemental NAT procedure or follow‑up testing on an alternative sample.
[Slide.]
In terms of the phasing of the activity, like the Red Cross and, as indicated by Indira at the beginning, during the very early implementation phase, we do not want to jeopardize blood availability.  Were there some problems, our program is actually phased to try to implement on‑line testing as soon as possible, hopefully within weeks to months of implementation of initial testing.
But during this initial trial and implementation phase, we recognize that it may be necessary to release blood based on serology and we are planning to implement the phase‑I testing on April 15.  During this period, all frozen products will be released strictly based on NAT results plus serology.
And then we hope to rapidly transition to phase II.  The pool sizes are small enough and the centers testing distributed enough that we anticipate being able to do this in the first several months of primary testing.  This will be actually site‑specific and really based on the ability to work out the logistical issues that require availability of NAT data to release product.
[Slide.]
This is just an illustration.  There are actually about fifteen of these resolution algorithms.  I don't have time to walk through them, obviously, but just to give you a sense of the complexity of sorting through combining the serology with the NAT data and, depending on the results, various discriminatory processes kick in.
It is an extraordinarily process and I should comment, particularly, that Sally Cagliotti of Blood Systems has really been the drive of this ABC program and has done an outstanding job of pulling this whole process together.
[Slide.]
Finally, a few of the donor follow‑up issues.  Much of this activity has been modeled on the Red Cross' program.  I really compliment the Red Cross on being extraordinarily forthcoming and sharing with a number of procedures and policies that have been well thought out and have been adopted by the ABC programs.
We will be following, actually, at FDA's request, up to 100 persons who are found to be antibody‑confirmed positive and NAT negative.  This is something that is just sort of peripheral to the critical issues here.  We will follow all donors who are found to be NAT positive and serology negative.  This is the critical question yield of the program including HCV, NAT reactives monthly for one year or through seroconversion and HIV weekly for three months, then at six months and twelve months or until seroconversion.
The donors will be followed both using an alternative NAT procedure as well as standard follow‑up serology and the NAT test of record here.
That completes the presentation.  Thank you.
DR. HOLLINGER:  Thank you very much.
The next presentation will be by Mr. John Flynn of the Association of Independent Blood Centers.
Association of Independent Blood Centers
DR. GAMMON:  Actually, I am Dr. Richard Gammon, the principal investigator.  I am going to be presenting the presentation for the Association of Independent Blood Centers.  I want to start the talk off by giving a little bit of background of the Association of Independent Blood Centers and then I want to move to our testing strategies.
The Association of Independent Blood Centers is a 501(c)(3) non‑profit Florida corporation.  The IBC was founded in 1983 by two independent blood centers.  Membership in AIBC can be in two forms; it can be an owner member and it can be a user member.  Presently, there are three owner members and 30 user members representing approximately 980,000 volunteer blood donations throughout the eastern United States.
In order to be a member, an organization must be an independent blood‑collection center with the 501(c)(3) non‑profit status.  The basic philosophy of AIBC was founded to provide services that will allow stability for small to moderate‑sized blood‑collection organizations in the future.
In the early 1980s, the AIBC services were concentrated on providing group purchasing.  This has allowed the membership to have a stable cost base and thus assure a stable, safe and local blood supply to many regions of the United States.  After the establishment of group purchasing, user membership requested that the AIBC expand its services.  Today, it provides reference services in red cells, HLA and viral testing as an AABB‑accredited, FDA‑registered, Florida‑licensed and Medicare‑approved laboratory.
AIBC also has an active bone‑marrow program and is a member of the National Bone Marrow registry.  In 1998, nucleic‑acid testing began to be discussed as a serious possibility.  In the past, AIBC has always looked at contracts that allowed each of its members to test its own blood donations.  However, with NAT, individual testing became less likely.  The reason was the limited availability of tests and high costs.
It became clear to AIBC members interested in NAT testing that the only reason for its early introduction was to further increase the safety of the blood supply.  Although the European April 1, 1999 deadline mandating NAT testing was a catalyst to move forward, the economics did not make it attractive since the cost of this testing would easily exceed the value of the plasma.
If the question of blood safety was not part of this equation, blood banks may have been better off financially by not providing plasma for remanufacture in Europe.
NAT choices.  In 1998, AIBC became committed to the provision of this service through some method that had, as its key feature, the issue of blood‑component availability while maximizing the safety of those blood components.  AIBC's research into NAT resulted in several conclusions that were evaluated and acted upon.
Number one; blood‑component availability was dependent on the test‑pool size and pool size did affect cost.  Number two; testing for two viruses, HIV‑1 as well as HCV, when NAT commenced was better for the blood supply than for testing by HCV alone.  It was clear to AIBC that no pooling would provide the most rapid turnaround time of blood to assure its availability.
However, at this time, it would be cost prohibitive.  On the other end of that spectrum, large pools would reduce the availability of fully tested blood components due to the lengthy turnaround time, greater than 24 hours.  But costs would be lower.
It was determined that, in order to assure the continuity of fully tested blood components, including those tested by NAT to the hospitalized patient, testing would need to occur within 24 hours of collection.  Based on the estimate of 500,000 donations tested annually and the time constraints wanting to complete NAT testing within 24 hours, pools of 8, 16 and 24 were considered.
The potential high costs associated with smaller pools resulted in AIBC's determination that the pool of 24 would allow for a 24‑hour turnaround time while holding cost recovery to a minimum.  The pool of 24 will allow for standardization, also for some of the other Chiron‑Gen‑Probe users.
Once it was established that AIBC would offer its members the Chiron‑Gen‑Probe NAT test in a pool of 24 donations, other issues had to be considered.  Laboratory; since AIBC members are primarily across the Eastern United States, we needed a lab where the delivery of specimens would be least likely affected by inclement weather and access to multiple major airports.
We chose Citrus Regional Blood Center, an FDA‑licensed blood center located in Lakeland, Florida.  Its location in the center of Florida with two international airports less than 60 minutes away made it idea.
Personnel; although Citrus Regional Blood Center has a full complement of Florida‑licensed technologists, it was determined that a separate staff would be developed for the NAT laboratory and, in order to assure continuity of supervision, Citrus supervisory staff are also chosen to be trained in the NAT process.
All positions for the NAT lab have been filled and, by this presentation, will have been trained by Chiron‑Gen‑Probe facilities.  In order to meet the tight time constraints for the introduction of NAT testing, it was determined that part of the existing Citrus Regional Blood Center facility would be converted into a NAT lab.
This has three labs of pooling, preamplification and postamplification areas.  The laboratories are completed and functioning in the validation test mode presently.
Equipment; we have backup for all major equipment including the Tecan and luminometer.  Our IND was submitted on February 17, 1998 and the FDA received the IND on February 19, 1999 and we have received FDA approval on our IND on March 19, 1999.  Our IRB will be meeting in late March to deal with issues concerning the consent.  Membership in IRB has been sought throughout the community.
The nucleic‑acid testing; regarding that, the AIBC will begin to offer its member participants NAT testing using the Chiron process on April 1, 1999.  Since this testing is being done under an IND, it is understood that clinical objectives are the primary focus.  This will be accomplished by the collection of clinical data while assuring that all donations submitted will be tested with a 24‑hour turnaround time.
The rapid turnaround time will be more costly but will assure that all blood components, including platelets, will be fully tested.
Participant profile; all the participants in AIBC‑‑the collection centers range from a minimum of 5,000 to a maximum of 150,000‑plus donations annually.  All donors will have to meet the standard FDA and AABB requirements and routine serology infectious‑disease testing will be done by the individual participating collection centers concurrently with NAT testing.
Informed consent and specimen collection.  Since the NAT process is being accomplished under an IND, it ill not fit the standard blood donation consent.  So, as part of AIBC's IND, an informed consent was included.  This is a single paragraph that would need to be used by the collection center either as part of the standard donation consent or as a stand‑alone consent.
The informed consent must be obtained prior to specimen collection.  Refusal to agree to NAT testing will result in the donor being deferred.  The NAT specimen will be collected in a PPT tube or a dipotassium EDTA tube.  No other anticoagulant will be acceptable.  We have a 24‑hour window available for the collection process and transportation of NAT samples to each collection center provided the temperature does not exceed 30 degrees celsius.
Samples store at less than 24 degrees celsius are acceptable for up to 70 hours as whole blood.  Samples may be stored for an additional five days a 2 degrees celsius to 10 degrees celsius as plasma following centrifugation to separate plasma from cellular components.
Shipping; prior to shipment to the NAT laboratory, the collecting facility will use a donor number replicator, DNR, Computype, that will produce a NAT sample number that combines the collection site ID and the unique donor‑collection number.  This label will be applied at the NAT sample tube and used for tracking the specimen throughout the process.
This method was chosen to prevent problems with duplicate donor numbers from different blood‑collection sites.  All shipments will be made on wet ice at 2 to 10Êdegrees celsius.  Late arrival, 3:00 to 4:00 a.m., is designated to assure that all late apheresis platelet collections will be part of the first NAT run of the day.
Testing; on arrival, all specimen samples will be unpacked and checked for temperature.  All pools will be composed of 24 samples.  AIBC does not intend for NAT testing to be delayed while EIA testing is completed since this would extend the turnaround time.  Again, we will be using the pools of 24.  We will be using the Chiron‑Gen‑Probe process so I won't go into too much detail here other than to say we will be having the pools of 24, we will be having the target‑capture phase, the transcription‑mediated amplification process and the detection phase using the hybridization‑protection assay.
The results will be either reactive or non‑reactive and will be available by mid‑afternoon the day of specimen arrival.
All breakouts of reactive pools will occur on a next‑test shift or late evening the day of specimen arrival in order to minimize turnaround time.  In the breakout, each of the 24 pooled samples will be treated as a separate sample and tested by the multiplex assay.  The results of the breakout will define which of the pool samples is or are reactive
All non‑reactive samples will be reported as such to the submitting blood‑collection center for a turnaround time of less than 24 hours.  The reactive samples will be fully defined as to which of the two viruses or both were reactive, the HCV or the HIV‑1.  This identification process will be performed at least once per week.
Reporting will be done by computer modum, E‑mail or fax hard copy.  Follow up; a reactive donation will start the NAT donor testing profile which is a single form that will track the status of the donor in the follow‑up process.  This form is composed of collection data, NAT test data, serologic test data, follow‑up donor counseling, follow‑up data and comments.
HIV‑1 reactive donors will be followed monthly for a period of six months.  HCV reactive donors will be followed monthly for twelve months.  All NAT‑positive donors will be followed until the donor seroconverts.  Retesting will include both NAT and ELISA testing and appropriate confirmations.  The NAT donor‑testing profile form will allow the AIBC IND to meet its clinical objectives.
Wrapping it up, our primarily objectives are to determine whether the addition of NAT testing to blood pools eliminates more potentially infectious blood units than FDA‑licensed and recommended tests.  Two, to evaluate the evolution of serologic tests in NAT‑positive individuals.
Our secondary objectives were to evaluate the NAT blood‑pool testing process and to refer an NAT‑reactive donor for further medical evaluation and follow up.
In summary, the AIBC has determined that there is a need to provide NAT testing for its members in a timely and cost‑effective manner.  Again, on March 19, 1999 AIBC's IND using the Chiron‑Gen‑Probe TMA process was accepted by the FDA.  This testing is anticipated to begin April 1 and will continue for at least the next twelve months or as necessary until discrete NAT donor test is available.
As always, AIBC is committed to providing the safest and highest quality blood products to the communities it services.
Thank you.
DR. HOLLINGER:  Thank you, Dr. Gammon.
The final talk in this session on nucleic‑acid testing is from Roche Molecular Systems, Mr. Alex Weslowski.
Roche Molecular Systems
MR. WESLOWSKI:  Good morning, everybody.
[Slide.]
Over the next ten minutes or so, I would like to describe to you the COBAS AmpliScreen HCV test system, specifically the system description in clinical study design.
[Slide.]
This table summarizes the test‑kit components which comprise the COBAS AmpliScreen HCV test.  The components in the top box are those which are packaged together.  You will see that there are seven different components.  Actually, this test includes an internal control which is coamplified with the HCV target, although detection is done separately for the target and the internal control.
A wash buffer which is a high‑volume component of the kit is packaged separately.
[Slide.]
In regards to performance characteristics, I would first like to note that the test uses two different specimen‑processing procedures.  The first is called the multiprep procedure which is used for primary and secondary pools.  We will cover that in a little bit.  The other procedure is called the standard‑specimen processing procedure and that is used for individual donor testing.
In terms of analytical sensitivity, our in‑house data indicate that the multiprep specimen‑processing procedure gives us an analytical sensitivity, or a limit of detection, of 15 international units per ml and the standard specimen‑processing procedure gives us 25 to 50 international units per ml.
These levels meet the criteria provided by the agency here in the U.S. as well as the international agencies.  In terms of genotype inclusivity, testing was done with donor specimens.  Actually, I think these are HCV‑infected patient specimens that have been typed and actually sequenced.  All of the available genotypes were found to be detected by the COBAS AmpliScreen test.
In terms of analytical specificity, 21 different viral isolates tested including HIV‑1, HIV‑2, HTL‑1 and 2, hepatitis B, hepatitis A, various other viral isolates that may be found in human blood samples.  The levels that were tested were 104 and higher and we obtained negative test results for all of the viral isolates.
In terms of clinical specificity, 502 HCV seronegative blood donors‑‑we obtained specimens for these donors.  They were tested by both the multiprep and standard specimen processing procedures and negative test results were obtained for all.
[Slide.]
Just briefly about the COBAS AmpliCor analyzer.  This analyzer is 519(k) cleared by the Device Center and is currently in use in the United States for diagnostic testing.  This will be the first time it will be used in a blood‑screening operation.
This slide simply summarizes the five different units integrated into the COBAS AmpliCor analyzer.  Specimen processing is done off‑line.
[Slide.]
This slide summarizes the COBAS AmpliScreen system, itself.  You can see it is comprised of a few different analyzer components linked together by a File Server computer.  The Hamilton AT/Plus2 diluter pipetter is used for preparation of the pools.  Testing is performed on the COBAS AmpliCor analyzer.
The AmpliLink system is a Roche molecular systems computer interface which acts as the data input and brains for the COBAS AmpliCor analyzer.  Three COBAS AmpliCor analyzers can be linked to a single AmpliLink instrument and the File Server has the capacity for handling three AmpliLink systems and, therefore, nine COBAS AmpliCor analyzers.
Specimen identity and integrity is carried on through the entire system through the use of bar coding.  The Hamilton can read primary bar codes, translates that into bar coding that is assigned to the pools.  The COBAS Amplicor also has the capability of reading bar codes and the specimen integrity and identification of donors in a pool is performed that way.
The File Server serves to link together the Hamilton diluter pipetter as well as the COBAS test system and identification of negative or positive donor units are performed that way.  Finally, the File Server is linked to the blood center laboratory information system for reporting out test results.
[Slide.]
In terms of the clinical‑study objectives, the first two bullets summarize the primary objectives of the study and, as I am sure is no surprise to anybody in the room, the primary objective is really to assess the ability of HCV RNA, a test for HCV RNA, to identify positive or infected blood donors.  We are using 24 plasma‑specimen pools for this testing.
The second or related clinical‑study objective is to specifically determine if the COBAS AmpliScreen test can be used to detect the presence of HCV RNA in donor units that are negative by the licensed antibody test for HCV.  The secondary objectives, but important nonetheless, of course, is to evaluate the development of serological markers‑‑i.e., the seroconversion patterns and HCV antibody‑negative PCR‑positive or HCV‑RNA‑positive donors and, last but not least, to evaluate the clinical sensitivity, specificity and reproducibility of the COBAS AmpliScreen test system for HCV.
[Slide.]
The clinical study will be performed in collaboration with America's Blood Centers and the Stanford Medical School Blood Center.  There are 13 sites involved with the study.  There is a single protocol so everybody is essentially working under a single protocol.
The primary sites‑‑there are four in this study‑‑are responsible for developing the data that will be used to establish the clinical performance characteristics of the product.  All HCV serological and PCR test results from these sites will be reported to the agency in the product license application.
Of course, clinical follow up will be performed on all HCV‑positive antibody‑negative donors.  For the nine secondary sites, donor follow‑up, of course, will be performed for the HCV‑RNA‑positive antibody‑negative donors and that information will be reported to the agency.
All other study‑related data will be collected and kept on site.  The importance of the need for two sites really is brought out by the ability to find a sufficient number of HCV‑RNA‑positive antibody‑negative donors.  Having a large number of sites, as we are looking at here, vastly increases our ability to do so.
The important message here is that everybody is using the same singular clinical protocol.
[Slide.]
Actually, one of the bullets missing from and which just came to mind a few minutes ago is concurrent testing is being performed in this study.  So antibody testing and PCR testing is being performed at the same time.  We are not culling out antibody‑positive units or separating out first‑time donors from repeat donors.
The pools are comprised of 24 donors in this test procedure.  We are going to look at a minimum of 10,000 pools representing 240,000 individual donations from the primary clinical‑study sites and those will be tested.  We have used the rare‑event theory from Poisson distribution that only three PCR‑positive antibody‑negative donors are needed to establish the significance of the utility of nucleic‑acid testing for volunteer blood donors in addition to the licensed antibody test.
Donor deferral, of course, will be included for all PCR‑positive antibody‑negative donors and, for the follow‑up period, consistent with the other studies underway, a monthly follow up will be performed for up to twelve months for the PCR‑positive antibody‑negative donors.  And, also consistent with the other studies in progress or proposed, during the initial phase of the clinical‑study release of the cellular components will be based upon the licensed serological test results only.
[Slide.]
This table just summarizes the clinical sites involved with the study.  I would like to note that the four primary clinical sites are Gulf Coast Regional Blood Center, New York Blood Center, Oklahoma Blood Institute and the Sacramento Medical Foundation Blood Center.
For the thirteen sites, there are numerous collection sites that will be providing blood to these sites for testing and I believe the last number I had on the number of collection sites was approximately 118.
[Slide.]
As I have said already, the primary pools are comprised of 24 donor specimens.  Secondary pools are comprised of six donor specimens and it could be looked upon as four secondary pools comprise a primary pool.  All initial testing is performed in single on the primary pool specimens.  If the primary pool specimen result is negative, no further testing is required and all donors are considered NAT negative.
When a primary pool is positive, then the four six‑specimen secondary pools will be tested.  We would identify the positive secondary pool or pools and then, from there, test each individual donor specimen in the secondary pools.  In that manner, we can identify the positive donor or donors in each pool.
[Slide.]
This is an eye test for everybody in the back of the room.  Actually, similar to what Mike said, we are not going to go through this.  This just represents the test algorithm that will be used for the clinical study.  We have taken into account all possible test results and this will be the basic guide that will be used by the blood centers during testing.
[Slide.]
In terms of the discrepant testing that we will perform during a study, this table simply summarizes the possibilities for the types of discrepant results that can be obtained.  The column over on the far right‑hand side represents the maximum number of specimens that would go through discrepant testing.
I guess maybe one of the most important of these, of course, would be contained in the first row, the PCR‑positive and antibody‑negative donors.  They will have discrepant testing as well as follow up.  Discrepant testing, as defined here, would include PCR testing by three alternate targets; the 5‑prime UTR, the core and the E‑1 regions of the HCV genome.
For the other categories of discrepancy, a maximum of 250 of these specimens or donors will be tested with the exception of the NAT‑negative NIHCV test and confirmatory‑test‑negative category in which no further discrepant testing would be performed.
[Slide.]
This is the final slide.  In terms of donor follow up, HCV‑RNA‑positive anti‑HCV‑negative donors will be deferred and enrolled in the follow‑up study.  A different patient‑consent form is used for this study.  Subjects in this study, as we said before, will be followed on a monthly basis.  The testing at each monthly visit will include the licensed anti‑HCV test, RIBA for confirmation and, lastly, the COBAS AmpliScreen HCV test and, if necessary, additional testing for genotyping or other alternate primer pair will be done.
Follow up, again, will continue for twelve months or until such time that the subject has seroconverted.  Lastly, follow‑up subjects who have negative HCV RNA test results and non‑reactive anti‑HCV and negative RIBA, after twelve months of participation in the follow‑up study, are being proposed as being stated as blood donors.
Thank you.
DR. HOLLINGER:  Thank you.
This concludes the open session this morning.  We are going to take a break and then, after we return, we will have some open public hearing and then into the open committee discussion.  So we are going to take a break for twenty minutes.
[Break.]
Open Public Hearing
DR. SMALLWOOD:  We will hear from the National Genetics Institute, Dr. Andrew Conrad; Baxter Health Care, Dr. Susan Cushing; Centeon, Dr. Charles Watson; America's Blood Centers, Dr. Celso Bianco; American Association of Blood Banks, Dr. Steven Kleinman; and the Hospital and IRB Association, Dr. David Pittman.  That is the order of presentations.  If any of those individuals have overheads, would you please let us know.
DR. HOLLINGER:  Thank you, Linda.  Each of the speakers for this open public hearing will have five minutes for their talk.  I had to laugh.  We said ten minutes.  Everybody did real well the first session, but everybody just speaks faster when they have ten minutes.  It is sort of like submitting a grant when they tell you have five pages.  So you give it to them in 5‑point type so you can get the ten pages into the five pages.
I also want to commend the American Red Cross for relinquishing the word GAT for NAT so we now just have to talk about one type of thing.  Actually, I think NAT is a more preferred terminology anyway.  But now we can all just talk about nucleic acid amplification testing.
So we will start with the open public hearing today.  Our first speaker will be Andy Conrad from the National Genetics Institute.
Andy?
DR. CONRAD:  Thank you.  I am just going to give everyone the summary of the 6 million donations that we have tested in the plasma arena.  So, as our brethren in the whole‑blood arena begin this arduous task, I will give you some of the experiences we have had testing 6 million donations for HCV.
[Slide.]
We have tested approximately‑‑these are pools of 500, so 300,000 donations for HBV and about 2 million donations for HIV  This is the summary of the total number of donations that we found positive.  I am going to go over, literally in five minutes, some of the data that we have.
[Slide.]
Basically, the sensitivity of the assay we are using in a 512 pool‑‑we have a mean sensitivity of 1.4Êcopies for HIV, 3.1 for HCV.  That is with some fancy centrifugation et cetera.
[Slide.]
This is the prevalence in donors in two study‑group donors we looked at for HBV, HCV and HIV.  You can get those numbers.  These are not qualified donors.  These are anybody walking in the door, but the prevalence of these window‑period donations is higher than we really would once have imagined.
[Slide.]
About each of the different viruses and the way the constructs of those window periods‑‑for hepatitis C, we have learned some very interesting things.  We have seen window periods where we had pre‑NAT‑positive samples and window periods up to 120 and 103 days.  I think the longest one has now gone up to 160 days with seroconversion.  Dr. Cushing from Baxter wants to talk to you about the fact that we have had some donors without seroconversion using one antibody test but they really, truly had seroconverted.
So the importance of this real finding is that, if you use enough antibody tests, everyone actually does seroconvert.  We never found anyone who didn't seroconvert.  We found high viral loads and relatively long window periods.  So this was an interesting thing which really points to the need for NAT testing.
The viral loads, or the viremic levels‑‑they become highly viremic very quickly and then they wobble around.  But they are substantially viremic samples for HCV.
[Slide.]
For HIV, this is the case as well.  These are the NAT‑positive.  The yellow is NAT and p24 positive.  The red is just seroconversion.  These donors we were unable to follow up on.  They just didn't come back and let us follow them up.
[Slide.]
But, again, in cases like this, the important thing about HIV‑‑and Sue Preston from Alpha will talk more about this‑‑is that, of all the HIV samples we have encountered, we have never found one that is positive by p24 but not positive by pooled PCR, even at 512.
There has never been, in all our experience, Dr. Epstein‑‑never‑‑a sample that was positive for p24 individually that was not positive by pooled PCR.  I think that is an important message.  Dr. Preston from Alpha will really go into detail on that.
[Slide.]
For HBV, we have encountered four different scenarios.  We have followed these donors up fairly carefully and looked at the serology in them.  We found four different types of serology in these HBV‑NAT‑positive donors.  These eleven donors were all discovered in these pools and NAT positive and had various serology statuses.
We had a group that was HVC‑core‑antibody negative and S‑antigen negative.  We had some that were core‑antibody positive and S‑antigen negative.  We obviously had all four scenarios.  These ones were just ones that were quite close to cutoff on S‑antigen but the original laboratory, the screening laboratory, missed them.
[Slide.]
What is important about these is that these, arguably, represent, at least in this case‑‑that is, core‑antibody S‑antigen negative incidence information.  These are new infections.  Obviously, these are acute early infections.  We are encountering them much more frequently than we ever thought we would.
The viral loads are extraordinarily low for hepatitis B.  What is interesting about these is, as we will follow them up further, we don't know if this just represents an early phase or there truly is.  There used to be some arguments that, with hepatitis B, there was a long gestation period with relatively low viral loads.
As we follow these people along, we will see if that is the case.  These viral loads are nothing compared to what we see, really, with someone with an acute hepatitis‑‑with a clinically acute hepatitis B.
[Slide.]
The next group looks like people who are resolving their infection.  They are S‑antigen negative so they are the hallmark of seroconversion with core antibody positivity.  In the ones that we were measuring, we could see their viral loads drop.  These were ones that we, then, subsequently collected where they weren't always positive by PCR and their viral loads were decaying.
These look like people who were in the process of getting rid of the 95 percent of HBV acutely infected patients who are in the process of going ahead and getting of their infection.
That was my last slide for my five minutes.  But what was important about this is that in 6 million donations, we found HCV, high viral loads, long window periods, HIV, p24 brought nothing to the table and a new emerging issue, which was really a surprising amount of HBV which looks like new infection.
The importance about HBV is that we haven't seen anybody with high viral loads and no S‑antigen which would have been the hallmark of an S‑antigen mutant.  We have not seen that yet, but we are constantly on vigil for that.
So that is all for us.
DR. HOLLINGER:  Thank you, Andy.
The next speaker is Susan Cushing from Baxter.
DR. CUSHING:  Thank you.
[Slide.]
I am going to give you a brief summary of the clinical study that we did in conjunction with NGI.  This study is completed and it was done in two phases.  The first phase would be the screening phase of the study and the duration for this phase from which we found the donors for the second seroconversion phase was about four months.
The donor qualifications for this were to be EIA negative and p24 negative.  If the serology was positive, they were not included in the pool for PCR.  We had 46 plasma centers participating.  We screened approximately 341,000 donations and about 43,000 donors.  That came to about 666 plasma pools, master pools, which were the 512 samples.  That was a mean donation of about eight per donor.
[Slide.]
The seroconversion phase was done with donors who were found eligible by being either HCV or HIV PCR positive and antibody negative.  These donors were then invited to enroll in this phase.  They would return to the donor center weekly for blood draws and we would do PCR and antibody testing on them.
Of the 46 centers, we found ten centers had eligible donors.  This study duration was for up to six months or seroconversion, whichever came first.
[Slide.]
The results from this are here.  Because we knew we probably wouldn't find that many donors, we added blinded samples.  They were either positive or negative for HCV and HIV and we added them randomly to the pools.  We did accurately identify all 50 that were added.
We had no HIV‑positive donors to enroll in our phase II clinical trial but we did have 17 HCV‑PCR‑positive donors.  Five of these donors did not enroll.  Only two of them declined to enroll.  The other three, we were not able to find.  Four of the donors seroconverted prior to enrollment and we had six donors who did enroll and seroconverted within the six‑month time frame.
We had two donors, as Andy just mentioned, who were consistently positive by PCR but never did seroconvert within the time frame of six months.
[Slide.]
So, of the ten donors that were seroconverting, the time range between the first HCV‑PCR‑positive test to seroconversion was 30 to 115 days.  Now, the time range for the elevated ALT levels was 30 to 110 days.  There was a general correlation between elevated or deferable ALT levels and seroconversion.
However, we did have three donors whose ALT levels were elevated prior to seroconversion and we did have two donors whose ALT levels were never elevated.
[Slide.]
The viral loads for the seroconverting donors was also variable.  We did quantitative PCR testing and, at seroconversion, the donors had anywhere between 100 genomes per ml to greater than 5 million genomes per ml.
We also had two other donors who exhibited a transient negative PCR test following positive PCR test results and with one donor, the PCR‑negative test came one month prior to seroconversion.  Then the viral load rose to 290,000 genomes per ml.  Again, he was PCR negative one week after seroconversion.
In the second donor, the PCR negativity came at seroconversion but, a week later, he had a viral load of 30,000 genomes per ml.
The seroconverting individuals in our study were all male.  However, the mean male‑to‑female donor ratio at the centers was 68 to 32.  We didn't find any correlation with the number of prior donations that these donors had made and becoming infected with HCV.  It ranged all the way from one donor who it was their first time to donate up to three donors who had donated between 61 and 80 times in the past.
[Slide.]
Now, the non‑seroconverting donors; interestingly, they were both female.  Their HCV PCR test results were positive, greater than six months.  Their viral load, by quantitative PCR during that time ranged between 140,000 to 4.5 million genomes per ml.  We also went back and did branch‑chain DNA testing on them and they were consistently positive by branch‑chain DNA testing.
Their ALT levels were normal the entire six months.  The test that we use for screening is the Ortho HCV EIA antibody test.  I'm sorry; the test that we use is the Abbott 2.0.  It was negative the entire time.
When we went back and did the Ortho 3.0 test, we found that they were positive and, in fact, they were positive at the very first time they came into the center.  This is not to say that one test is better than the other because since we use the Abbott test for screening, we were not able to see if the reverse might hold true.
I do know that another clinical trial that is being conducted by a manufacturer has an individual who has not seroconverted according to either test for up to twelve months and they have been consistently PCR positive.
Both of our donors had different genotypes, 2b and 3a.  The other donor I just referred to is 1a.  So I think that what this says is that the implementing PCR is really going to make quite a difference because these donors, based on the Abbott screening test, would very likely still be donating otherwise.
[Slide.]
So, in conclusion, we have demonstrated that PCR testing of the pooled plasma can detect HCV‑infected donors.  We have also validated the process of our pooling and the testing of the samples by PCR and linking them back to the donations and the donor.  We have collected some data on the seroconversion of donors who are positive by PCR and nonreactive by HCV antibody testing.
Thank you.
DR. HOLLINGER:  Thank you.
The next speaker is Charles Watson, Dr. Watson, from Centeon.
DR. WATSON:  Good morning.
[Slide.]
This morning, I am going to update you on our experience with PCR testing which we have been doing now for about a year.
[Slide.]
The system that we use tests all plasma that we collect for fractionation for HCV, HIV and HBV.  It was developed by our research organization in Germany and is now being currently used in two laboratories, one in the United States and one in Germany.
We call it a system because when you collect large numbers, one of the most important things that you have to work out is a logistic system, to obtain the specimens, identify them, get them to where they are supposed to go, make sure you test them properly and then make sure they go back to the right location.
Then, the identification of the donor falls into the normal notification, as you would for serology.  So we consider PCR a system, not just a test.  In July, '97, we started in Germany and, in April of '98, we started in the United States.  To date, we have tested approximately a little less than 3 million units of plasma.
[Slide.]
We take out all serology positives and only test units that are serology negative.  We want to interdict all positive units prior to pooling for fractionation.  We also want to notify the donors so they can receive counseling.  And then, in the manufacturing process, we only want to manufacturer with non‑reactive PCR units.
[Slide.]
This is the viral load required in the donation for us to find it positive on a routine basis.  That includes all of our dilution protocols.
[Slide.]
These are the results.  What have we done so far?  It is broken out.  The first slide is the United States and the second slide is from Germany.  In the United States, we have tested a little more than 1.6 million units.  We had 96 positive donors and you can see the breakout by virus.  I have also shown the interdicted units; how many units have we stopped going through the manufacturing process that would have gone through the manufacturing process if PCR was not being used.
You can see that that is 458 units.  The only thing that is counted here on the interdicted units, if the donor became serology positive, and that unit would not have gone to manufacturing due to the lookback process from serology, that was not counted for this number for interdicted units.
So, for example, the three HIV‑positive donors, two became serology positive within 30 days.  Those units were not counted.  One donor never came back so never became serology positive.  Those four units are all from that one donor.
You can see our frequency, from we see in the United States based upon what we tested, let's say one donor per 200,000 for HBV, five donors per 100,000 for HCV and one donor in a million of HIV.
[Slide.]
From Europe, they have tested a little less; approximately the same number of positives.  One of the key things on this slide here is that Europe is where we do our fractionation pool testing.  We have taken 340 consecutive fractional pools from the manufacturing plants.  We have tested them by PCR for all three viruses and all 340 fractionation pools have been negative.
[Slide.]
We also do a substudy.  As you have heard this morning, all of the INDs have a substudy, a clinical part of it.  Ours consists of following positive donors for six months on a monthly basis or until they seroconvert.  We bring them back.  We repeat the PCR testing for that virus.  We repeat the serology testing for that virus and we also do the confirmation test for that virus.
We started with eight centers.  We have extended that to all of our locations, all 32 collection centers.
[Slide.]
The next slide shows you the results of that, where we are at right now.  If you notice, there are only 51 donors that are eligible.  That is because we started with the eight and then we extended to everyone. So, of the 96, we found 51 have been eligible.  We have enrolled 20.  To date, seven have completed the study either by finishing the six months or by seroconverting.  Five of those seven have seroconverted.
There was one HBV that did not seroconvert and one HCV that did not seroconvert.  And we had one dropout.  It was an HCV positive.  They came back.  They were PCR‑repeat positive and then they decided not to come back again.
In addition to this number, we have seven HCV‑positive donors who seroconverted but declined to enroll.  The status of the ones that are not finished yet; some are first time.  Some have repeat positives.  Some have come back and been PCR negative.
What I have tried to do here is give you a real‑world experience, what can PCR do, is it beneficial?  Can PCR, in a pool environment, improve the safety over the licensed tests that are performed today.  I think that we have shown that and, hopefully, this information is of benefit to you.
Thank you.
DR. HOLLINGER:  Thank you.
The next speaker is Dr. Bianco representing America's Blood Centers.
DR. BIANCO:  I will dispense with it.
DR. HOLLINGER:  That was a good talk, Celso.
The next talk, then, is Dr. Kleinman from the AABB.  I'll bet Steve will have something to say.
DR. KLEINMAN:  The major risk of transfusion‑transmitted HIV, HBV and HCV infection results from collection of a unit of blood during the infectious window period for these agents.  This window period represents the time in early infection when virus is circulating in the blood but conventional tests are unable to detect viral antigens or antibodies.
During at least a portion of this window period, viruses can be detected by nucleic‑acid amplification techniques.  Data on the seronegative viremic window period and the dynamics of viral replication suggest pooled NAT for HCV will offer the greatest reduction in the number of potentially infectious units.
It has been estimated that such testing could reduce the window period for HCV from the current 70 to 80 days to ten to 30 days, thereby reducing the per‑unit risk of HCV transmission from the current estimate of about one in 100,000 to one in half a million to a million.
In the case of HIV, preliminary data suggest pooled NAT testing may reduce the window period from the current estimate of 16 days to about 13 to 14 days with a best‑case scenario of ten days for individual unit NAT testing.  Given the very low incidence of HIV infections in the volunteer blood‑donor setting and this small window‑period reduction, the introduction of pooled NAT for HIV will result in few detected infections.
This projected low yield is supported by the actual low yield is supported by the actual low yield of HIV infected units in the three years following introduction of HIV‑1 p24‑antigen testing.  I would say that there have only been five units that we know about.
Nonetheless, continued public concern over the threat of transmission of HIV through the blood supply appears to support the implementation of pooled NAT for HIV.  The low level of HBV viremia present during the window period prior to positive surface‑antigen results makes it unlikely that HBV DNA will be detectable by NAT applied to pooled plasma specimens, although we have seen some examples today from NGI in plasma donors where it has been detected.
HBV NAT will most likely require single donation testing to significantly impact residual HBV risk.  At this time, the complexity of NAT and the lack of widely available automated testing equipment and reagents make it impossible to perform single donation testing.
The approach of pooled sample testing is currently practical and, in the case of HCV, has relatively little impact on the ability of the technology to detect infection earlier since HCV nucleic acids reach high levels rapidly after infection is established.
The ultimate goal for operational NAT programs is to complete testing prior to issuance of blood components for transfusion.  However, in the early phases of NAT implementation, the logistics may require the release of blood components before NAT results are known in order to avoid shortages of labile cellular blood components with short dating periods such as platelets.
The turnaround time for pooled NAT is likely to be longer than for current blood‑donor screening assays due to the time required for pooling, the performance of the test, itself, and the additional testing required to identify the reactive unit in a reactive pool.
The AABB agrees with FDA's policy to allow for release of blood components prior to obtaining NAT results until the logistics of the operational NAT programs permit the more rapid turnaround time required to complete testing before component release.
Due to these logistics, there is a possibility that a component that is negative by all required serological assays will be found to test NAT positive after it is transfused.  In these rare instances, it is important to remember that such a component would have been transfused in the absence of pooled NAT testing.
In such cases, the AABB believes that the management of recipients who have received such units should be similar to the management of other lookback cases with the exception that the rapid availability of information about the transfusion event may allow early intervention to treat infection in the recipient and prevent secondary transmission.
Potential issues to be addressed by FDA.  The AABB recommends that the FDA establish a standard for NAT sensitivity for each analyte, HCV and HIV, based on the requirement that an operational pooling algorithm must detect a given number of copies in an individual donation at a 95 percent frequency.
I think we have heard today that there is a suggestion that the FDA is considering a 5,000 copies per ml number.  This type of standard would allow for variability in analytic sensitivity and in pool size in different NAT programs as long as the product of the analytic sensitivity and the dilution factor introduced by pooling meets the minimum sensitivity standard.
Consequently, this type of standard would insure that any individual donation interpreted as NAT negative for a given analyte would have less than a designated number of copies per ml of viral nucleic acid at a 95 percent probability.
Although the ultimate goal in setting an NAT sensitivity standard is to detect a large majority, if not all infectious viremic window donations, the standard set in the initial stages of pooled NAT must be achievable using current technology.  As the technology continues to evolve, the standard can be evaluated and adjusted, if needed.
In light of the anticipated use of several different NAT pooling and testing algorithms for donor screening and the significant actions that will be triggered by a reactive NAT result, the AABB urges the FDA to adopt standard nomenclature to describe test results and to define various stages of testing.
A suggested nomenclature is as follows, and maybe the specific terms can be altered but I think the principles are correct.  In our suggested nomenclature, master pools are the pools of plasma from individual donations so it the first pool that is made, that is initially tested by NAT.
Master pools, once tested, are either negative or reactive.  In some programs, intermediate pools are prepared from individual donations and then pooled to make a master pool.  When a master pool tests reactive, either the individual samples comprising the master pool or the intermediate pools comprising that master pool are then tested.  If intermediate pools are tested, the results are either negative or reactive.
Both master and intermediate pools generate interim results in the testing process that is designed to identify and test specific individual donations.  Individual donations, when tested, will be either negative or reactive.
The definition of a positive test result should be reserved for results obtained on an individual donation that is reactive by NAT and confirmed.  Confirmation is currently not really defined but may either be by subsequent seroconversion or by a different NAT procedure.
This definition of a positive NAT result is likely to evolve as experience with NAT is gained and donor follow‑up data are obtained.  Pooled NAT methodology involves testing samples with progressively higher concentrations of viral nucleic acid as the testing proceeds from master pool through intermediate pool to individual donation.
In contrast, current individual unit blood‑donor serological screening assays require repeat testing of the same sample source if initially reactive results are obtained.  The AABB believes that there are sufficient differences between pooled NAT and conventional EIA testing such that it urges the FDA to consider interpretation of NAT reactivity differently from current EIA algorithms.
Specifically, if all individual donations in a reactive pool tests negative on individual donation testing and no implicated unit can be found to explain the reactive pool result, the AABB urges that mechanisms be designed to allow such units to be released for transfusion.
The AABB urges that the policies with FDA adopts concerning notification of consignees of previous donations from NAT‑reactive donors and policies for donor notification and counseling be based on reactive NAT results at the level of the individual donation and not on results obtained at previous stages of the NAT resolution algorithm.  In fact, this seems to be the case with all the INDs described today.
The AABB urges the FDA to encourage and support the development and validation of supplemental testing algorithms and follow‑up protocols for donor counseling and donor reinstatement.  Protocols for reinstatement of donors who are negative on licensed serological screening assays and have false reactive NAT results should be consistent with the following principles; failure to demonstrate persistent NAT reactivity or seroconversion after a six to twelve‑month period offers a high degree of assurance that the donor is not infected; that is, follow‑up serological testing with FDA‑licensed tests for HIV or HCV should become positive if the donor really has been infected.
Negative NAT results on a single sample are more specific than a reactive result in a sample pool and, with respect to HCV, the unusual individual who does not develop detectable HCV antibody, and I think we have heard of at least one case today in the plasma sector, should, however, reveal persistent viremia on repeat NAT testing and be reactive by a different NAT test.
The AABB requests that the FDA also consider eliminating the requirement for specific serological tests subsequent to the implementation of NAT.  Such decisions, of course, will need to be supported by data.  Existing data suggests that elimination of HIV antibody and HCV antibody testing will not be possible.
Now, although ALT testing has never been required by FDA, and an NIH consensus conference recommended its discontinuation in 1995, such testing is still performed by most blood‑collection agencies in the U.S. for the purpose of conforming with German regulatory requirements for importation of recovered plasma or manufactured plasma derivatives.
Data from pooled HCV NAT programs may be helpful in influencing the German regulatory agency to modify its ALT testing requirement.  With regard to pooled HIV NAT, existing data suggest that elimination of HIV p24‑antigen assay may be feasible.  This topic will be discussed later today.
The AABB commends the FDA for initiating such open public discussions at this early juncture about the elimination of p24‑antigen testing.
A final comment; the AABB is sponsoring a conference on April 7, a one‑day conference, in Crystal City to talk about nucleic‑acid testing primarily for the blood‑transfusion user community, but I think there are people in this room who may be interested in attending.
Thank you.
DR. HOLLINGER:  Thank you, Steve.
The final speaker today is Dr. David Pittman representing the Hospital and IRB Committee.
DR. PITTMAN:  I am addressing the committee regarding concerns with NAT testing, its IND process‑‑not the eventual outcome but the logistics of implementing it.  I am the transfusion medical director at a 350‑bed hospital in Columbia, Missouri and the transfusion medicine consultant for sixteen other pathologists in my group who are responsible for 17 hospitals and about 1500 beds.  So we are consumers, essentially.
This bridges both the Red Cross and community blood‑center supply.  I am also the chairman of the Medical Advisory Committee for the Missouri‑Illinois region of the Red Cross based on St. Louis which covers between 75 and 100 hospitals.
I am been chairman of my hospital IRB for four years.  I am here at my own expense.  I am not paid by any of these except the patients but I represent what I believe, if you look at web sites and list serves are a lot of hospital tranfusionists in my position as well as hospital IRB chairmen.
What I am about to tell you is from a practical, hands‑on practice of transfusion medicine and the incorporation of views of these other people.  I believe that the FDA has impugned its own standards of research conduct in forcing hospitals to participate in this research.
I and probably other transfusion‑medicine professionals do not wish to withhold a test which makes blood safer, even this very small amount of greater safety, as this test will do for HIV.  However, what research in this century has been approved by the FDA without informed consent of the subject, perhaps short of syphilis research down south.
There seems to be a great desire by the FDA, blood and blood‑derivative industry, to rush this research despite little incremental benefit to the American public.  I have been told that this committee ignores cost issues and so I am sure that this doesn't relate to any European time tables for the NAT testing.
However, the annual cost to the United States hospitals, many of whom are not profitable and many of whom fold each month, as you know, will be asked to absorb a $75Êmillion bill during this research period per year being able to recoup only a small percent because of prospective medical reimbursement from inpatients and operative patients.
The FDA has approved this IND believing the donor is the only subject.  If this is so, why are transfusion services across America being asked to add a two‑paragraph statement of risk to our transfusion consents?  Those of you who don't transfuse blood every day should be aware that nearly 40 percent of American hospitals do not have separate transfusion consents, separate from an admission consent.
Why, then, am I asked to "advise the NAT‑positive patient of the implications of the NAT test result for their health and any treatment that may be appropriate?"  How can I do that if my hospital has not agreed to participate or if the investigational subject is not informed and if the implications, such as false positives, are not known since that is what this research is trying to figure out.
How many on this committee have had to sit in a room with a patient that has developed a positive test after transfusion and tell them that they are HIV positive.  Now we know that up to 5 percent of those confirmed Western Blot positives were not positives at all.
These people have gone and told their families.  They may have told their workers and been discriminated against and that wasn't even a research test.  This is kind of analogous to me of not having the recipient of the blood, the investigational subject, as designing a protocol to test new bumpers for GMP suburbans.  They are new soft bumpers.  They are supposed to hurt pedestrians less if they run into them and so you consent the driver, the volunteer driver, of the car.
It is ridiculous.  FDA is violating their own standards.  Statisticians and many scientists recognize that the lower the prevalence of the disease, the higher the false‑positive rate.  For HIV, you have heard prevalence of 1 in a million and for HCV 1 in 20,000 to 100,000.  That is great that our tests have got us that low.
But, furthermore, just based on ABO Rh clerical errors in transfusion medicine, we know the clerical rate is closer, the error, to 1 in 20,000 for ABO Rh.  How many of you on the committee have made 20,000 in your checkbook, which is pretty important to you, and not found that you have made an error?
I think that is what a lot of the false positives are going to end up being.  Please make your decision carefully.  You should know that many of us who transfuse as physicians, not as industry, not as government, not with conflicts of interest are amazed at your vote last quarter on universal leukodepletion which has a minuscule scientific validity for indications other than what we already selectively leukodeplete for.
Finally, as an IRB chairman, I often deny local researchers with protocols that are far superior to this IND protocol that I have seen because I, as an extension of the FDA for my hospital, read your rules and enforce them.  This IND is not acceptable to physicians, blood banks and hospitals responsible for daily transfusing America's blood and it shouldn't be acceptable to you on this committee.
We petition that you withdraw this until there is revision and I'll bet you there are about 100 IRB chairmen that would be glad to help the FDA figure out how to revise this.
Thank you.
DR. HOLLINGER:  Thank you, Dr. Pittman.
The final item in this open public session‑‑there is a letter that the committee has from the American Society of Clinical Pathologists.  Dr. James Linder is president.  I am reading it into the minutes.  I am not going to read the whole thing but I do want to point out a couple of aspects of it.
He states that, "The American Society of Clinical Pathologists is made up of board‑certified pathologists, other physicians, clinical scientists and certified technologists and technicians."  He is concerned about‑‑it is very similar to what Dr. Pittman says about, "requiring that all derivatives be prepared from plasma, that this is being promulgated by the European regulatory agencies."
The concern that he talks about is, "It is apparent that the rush for implementation of the gene‑amplification technology will require the release of blood and its components before test results are known."  He says, "The management of patients in potential lookback cases raises concerns for patients in the laboratory."
He goes on further and says, "To conduct this research protocol under an investigational new‑drug process, donors must be informed of the investigational nature of the testing."  It says, "ASCP agrees that donors must be informed.  However, concern arises when it is noted that recipients of nucleic‑acid amplification‑tested blood may receive blood or blood components before the test results are complete."
He then says, "It has been suggested that laboratories have patients sign documents acknowledging that the blood they may receive through this investigational process may be contaminated.  This is just not feasible, especially in very large facilities.  Getting informed consent from blood recipients is likely to create anxiety in patients that may cause them to refuse blood completely which may place them at greater harm than the theoretical risk of a nucleic‑acid‑tested positive unit transfused before the test result is known."
Then he gives a solution.  He says, "We suggest that clinicians transfusing blood should be educated about the nucleic‑acid testing issue.  Patients should not be charged for the testing during the investigational procedure or period and testing should continue to be unlinked until it can be performed uniformly prior to transfusion."
He then completes this by saying, "These comments should not be construed to be speaking against nucleic‑amplification testing.  Rather than relying on the pressure from the European community, we urge that more time be given to assess patient needs and laboratory concerns in the United States."
That's basically the gist of that letter.
Is there anyone else from the public that wants to make a statement or anything at this point before I turn it over and close it and then open it up for discussion among the committee?
State your name and association.
DR. SCHOCHETMAN:  Jerry Schochetman, Abbott Laboratories.  I just wanted to raise the issue‑‑we heard this morning that our serologic EIA 1.0 tests require HIV‑1 Group M, HIV‑1 Group O and HIV‑2 detection and must have antigens in them.  We heard this morning that nucleic‑acid amplification testing apparently does not require HIV‑2 testing and seems to only require HIV‑1 Group M and possibly detection of Group O in those cases where the assays can detect the Group O.
In rapid testing, we heard that the FDA may only require HIV‑1 Group M, no Group O and HIV‑2.  We now have a whole series of standards and the rules seem to be changing as we go along and sends a very complicated message to manufacturers who start along a particular path and then the rules change and either have to pull tests that are before the FDA or certainly would have to come back in and modify them as we go along.
I am wondering if somebody from FDA would like to comment on this varied standard which doesn't seem to be occurring, as we can tell, within Europe.
Thank you.
DR. HOLLINGER:  Anyone wish to comment from the FDA?
DR. HEWLETT:  I just wanted to make a comment in regard to the nucleic‑acid test.  We are actually asking manufacturers to test the Group M variants for the nucleic‑acid test.  HIV‑2 has been an optional requirement.  In regard to the blood‑screening assays, of course, you know that the antibody tests are also required to be validated against the Group M variants.
In that instance, of course, we are also requiring Group O.  But that is primarily because of their broader utility.  They are the primary screen and we view nucleic‑acid test as an add‑on screen for the window period.
DR. EPSTEIN:  I agree with Dr. Hewlett's statement.  Let me just add that we are aware of this disparity and that we have a dialogue ongoing with the sponsors of the nucleic‑acid tests.  We will obtain commitments that these tests will be further modified to broaden the sensitivity to include other virus variants.
We do think that is appropriate although it is true that the vast majority of window‑period cases currently seen are Group M.  So I guess the problem is always a moving target.  Had we decided a year or two ago that we would make it an up‑front requirement, we simply would have delayed the development that we are now seeing moving into the clinical domain.
So we agree with Dr. Schochetman.  Right now, we do have a set of different standards in different contexts but we do see this as evolving stages of technology and the standards will evolve.
DR. HOLLINGER:  Anyone else under the public hearing have a comment?
If not, then we will open this up for committee discussion.
Committee Discussion
I'm sorry we didn't have time‑‑unfortunately, we don't know how long each of these talks are going to take and so on.  If you are like me, I really would much prefer to ask questions as speakers present things because it is fresh in my mind, but I would like to see if anyone can comment on some of the items that have been brought up this morning, both in initial talks as well as from the public hearing, too.
DR. NELSON:  A couple of issues were raised but just in the context of a case or two, and that is disparate results between PCR and antibody, particularly with hepatitis C where patients were persistently antibody negative, PCR positive, and then some where the PCR result was intermittent in the face of antibody.
Individual cases‑‑that issue has been known for some time, those two scenarios.  But the real issue is is there any data on how frequently that occurs.  As I recall, Miriam Alter's data suggested a fairly high rate of PCR positivity or at least infection with no antibody occurring for up to a year or longer.
The rate, as I remember, was something in the range of 10 percent.  I think that is probably much higher than reality.  But, with the data that were presented, I couldn't really get a handle on how frequently this is.  There were large numbers of people screened and then a few cases were presented.  But I wonder if anybody could put any quantitative figures on the disparity, at least for some period of time, on those two scenarios for hep C.
DR. CONRAD:  I self‑elected myself to answer this just because those data that you are referring to were derived in my laboratory.  It is very important that you know that the two women that we saw how never seroconverted, they never seroconverted only by a single assay, which was the Abbott assay.
When we ran them on the Ortho assay, they had seroconverted from the original moment.  So those are truly not cases of non‑seroconversion.  They are just non‑seroconversion by a single screening assay.
We did not look for the inverse, so it is entirely possible that, had we screened with Ortho, found PCR positivity for a long period of time and then tested with Abbott, some of those would have been.
So it is our experience that in every single donor who we have identified in these periods of follow‑up clinical study seroconverted.  So we did not see anyone who did not seroconvert.  In the careful clinical follow‑up period where we followed all donors up to six months, that is 32 people that we followed from pre‑NAT positivity all the way through, and all of them seroconverted.
The issue of transient positivity is to be expected with some people‑‑remember that was transient positivity at the time of seroconversion.  It is well known that some people resolve their hepatitis C infections.  They would remain antibody positive but nucleic‑acid negative.  That is expected.  And so we saw nothing out of the ordinary and nothing that didn't seem to make sense.
And so the original supposition by Miriam Alter that there was a persistent window‑period patient that never seroconverted is probably not the case and, in fact, from some sedimentation studies, many of these patients are actually manufacturing antibody.  It is just not detected yet.  In other words, it looks like it is immune complex to the way how fast it precipitates.
So it is not as bad as it would seem from that data.
DR. NELSON:  We have been following a cohort of injection‑drug users who, as you know, are commonly infected with hep C.  We do find, not only during the seroconversion period, but we find people who are PCR positive, lose their PCR positivity and then it reoccurs.  It is possible that some of these could be reinfections, but we have done some sequencing and I think that that is not always the case.
I think that there is, not only during the seroconversion period but in the natural history of hep C, people who become PCR positive, it goes away, it comes back again.  So I think, from a practical standpoint, I don't think that it is likely, as Dr. Kleinman mentioned, that we would be able to replace antibody testing, at least for hep C, with PCR because, if we did, we would miss maybe not people that were infectious at the moment but certainly were at high risk and were infected and, perhaps, possibly, infectious by just doing PCR testing.
DR. CONRAD:  None of us advocate replacing antibody with PCR for a host of reasons, especially pooled testing because it would become prohibitively expensive in the resolution algorithms.  We only recommend this and certainly advocate it as an addition, with the exception of some of the antigen tests which we find to be less than effective.  But not the antibody tests.
DR. HOLLINGER:  A comment on that, too.  As you know, Jack Stapleton has done some studies which are reported in, I think, March or this month's edition of the Journal of Clinical Microbiology but also had reported a year or two ago in the Journal of Infectious Disease using whole blood for PCR testing.
The one in the Journal of Clinical Microbiology, they found six of 16 individuals, about 38 percent, actually, of the patients with clinical hepatitis now who were PCR positive, antibody negative, which they followed for a period of time.
They felt that a majority of that was maybe due to cryglobulins formed.  But that was only in three of them.  The earlier paper, however, followed patients for a period of time that remained PCR positive, antibody negative.  This often wasn't the case.  These were patients who were not initially felt to have hepatitis C.  They cloned them and sequenced the samples.  Some of them were just sampled in the core regions, and so on.
But the issue that has come up is‑‑and his feeling is that, because they used whole blood and since hepatitis C can be found in not only leukocytes, PBMCs as well as in red cells, possibly platelets, et cetera, that that might be why they are finding this kind of thing.
I think it is too early.  I think we need to really look at it but it is a very interesting concept.  So I might ask you, Andy, did they look for cryglobulins in those two patients?
DR. CONRAD:  Yes.  It was interesting.  That was obviously one of the confounders and neither of them exhibited that.  So we did find that confounder there.
DR. KHABBAZ:  I thought the speaker who followed you mentioned an additional HCV‑positive genotype 1A was negative by both Ortho and Abbott.  Was that done and, I presume, followed?  Was this person persistently HCV positive?
DR. CONRAD:  That donor was not in my group, in my study.  She mentioned that someone had reported that.  I don't know whose group that was in, but we never saw that.
DR. HOLLINGER:  Just one thing, while you are up, Andy.  There were some what I thought were discrepancies, not in your numbers but‑‑you stated something like 11 out of 43,000 donors were HBV positive, PCR positive, antibody negative; is that correct?
DR. CONRAD:  That's correct.
DR. HOLLINGER:  Then the speaker from Centeon stated that it was a half per 100,000.
DR. CONRAD:  I think he gave donor per donation numbers.  I did donor‑donor.  He went donor‑donations which are different.  So, obviously, in the plasmapheresis setting, donors can donate‑‑
DR. HOLLINGER:  Could the person from Centeon go to the microphone just a moment and clarify if that was per donation and, if it was, how many positives were there per donor?
DR. WATSON:  That was donors per donation because I did not have a figures for the number of donors.  That is in a different computer system in the company that I couldn't get in the short time prior to the talk.
DR. HOLLINGER:  Thank you.
DR. CONRAD:  If we were to look at the donor‑donation numbers, they are quite similar.  It is the donor to donor.
DR. STRONCEK:  I would like to congratulate all the groups this morning.  I think this is outstanding data and it shows outstanding cooperation between a number of groups.  It is really a unique situation for blood banking and transfusion medicine in that we have an outstanding test that we know can improve the safety of the blood supply.
But it is far from universally available.  Where it is available, it is really under INDs.  They are fairly tightly defined on how you can submit tests through these.  These INDs will work very well for the large blood centers but, in the interim, until this technology does expand, we are going to see a number of potential problems with smaller centers, particularly hospital transfusion services that do specialized collections and transfusions, platelet things, stem‑cell donors, organ donors, where this testing won't be available.
I would encourage all the groups to continue to work together to develop, advance the technology quickly even further so we have a low‑cost test that is widely available as a licensed test so all appropriate donors can be tested with this technology.
DR. HOLLINGER:  Do you, David or Gene, perhaps even Dr. Fitzpatrick or any others here on the committee, want to comment about the informed consents that were discussed both from the donor standpoint, or give some comments about that from the donor standpoint as well as from the recipient standpoint, if this is going to be required by most hospitals or not, or what the feelings are?
I know it is real early in this, but I think that would be helpful.
DR. STRONCEK:  I think, because it is a research test, all donors have to be told that an experimental test is going to be done.  But I don't see that as a problem.  These donors are wonderful people that will virtually sign anything.
As far as a transfusion recipient, most hospitals do have some informed consent process.  But this is going to be such a rare event that we have a person that is tested, gets a blood transfusion from someone tested positive by NAT testing and negative by antibody that I don't see the need to add that specific information to the informed consent.
We, as physicians who run these transfusion services, can deal with these cases on a case‑by‑case basis.
DR. EPSTEIN:  I just wanted to comment on this same point.  Dr. Pittman raised some very pertinent and difficult issues that, of course, the FDA was aware of.  I guess that there were a couple of factors that led us to think that allowing the INDs on a very large, indeed near national, scale was the appropriate thing to do.
One of those is the point of view that there was no added risk from the blood to the recipient.  In other words, the recipients could only ever get the same screened blood they would have gotten otherwise or blood that had been additionally screened by the experimental test with some potential benefit.
The second point is that the FDA felt that, with all of the concern that we have heard for a number of years about window‑period risk, that we wanted to bring that potential benefit, albeit at the investigational stage, to the maximum number of blood recipients as soon as possible.
Third, recognizing Dr. Stroncek's point, we recognize that, because of the very complex logistics involved with NAT testing, particularly if done on fairly large pools and in centralized labs, that it would be important to shorten the time from the investigation to full implementation to allow, again, as many centers as possible to be participating in those logistic developments so that they would be ready to roll out very quickly.
Lastly, a point of clarification about the informed consent.  There is, perhaps, a little bit of misnomer or misinterpretation.  FDA's point of view was that the local institution, the hospital, should make its own decision whether any change was needed in its own practices of transfusion informed consent because, really, there is not an independent informed consent for whether you do or don't get an NAT‑screened unit.
You don't have the option of rejecting the unit that the blood center provides to the hospital.  It was more a question of allowing hospitals the awareness that this practice was going to go on in donor screening and to allow independent local determinations whether that necessitated any change in what was told to the recipient or prospective recipient.
Indeed, some hospitals have no message to recipients.  They don't do informed consent.  Other hospitals do and thought it was appropriate to add mention of NAT.
I wouldn't disagree with Dr. Pittman's point that there is a certain risk to the recipient in that same very small number of recipients may be told that they got blood that had a reactive investigation of result.  That is true and, unfortunately, that is unavoidable given the current logistics and stage of development.
But our point of view is that that factor would be something known to hospital risk committees and they could then decide whether or not it merited additional information to the recipient within the transfusion practices of the hospital.
So it is a bit subtle because it is not quite what we normally think of as informed consent.
DR. ELLISON:  I have a question.  Dr. Linder's letter, at the bottom of page 1, implies that we are responding to a global market and the force of the European community make it a deadline of July 1 and we are meeting that.  That is not a consideration, then, in this?
DR. EPSTEIN:  I think that it was not the driver for FDA but it didn't surprise us how many of the organizations in the private sector became highly motivated to develop their PCR testing or NAT testing strategies.
The requirement that has been put in place for July 1 pertains to plasma for fractionation.  So it is not a surprise that American‑licensed fractionators sought to have in place their PCR testing in time to provide PCR‑screened pools for fractionation by July.
There, then, was a secondary effect in that there is sale of recovery plasma off whole‑blood collection.  Collection centers had the choice either to stop selling that plasma for European fractionation or to the fractionators in the U.S. who would potentially market in Europe or to try to move themselves.
I think that FDA's point of view in this was really not related to the European requirement except to introduce the notion that if PCR were implemented on plasma for fractionation, we would regard that as a donor‑screening test subject to validation and ultimate approval under a license.
That has been where the FDA has been coming from, not simply to regard it as a process control on fractionation but to regard it as part of fundamental donor screening and to put forward the goal of achieving it for transfusable components as soon as possible.
DR. KHABBAZ:  I, too, was intrigued by a point raised by both Drs. Linder and Pittman.  I realize that the issue of recipient is a temporary one but we can hopefully move soon that people will not get blood that is NAT positive before the test results are out.
But what I found a little odd is that, at this point, at least, the recipients of components‑‑they may not be of benefit to them in that the results are not out yet.  Yet, it seems that the cost is being passed to the users.  So if there is not benefit, I felt that it is odd that we will pass the cost.
DR. HOLLINGER:  I think that is an important issue.  I have seen this more and more, now, in studies where commercial companies‑‑for example, in hepatitis C‑‑doing studies out in the community in which the costs of those studies are being passed on to the healthcare system in test being asked to be done and things which we would never do if we were just following patients, treating them ordinarily, asking for monthly tests, except for, perhaps, the medications, and so on.
I think this is a very important issue.  I would like to hear what the FDA has to say about that.
DR. EPSTEIN:  It is difficult and, perhaps, it is also a novel paradigm.  But I think the way we understand it is that 70 to 80 percent of the recipients are benefitting from the investigational test.  A percent of individuals, of course, don't.
But, with certain exceptions, particularly platelets, the majority of products released will be after the NAT result.  That will be true for all frozen components and it will be true for well over half of red cells.  So, yes, it is true that not every individual benefits but the population, as a whole, does benefit.
Unfortunately, these trials needed to be done on a very large scale because to measure any actual benefit, you have to look at huge denominators.  You have to remember that the expected pickup rate for this testing was low.  One had to be thinking in terms of hundreds of thousands to millions in order to get the validation that we are talking about.
So putting these things together, I guess the answer is that, on the average, the recipient benefits and, therefore, on the average, the recipient is also paying.  It is true that there will be a small number of recipients who paid through reimbursement of care but who didn't actually benefit.  But they benefitted future recipients because the studies benefit everyone.
So it is tricky.  I do think these are very legitimate points and well worth reflecting on.  This isn't the last time we are going to face novel technology in a large scale.
DR. LINDEN:  Dr. Busch, could you give us a little bit more information in terms of the question of how many products we are talking about that would be released without the benefit of this testing and what type of time would be involved in phase I, and what about phase II?  When you talked about selecting specifically units from first‑time donors to hold off on testing, are you going to be making platelets selectively out of repeat donors or is the time all going to be over five days so that none of the platelets are going to be tested anyway.
Can you explain that a little bit better?
DR. BUSCH:  You have several questions there.  I think in terms of the programs during this so‑called phase I when products may be released based on serology with NAT data following several days later, the risk to these recipients is really the risk today which we have been projecting at around 1 per 100,000 for HCV and much lower, probably 1 in a million, for HIV.
The truth is, in the whole blood‑sector screening so far, we haven't seen that yield of HCV.  In the plasma industry, we are seeing a very good yield, or high rates of viremic seronegative units for HCV, essentially as would have been predicted by their incidence rates.
So I think that models, the approaches to measure and estimate yield are accurate but, perhaps, it is just that we haven't tested enough.  But, as we heard from Sue Stramer, they have tested, now, several hundred thousand and have yet to pick up an HCV viremic seronegative.
In Europe and in Germany, several programs have picked up in the rates of 1 in 200,000 to 1 in 300,000.  So we are in that ballpark of risk.  So the truth is that we are willing to get a unit from a NAT unscreened, serologically screened donation.  The probability that that recipient will subsequently be told they got a NAT‑positive unit is exceedingly small.
Most of the programs are designed to move beyond phase I in the three to six months following implementation.  So I think, reasonably, one could say that by the end of '99, all of the programs will be designed and operating in an on‑line mode that will not release product other than after NAT testing other than in exceptional circumstances.
One of the things that we had to build in is the potential reaction to the fact that we are dealing with both manufacturers and test reagents that have never been tried in the massive scale that we are going to be facing.
So we don't know whether we may be testing for six months; fine.  And then, all of a sudden, there is a problem with respect to reagents or other issues.  So we have to build in the reflex that if, after we have transitioned to phase II, that it may be necessary, on some interim basis, to release based on serology again.  So all the programs have kind of designed in that potential reaction.
In terms of the specific program I described where we are looking at trying to sort first‑time and repeat donations and parallel test the donations from the 80 percent of repeat donors, yes, indeed, the programs are being designed to predominantly prepare both‑‑obviously, our pheresis donors are all repeat donors, but, in addition, the whole‑blood‑derived platelets will be predominantly derived or exclusively, in many of the centers, from the repeat donor subset.
Again, the systems are designed such that even that 20 percent of first‑time donations, the NAT data will follow within about 36 to 48 hours of time of collection, so, literally within 12 to 24 hours of the serology data.  So that 20 percent of whole‑blood collection of red cells from the first‑time donors will be entering active inventory very shortly after collection.
DR. KHABBAZ:  I am a little confused.  Can you clarify for me?  You said you are going to exclude seropositive from NAT testing.  Yet, later on in your talk, you said that you are going to follow some maybe seropositive, NAT‑negative‑‑
DR. BUSCH:  Actually, as I indicated, our trial, itself, has two components.  Two of the testing laboratories will test all comers, will not sort first‑time and repeat.  We will pool them altogether.  The other program is devaluating this strategy add will formally evaluate the benefits of the strategy that sorts.
In addition, we are planning to test all seropositive donations from first‑time donors as a single donation NAT independent of the pool testing designed to release product.  So all donations will be tested.  One of the peripheral values of NAT will be as an adjunct assay to more properly counsel serologically reactive donors for HCV and HIV most of whom are false positive or indeterminate.
So now we are fortunate to have an RNA test to better counsel those donors.
DR. HOLLINGER:  I would like to pose a question, then, also.  Does somebody else have something?
DR. STRONCEK:  Just one more comment.  You asked about the informed consent from a transfusion‑medicine point of view.  I don't think that is a huge issue.  I think what is going to be the biggest issue down the line is when we move to using this, to using NAT testing to release red cells and platelets.  Everyone is going to try and move to that as quickly as possible, but there probably is going to be an extra day of quarantine for these products and there maybe shortages.
There may be issues where centers may elect to have emergency releases.  So I trust that will go well and that will be a short period of time.  But that is going to be a major problem for a while with the blood supply.
DR. HOLLINGER:  I would like to ask a question to either Sue Stramer, Mike Busch or Dr. Gammon.  In dealing with a shipment of samples, I would like to know what is in place in terms of shipments getting lost and so on.  I have had a fair amount of experience in shipping things across the country for proficiency testing and receiving huge numbers of samples in some studies being done with the CDC.
I will tell you that shipments get lost.  Samples get lots.  The question of cold and hot.  They sit in a warehouse in certain places.  It may be very hot.  It may be cold.  I would like to know what you have in place for documenting and determining the temperature of the sample, whether it gets frozen, whether it gets too hot, what happens when it is lost, it is shipped to Minneapolis instead of San Diego and it sits there, or they can't find it in all or it ends up in Puerto Rico.
Why don't you give us some ideas of what you have in place, what the problems are that you anticipate, et cetera.
DR. STRAMER:  Blaine, you asked a series of questions.  Let me first address lost shipments and then return to temperature recording, et cetera.  While the testing is going on under IND and this is not required, obviously it is our goal to test all of the collections by NAT.  But, under IND, we will be collecting a separate tube for the entire program.  So, if that separate tube gets lost, we basically have two options; not to use the products or to have released to products based on serology.
As Mike Busch said, during the IND phase, it is certainly an option to release products based on serology while we are working through the kinks in the system.  Once this becomes an FDA‑licensed test, if a shipment gets lost, as it does now for serology, the test isn't performed, the unit isn't released and we don't have the product available.
As far as temperature recording, we do that today and we record times and temperatures because we have other requirements for other serologic tests that require those.  We will be using the same validated shippers, as an example, we use today to ship tubes around the country for serology.
So we will be using systems that are already in place.
DR. HOLLINGER:  But it is obviously not just one sample that is going to be lost.  There are going to be samples that might be sent from a regional site that might have 500 samples in it.  I don't know what your largest numbers are.  They are going to be shipped on any one‑day basis.  So you have a huge number of samples coming from one site.
DR. STRAMER:  I can't tell you what the maximum number of tubes for shipment for an example.  But these are the kinds of studies and these are the kinds of other logistics that will also have to be worked out during the IND phase.
DR. BUSCH:  The only other comment is all of these programs have what is called retention tubes built in.  So whenever samples are shipped, in the case of the Red Cross, they are already centralized in the national testing labs.  Each of the collection centers hold back one tube that is, then, potentially available were there a lost or discarded shipment.
At present, that tube is not a PPT.  It is not designed in this early IND phase but, obviously, once it is a required assay, I think the retention tube will have to be of a nature that is amenable to lab testing as well as serologic testing.  Non‑Red‑Cross programs who are not using PPTs, the retention tube will be an EDTA tube that could be used for NAT.
DR. GAMMON:  We are trying to minimize the loss of samples by having the blood‑collection centers ship their specimens by direct flight.  A large number of our specimens will be coming by courier, so it will be ground transportation directly to the NAT collection laboratory.  So we will try to reduce loss of specimens that way.
Temperature indicators can be put on the specimens when they are shipped.  When we receive the specimens, we will know what the maximum temperature was that the specimen was received.  We did do some validation studies to try to determine what size shipment containers would be most appropriate for receiving any of these specimens.
DR. BIANCO:  Blaine, you would have to change shippers.  There is a lot of movement of samples and units of blood that go around.  For instance, we outsource all our testing at the present time for New York Blood Center, over 600,000 a year.  There are no losses.  It is rare to have an event when there is a snowstorm or something that would delay the shipment or the arrival of a sample.
Those systems are much better than they were in the past.  Actually, I can say one of the major carriers for all those are companies that carry checks around to exchange with banks.  They never lose anything.
DR. MITCHELL:  I think that the AABB brought up a good point about the sensitivity of the NAT testing that the FDA is proposing, 100 copies per ml of viral units to be detected.  They are proposing that it be much higher and that, rather than 100 percent, that it be 95 percent.
I wanted to find out whether there is a basis for deciding what the level of the sensitivity should be and if there is going to be a difference between what is going to be required of the pooled sample versus the individual sample.  Is there a level, on an individual sample, for example, where the number of virus particles may be low enough that it will be considered non‑infectious, I guess.
I don't know if FDA or CDC might be able to answer that.
DR. HOLLINGER:  Any comment?
DR. EPSTEIN:  FDA does have the intention, as Dr. Hewlett explained, to set a minimum sensitivity for detection of the individual sample, regardless whether it is tested in a minipool or as a single unit.
That is not to say that, below that level, the unit is not infectious.  It is just that the way that you set it is by looking at how fast does the viremia come up.  If you can figure out a practical minimum level of detection which captures virtually the whole viremic period, then you succeed in setting a useful standard.
Data have been presented, including publicly by Mike Busch, both for HIV and for HCV which have suggested that if you can detect in the pooled format individual units which have 5,000 or greater copies per milliliter, then that assay will capture virtually the entire viremic period detectable by a gene amplification.
So we are not saying that below that level units are not infectious.  We are just saying that at that level you will capture the vast majority of units that are infectious.
So there are two sensitivity standards then being set.  One is the sensitivity for the assay per se on the pooled sample.  That is the 100 copy per milliliter level.  That is what is achievable right now with state‑of‑the‑art technologies although we are starting to see some that are better.
And then, secondly, in terms of being able to interdict infectious components for transfusion, we are saying there has to also be a sensitivity limit set for the system, as a whole, such that it could detect any individual unit when it contains that number of copies of 5,000 regardless of what the pooling and the extraction and the amplification and the assay scheme are.
So that is a system sensitivity to defined as a threshold for individual units.
DR. HEWLETT:  I just wanted to add a couple of comments to what Jay was discussing and that is that the 5,000 limit at the present is, again, a proposed limit and it is based on data that we have seen presented at various meetings, particularly by Mike Busch.
I think that there are efforts ongoing to look at infectivity‑‑that is, how much virus is, infectious, in the individual donation.  Obviously, this limit that we are setting at this point is, again, going to evolve as these tests develop and we learn more about the infectivity titers in terms of RNA copies.
So, at this point, the 5,000 limit seems to be the best number that we can come up with.
DR. McCURDY:  While we are talking about standards and copies per ml, I wonder why it wouldn't be equally good or, perhaps, better to reference the international standards that are available and talk about international units rather than copies per ml.  I think the rest of the world is going to the units.
DR. EPSTEIN:  The international units have only, as yet, been defined for hepatitis C.  Based on the assays in our hands at CBER, we believe that one international unit represents four genome equivalents.  I think you are correct that, as international units are defined for various agents, we should start to speak in terms of them.
It is just that we had set forth our sensitivity standard prior to the development of the international unit.  Let me also remark that the European standard for single‑unit detection for hepatitis C, as defined by the CPMP, is 5,000 international units which would then be, in our hands, fourfold less sensitive than what the FDA standard is likely to be.
So I take your point that, as the international units are defined, we will start talking in terms of them.  It is just when things happened.
DR. NELSON:  How are these standards, then, developed into a pool size.  It would seem to me that if you take those criteria and the fact that hepatitis C, particularly in a serologically negative‑‑or HIV in a serologically negative‑‑there shouldn't be more, probably rarely, more than one unit positive in a hundred, even.
So would that dictate a pool size of 50, or 5,000 and 100 because there could be‑‑maybe it is a small point and maybe the practical issues of cost and how you can detect a positive, a needle in a haystack, if you will.  But shouldn't the criteria, somehow, relate to the pool size?  Maybe not.  I don't know.
DR. EPSTEIN:  The beauty of setting the standard for the system is then it liberates you from defining the pool size and you can then have a different range of sensitivities, of the analytic sensitivity of the assay.  So what is going on, in effect, is that if you have a pool size of 500, you are going to need a ten‑copy sensitivity on the pool to detect neat samples at 5,000.
Conversely, if you have only an assay at 100‑copy sensitivity on the minipool, then you can't get your pools bigger than 50 to comply with that individual unit standard.  So the virtue in having a standard for the system is that it relieves us of the burden of attempting to define to pool size.  That can then vary.
We did feel, however, that, at a practical level, it was necessary for us to set some minimum for the analytic sensitivity of the assay that could be used on the pool because there are assays that are very insensitive and can't pick up under 50,000.
So we set 100‑copy sensitivity limit knowing that there might be better assays and that better assays might permit larger minipools.  But assays that met that standard would, ultimately, require smaller minipools.  So we are allowing some tradeoff and then that permits us to allow development of varying systems which have different virtues.
DR. FITZPATRICK:  I have a question for Sue Stramer along that same line.  One panels 6211 and 6213, there is a marked difference between the neat and the diluted results.  Could you explain that, or say what you have done to look into that?
DR. STRAMER:  I think that the panel that you are describing is the one I showed where the neat sample was reactive.  And then, in the following bleed, the neat sample was reactive and the first pooled diluted sample was not reactive, then, until the third bleed.
Our explanation for this, through reproducibly seeing this type of finding for some HCV‑positive individuals is we see a degree of aggregation.  So the degree of aggregation, obviously, has a greater impact of your using larger pools but, in this degree, with 128‑member pools, we only saw this on two individuals that have copy numbers, that we would have predicted that we should have been able to detect them, we didn't.
And, again, we attribute this to aggregation but we haven't done disaggregation studies yet to actually say that that is, in fact, the cause.
I hope that answers your question.
DR. FITZPATRICK:  That is a good start.  There will more late, I'm sure.  Thanks.
DR. BIANCO:  Coming back to the number of copies in international units, there is a certain variability of methods both to determine the units and the copy numbers.  Does the agency plan to provide those that are using the test with a standard, a reference sample, that would, for instance, have these numbers of copies so we could adjust our systems.
I remember in the meeting, I think we had last September, the international unit was 2.7 copies.  Now it is 4.
DR. YU:  This is Mei‑Ying Yu from the Division of Hematology.  I just want to tell you that we do have a HCV panel in CBER but it is not really formally accepted as a panel.  This panel consists of ten members and the concentration is from 105 copies per ml to none.  So there are some negative.
Now, one of the members, which is member No. 1 which contains 1,000 copies per ml, has just been standardized in a collaborative study that is really, mainly, carried out by NIBAC.  It is an international study.  So that particular panel member No. 1 of CBER has been assigned as 250 international units per ml.
So we do have such a standard that is assigned with international units assigned already.  Now, it is true it depends on nucleic‑acid test methods.  So, based on John Savannah's data he recently presented at a couple of meetings, one international unit can be a high as more than 6 genomic equivalents and as low as 2 genomic equivalents.
So we rely on the manufacturer's validation data with various standards available, at least for HCV because there is an international standard available.
DR. BIANCO:  Mei, it would be much easier for all of us if you gave each one of us a little bit of that panel member and you told us this is what you are going to call a unit, and we will do it.  It will allow for standardization of the entire system if one, or a group, of those samples were made available to all the manufacturers and people working in the field.
DR. YU:  The first member is 250 international units per ml.
DR. HEWLETT:  I just wanted to talk about the HIV reference reagent that CBER has developed.  Obviously, people in the field are aware that there is no international unit at this point for HIV RNA quantitation.  But there are intensive efforts within the WHO and they are collaborating, in fact, with FDA, and the NIBAC is putting this effort together to actually develop a candidate reference reagent for the WHO and, from that point on, to establish the international unit.
But, in terms of copy numbers, the CBER panels are configured to include members that are at 100 copies per ml and at 5,000 copies per ml which we can actually provide to manufacturers and have provided to manufacturers in the past to calibrate and to validate their tests.
DR. HOLLINGER:  It is a very complex issue, obviously, because there are so many types. It is not like having a very pure protein like albumin from which you can have an international standard.  I am not even sure how you can have an international standard with so many types and subtypes and other things that go on.
But at least it would be a start to have something based on certain primers and so on.
Sue Cushing, are you going to be here through this afternoon?  I will save my question until then.  If not, I am going to ask it to you now.  Is she even here now?  Maybe Andy, some of the data may be yours.  She presented a slide which showed people who had been followed for a long period of time, some of which had donated multiple times and then became positive.
The only question I was going to ask her is why did they become positive.  They obviously were asked questions like anyone else on donation about safety and so on, about their history and a donor questionnaire.  The question is what was their transmission route.  Don't tell me it is sexual transmission.
Did they look for that and try to evaluate it in any way because some persons donated multiple times and then became positive.
DR. CONRAD:  Blaine, in those finger plats that I showed you, many people donated prior to‑‑and if you look at the graph that Sue showed, it didn't matter if it was their first, fifth, tenth, sixtieth donation.  So the answer is they must have lied because they didn't claim they did something or they did something that they didn't know.  You know those donor questionnaires as well as I do.
DR. HOLLINGER:  But did they follow up on it afterwards to ask them and try to seek that information
DR. CONRAD:  Oh, yeah.
DR. HOLLINGER:  And?
DR. CONRAD:  Nothing came of it.  They just said, "I don't know."  I don't think anyone was willing to admit‑‑although there was some early data that showed that there was an odd break or a lapse in the timing between the donations.  In other words, they had been donating regularly at some pace and usually there was some early data.  It is just anecdotal.  It is not enough to be statistically significant.
But there seemed to be a lapse.  In other words, there was some behavioral indication of that conversion, that there was this greater time in between donations surrounding that conversion to NAT positivity.
DR. KLEINMAN:  I think that is an important research issue.  I don't know, in the plasma‑donor sector whether they have really done the donor follow up with detailed questionnaires.  Certainly, that is something we hope to do in the whole‑blood sector to try to find out what people's risk factors are.
Maybe the plasma‑collection agencies are also talking about more formal questionnaires to be given to these donors after the fact to try to get to what you are describing.
DR. EPSTEIN:  I believe that at previously meetings, we have seen data from the CDC that approximately half of all acute HCV infections, whether community‑acquired or in donors have no identifiable risk.  The problem is that we don't ascertain it with questioning.
We think we know most of the underlying mechanisms but, when you ask people, they cannot identify the risk.
DR. HOLLINGER:  That's not true.  I won't let that stand at the present time.  You can get that information and, in fact, it is not being done.  That is because the patient might not tell it to individuals who are acquiring that information in the first place.
Our experience has been that almost all of them have a risk factor.
With that in mind, it is now 12:45 and we are going to take a break now until 1:45 for lunch.  We will meet back here at that time and begin our deliberations on the p24 antigen.
[Whereupon, at 12:45 p.m., the proceedings were recessed, to be resumed at 1:45 p.m.]

A F T E R N O O N    S E S S I O N
[2:01 p.m.]
DR. SMALLWOOD:  We will proceed with our afternoon session.
DR. HOLLINGER:  The first session is on HIV p24 antigen testing, potential criteria for discontinuation.  The first speaker is going to be Dr. Hewlett who will give us an introduction and background to this particular session.
II. HIV p24 ANTIGEN TESTING:
POTENTIAL CRITERIA FOR DISCONTINUATION
Introduction and Background
DR. HEWLETT:  Good afternoon, everyone.  I am going to actually provide you with a very brief background and introduction to the issue.
[Slide.]
Today, we are going to initiate a discussion of the feasibility of replacing HIV p24 antigen testing by nucleic acid testing of minipools in the U.S. plasma blood donors settings.
I want to emphasize that this is also an informational session like the one this morning.  FDA is seeking feedback in the form of discussion on the issue of replacing p24 antigen with pooled NAT and the adequacy of the criteria proposed by the FDA should such replacement be considered feasible or appropriate.
At such time as the sponsor submits an IND to us for replacing HIV p24 antigen by NAT, we intend to bring the issue before BPAC for formal advice.  Consequently, today, we invite your discussion, but we are not posing specific questions to be voted on.
[Slide.]
When HIV p24 antigen testing was instituted three years ago, it was recognized that antigen tests were less sensitive than NAT, particularly NAT for viral RNA.  Based on seroconverted data, it was estimated that NAT could eventually reduce the window period for HIV by an additional five days over the reduction achieved by antigen testing.  However, NAT was only feasible at the time in a research setting, and it was decided to adopt p24 antigen testing as an interim measure for interdicting window period donations.
Since the initiation of antigen testing, a total of five window period units have been interdicted by HIV antigen testing in the U.S.A. and Puerto Rico, and this is data that we obtained from the Red Cross.
[Slide.]
With the imminent implementation of NAT testing of U.S. volunteer donor blood using pooled donor plasma, which has been sparked by European requirements, the feasibility of replacing HIV p24 antigen testing with NAT testing for early detection of window period donations has been raised by many in the field.
NAT for HIV and HCV is currently being performed by plasma collection facilities towards further improving the safety of the blood supply, and, in addition, as you heard this morning, establishments that collect whole blood and transfusable components are also initiating NAT.
Although FDA has no stated position on this topic at the present time, we have begun to discuss the issue both internally and externally.  Today's presentations are part of this discussion.
[Slide.]
Here, outlined on this slide, are some considerations that relevant to this topic for the committee to bear in mind.
One.  NAT testing be pooled or single unit testing must be able to detect all available specimens which are antigen positive, antibody negative, that is, window period specimens.  In other words, NAT sensitivity should be equal to or greater than p24 antigen testing for the window period, and this is NAT testing on minipools.
Comparisons can be made between HIV detection by NAT versus p24 in the course of clinical trials of pooled NAT technologies.  We expect this data to be collected prospectively over the course of a year during which individual sponsors are expected to test over roughly six million donations.
An analysis of this prospective data will include, amongst other considerations, analysis of antigen‑positive antibody positive and antigen negative antibody‑positive specimens.
[Slide.]
Also, NAT minipool testing must be able to detect appropriate samples from seroconversion panels.  NAT minipool testing must also be able to detect HIV variants that would be detected by p24 antigen tests, and this can be demonstrated on selected HIV antibody‑positive samples and on cultured virus spiked into normal plasma or sera.
We are working with industry to identify and collect such specimens and to use them to possibly establish a validation panel.  Details of administration of this panel have yet to be determined.
Finally, individual testing organizations will submit INDs to replace HIV p24 antigen testing with NAT.
With that brief outline, I will conclude my presentation and look forward to some interesting presentations today, to continued cooperation from industry, and to input from BPAC on this important issue.
Thank you.
DR. HOLLINGER:  Thank you, Dr. Hewlett.
The first speaker is from the American Red Cross, Dr. Susan Stramer.
American Red Cross
[Slide.]
DR. STRAMER:  As you hear earlier this morning, I mentioned one of our IND goals for the NAT test IND at the American Red Cross was the replacement of p24 antigen, and studies to be presented to FDA in PLA to support those claims.  I will describe some of those now.
[Slide.]
But first to give you some background in our use of p24 antigen, Indira basically said we had five yield samples.  Let me describe the experience in a little bit more detail with p24 antigen since its implementation on 3‑14‑96.
We have been using the test for three years.  The three‑year experience in the United States has been 5 p24 antigen confirmed positive/HIV antibody negative samples per approximately 36 million donations screened in the United States, and that yield is 1 per 9 million if you exclude the 1 donor from these 5 who was CUE, who had self‑deferred because he had other risk factors.  So, that unit would not have been used.  Including, then, those 4 and 36 million screened, we have a yield of 1 per 9 million.
What I presented in detail at the AABB is summarized in this bullet.  Our two‑year experience with p24 antigen at the Red Cross, we have 132 total confirmed positive.  That is neutralized positives by p24 antigen.  Of those 132, they break out as follows:  74 have been in antibody positive individuals, so these antibody positive individuals were also antigen positive, and per our procedures, we repeat the neutralization, so we know this is a real finding that is repeated in duplicate, and the particular individual was also RNA positive.  So, this is our benchmark for really establishing HIV infection in this individual, a combination here of antibody, antigen, and RNA.
We have also had, in contrast, 54 false positives.  The way we define false positives is these neutralize once in the index sample, but then when that same sample is repeated, the antigen test does not repeat in duplicate, it is RNA negative, and there is no seroconversion of the individual on follow up.
So, in addition to these 74 and 54, then, over this two‑year time, we have 4 index case p24 antigen‑confirmed antibody negative.
So, let me show those, and I will come back then to my next bullet.
[Slide.]
This slide summarizes what we know about these four yield samples, that is P24 antigen confirmed antibody negative.  Here is their index and time of donation, RNA viral load, p24 antigen signal indicated in yellow here except this one should be yellow, too.
So, these are all the positives, percent neutralization on confirmatory testing, development of antibody, and then development of bands on Western Blot.
So, what is important to note here, if we are talking about the p24 antigen positives, which you can see here, by either start at the peak viral load, if you look at the concentration, the minimum concentration here is 100,000 copies per mL, so in our p24 antigen positives, the minimum concentration was 100,000 copies per mL.
[Slide.]
Another feature of p24 antigen testing, since we have implemented it, has been the lack of a negative result on repeat reactive samples.  In most confirmatory strategies after a sample is repeat reactive and it goes on to supplemental testing, you have the ability to call the donor either negative or positive, and with western blots we all know there is indeterminate.  But in this case, actually, there is no negative criteria.  If a donor is repeat reactive, that individual goes on to neutralization testing and is either called confirmed positive or indeterminate.
[Slide.]
To further indeterminate donors, the Red Cross, in collaboration with REDS, did a large study looking at the repeat reactive donors coming from 6.97 million screened, and of those, we had 1,500 repeat reactive donations, 1,157 of those were submitted for PCR, and on PCR testing, all of these were negative.
So, we do know from the study that indeterminate donors do not represent HIV infection that is for p24 antigen, but it represents a challenge to the assay because it is now very difficult to counsel an individual.
[Slide.]
We do know that when FDA licensed the p24 antigen test, it was licensed as a interim recommendation, and we do also understand or we believe that this will require replacement of p24 antigen, will require an FDA licensed NAT test and, of course, with that the release of all products based on NAT, as I described for the Red Cross program Phase II.
Now, to go into specifics of how p24 antigen compares with NAT, at least NAT on pools because that is what is relevant in this discussion, what we have submitted in the IND is really four types of studies.
One.  We know that NAT has brought subtype detection, at least by the Gen‑Probe methods as Christina Giachetti described this morning, including testing of greater than 219 samples from Subtypes A through F, Group O, and Group N samples.
Also, NAT has a broad detection of RNA as compared to p24 antigen.  For example, you have seen in seroconversion data‑‑and I will show you more‑‑that RNA is picked up first, prior to p24 antigen.  In addition, on the other side of the coin, as people seroconvert and become p24 antibody positive, RNA is also detected, so it has a broader base of detection, and therefore, an increased number of samples would be detected by RNA as opposed to p24.
[Slide.]
Looking at a seroconversion profile‑‑and these are all very reproducible‑‑what you see here again is the frequent donation on a plasma donor.  Here is the antibody test for HIV 1/2, the antigen test, and then in red you see the quantitative RNA values.
As you can see clearly from this, the p24 antigen represents a subset of the total that is detected by RNA.
[Slide.]
If you now add the TMA data that we will be using per our IND, here again is the p24 antigen line, so even using a pool size in this study of 128, the pool test picked up p24 antigen two days prior to the p24 test, and then there was another five‑day window from the 128 to detecting the donor in a neat sample.
So, in this case, and in all the cases we have looked at, as I have showed you, p24 relative to diluted NAT diluted NAT is always more sensitive than the individual testing of p24 antigen.
[Slide.]
Looking at all of the samples we did combined in a larger data sat, this is our NGI data set from the first IND, so this is all from quantitative PCR, these are the different stages that an individual goes through in seroconversion, so here we would first have PCR positive, antigen negative, antibody negative followed by PCR positive, antigen positive, antibody negative.
So, in this case, this is the case that we are talking about here, here, the median value of p24 antigen was 100,000, which again was the minimum number that we detected in our p24 antigen yield samples.
So, we believe there is adequate levels of RNA to detect if p24 antigen was not present.
[Slide.]
Looking at the data now in our Gen‑Probe IND, we tested samples undiluted, diluted to 1:128, and p24 antigen.  So, if you look at 25 panels that were tested on two different master lots, of the world of positives in these 25 panels, we could detect on one lot 162 positives, and on another lot 167 positives.
When diluted, we detected 90 percent of these samples and 89 percent of these samples, but when we looked at p24 antigen, we only could detect 82 across both lots, and all 82 of these were reactive when tested in pools of 128, so we didn't miss any, and this represents again a smaller subset of this population.
[Slide.]
Looking at just the seronegative bleeds on a 2 by 2 plot with p24 antigen against the undiluted test, here you can see the undiluted NAT test reactive samples, none of which were p24 antigen reactive, so we have many low‑level positive samples here by the NAT assay that could not be detected by p24.
[Slide.]
So, what happens when you do a 1:128 dilution?  These same samples here that are weakly positive by NAT remain weakly positive at 1:128 dilution again, but nothing is reactive by p24 antigen.  So, there is a whole population of samples here that can be detected by the multiplexed diluted assays that are not detected by p24 antigen.
[Slide.]
In addition to those studies, what we plan to do, although our yield from p24 antigen screening is very low, we hope as we get additional p24 antigen positive donors, we will submit those sample for pooling in our prospective study to introduce into the pooling mechanism and then test on‑line as it were a routine donation.
In addition to that, the last thing we are doing are NAT reproducibility studies to demonstrate that even a weakly reactive p24 antigen sample will be detected by the pooled NAT test across multiple days, instrument systems, technician, and product lots.
In order to do that, we are building a control, an external control sample which will fit into an external control panel, and that sample is a combination of three weakly reactive p24 antigen units that start with an S to CO of 1 to  2.  they are pooled, diluted to 1:16 in negative plasma, and we have the quantitative data before and after dilution.
[Slide.]
They will be included in your LINK study, and we have the opportunity to replicate this 3,000 times.  So, in our external control panel, we have an HIV‑1 RNA positive sample and a HCV RNA positive sample, a negative sample, and we have added this weakly reactive HIV‑1 p24 antigen sample that, when diluted, had a quantity of 2400.  So, with each and every test, we will guarantee detection of that one sample.
Thank you.
DR. HOLLINGER:  Thank you, Sue.
The next speaker is Sue Preston from Alpha Therapeutics.
Alpha Therapeutics
MS. PRESTON:  Good afternoon, ladies and gentlemen.
[Slide.]
We are very pleased to be invited today to speak to you on the results of our clinical trial and comparison of the p24 antigen to HIV RNA results in our pooled sample PCR testing.
[Slide.]
The prospective clinical study was sponsored by the National Genetics Institute, and conducted jointly with Alpha Therapeutic Corporation.  ICRC, Inc., was contracted to run the clinical trials.  The IND was filed February 17, 1997.  The study was actually conducted for HIV from June through September of 1997.
[Slide.]
The design of the clinical trial was to enroll anyone who was antibody negative and p24 antigen positive and/or PCR positive, and follow three months or to seroconversion.
[Slide.]
The clinical participation included 33 of our plasmapheresis centers.  We have 63 licensed, so approximately half of our centers were enrolled in the study.  We tested over 342,000 donations over that four months and greater than 10,000 donors were tested in the study.
[Slide.]
Our source plasma screening program includes about close to 3 million donations per year.  They are collected in 4% sodium citrate.  For our testing new donor plasma units or the applicant donors have their viral marker serology performed and they are found negative before those samples for pooled for PCR screening.
For applicants donors or repeat donors, those units are pooled concurrently with the serology for the PCR.
[Slide.]
I decided not to show you the cube today, but I tried to do it a little differently.  We do have a cubic matrix, eight primary pools in each of three dimensions.  That includes the rows, columns, and layers.
There are 24 primary pools with 64 samples per primary pool, and aliquots from each primary pool contribute to the formation of the master pool.  So, there are a total of 512 samples per master pool.
[Slide.]
In terms of the stability that we found for the source plasma donations, we have tested that with NGI, and we can store up to 60 days at minus 15 degrees, up to 7 days at minus 5 degrees, up to 7 days at plus 8 degrees, up to 10 hours at 24 degrees, and it will withstand 5 freeze‑thaw cycles, sample will withstand 5 freeze‑thaw cycles.
The actual logistics for the testing, the plasma samples are shipped to the Memphis laboratory, which is the Alpha Therapeutic Corporation's central testing laboratory, where plasma samples are pooled.  We have T‑can equipment to assist with that.
The master pools are then shipped to National Genetics Institute for the PCR testing where they undergo preparation, amplification, and detection.
[Slide.]
Following the PCR testing at NGI, the results are reported back to the Memphis laboratory.  Positive master pools are retrieved or we retrieve the primary pools from the positive master pools, so there are 24 primary pools per master pool that are shipped back to NGI.
The PCR test results are then reported to our Memphis laboratory where we identify the donations and confirm with the individual sample.
It takes right now a mean of 20 days to resolve, and that is well within, for the source plasma, the 60‑day inventory hold, so that does not present a problem to us because there are several back and forths with respect to samples.
[Slide.]
For the clinical study itself, we had four eligible subjects, two enrolled and two did not.  The number of donations that were found to be PCR positive were 10 from the two enrolled and 6 from the two that were not enrolled, and that is presented in the next overhead, which is a finger plot that Dr. Conrad showed earlier today, but I will go through and describe a little bit in more detail.
[Slide.]
Each little tick mark there represents a sample or donation, so each of the black marks.  In green, all of these units were tested in the 512 pool.  They were by PCR, and they were negative.
So, plotted at the day of the first positive result, we can see that blue represents PCR positive only, that yellow represents PCR positive in the 512 pool, as well as p24 antigen positive, and red is the PCR positive, p24 positive, and antibody positive donations.
For each of four donors, we did detect by PCR prior to p24 antigen test results becoming positive.  However, this was only four.  That is a small number.  We worked through, and if we can have the next overhead‑‑
[Slide.]
‑‑ additional samples and the sources for these window period samples included the clinical study period subjects, additional subjects that were HIV antibody or antigen positive, some of the plasma units we had in seroconversion panels.
So, what I am going to present you now is in the process of being finalized for a report, so I would all it a preliminary analysis.
[Slide.]
This is a description of how we actually selected these window period units.  NGI performed their quantitative reverse transcriptase PCR.  If they were positive, then, these units were diluted to 512, and the qualitative test was performed.  This is a test that we do on the 512 for the donor screening.
If they were negative, however, by the quantitative, we then did them by the qualitative method, and again if they were positive, diluted to the 512 to obtain the test results.
[Slide.]
This overhead is a 2 by 2 contingency table.  PCR along here is PCR positive or PCR negative.  It was either positive by Coulter or Abbott, we didn't care which one, but just as long as it was positive by at least one of those, and these are for antibody negative specimens.  We found 61 of these specimens were concordant, they were positive for PCR, and also positive by p24.
There were 32 samples that were positive for PCR, but negative on p24.  There were 71 that were concordant being negative for both p24 and PCR, and as Dr. Conrad pointed out, there were none that were positive for p24 and negative for PCR.
[Slide.]
This overhead is the same table, but for all samples, so there were antibody positive samples also included in this, and as we look at this, there were 140 concordant samples PCR positive and p24 positive.
There were 91 samples that were p24 negative and PCR positive, 109 that were negative by both tests, and again zero where p24 would have picked them up and PCR didn't, so there was absolutely none.
I think another important thing, since we talked a little bit about this, and you discussed it a little bit earlier, there were 6 samples that were antibody positive only, in other words, they were not p24 positive, nor were they PCR positive, however, all of these‑‑I want to make the point that all of these would have been caught by lookback in our 60‑day hold.  But I think that is an important point as to why we are not requesting consideration for deleting the antibody test.
[Slide.]
This is a plot just to show these are the number of incidences, the number of donors, if you will, and a plot as to the days that they were detected before p24.  Now, this doesn't mean that this was sampled every day in between there, but this is the way these panels broke out.
There were 27 donors that were detected basically the same day they were p24 antigen positive, they were also PCR positive, and then there were 36 donors that were represented in here where PCR detected the viremia earlier than p24.
The mean turns out to be about three days here with the median of about two days earlier, and during the quantitative analysis of these samples, they ranged from anywhere from 100 copies per mL to 20 million copies per mL in the PCR positive donations.
[Slide.]
I would just like to acknowledge all of the collaborators on this study ‑ Andrew Conrad, Peter Schmid, Jeffrey Albrecht, and Richard Smith from NGI; and then Alpha Therapeutics, Bill Craig, Chuck Frisbie, Chuck Heldebrant, Lorraine Peddada, and Lolita Mercado.
Thank you.  I will be glad to answer any questions.
DR. HOLLINGER:  Just at this point‑‑I should have done this the first time around‑‑but any questions for Sue Preston on the presentation here?
[No response.]
DR. HOLLINGER:  If not, let's move on to the next speaker, Michael Busch from the Blood Centers of the Pacific, Irwin Center.
Blood Centers of the Pacific, Irwin Center
DR. BUSCH:  Thanks, Blaine.
Just a few I think sort of historical comments.  I think many of you in the audience were probably here about five years ago or so when the antigen issue was first debated, and I think it is worth going back and remembering that the Advisory Committee to FDA voted based on the projected yield data from the models that we had developed and that I will briefly review now that indicated that the yield would be something in the range of five or so antigen positives per year, and that the cost effectiveness of antigen testing would be extremely poor, voted against introducing antigen testing.  I think, as I recall, the vote was something like 12 to 5 or something like that.
Within several weeks of that vote, the Congressional Oversight Committee, chaired by Shays, issued a letter instructing FDA to, in essence, override the committee's decision.
In that letter, somehow projections were derived that estimated that there would be something in the range of 65 antigen‑only donations detected in the whole sector per year.  I think, as we have come to see, the antigen yield is actually much lower than projected, and I will briefly address a few studies that have tried to understand why has the yield been lower than we originally projected.
Just another comment.  The focus of discussion on antigen implementation at the time was exclusively focused on the whole blood sector.  I don't recall any considerations at the time because there has not been an HIV transmission from plasma derivatives since essentially screening was introduced in '85.  Any discussion about requiring antigen testing of source plasma donors, and many people including myself were very surprised when the FDA memo came out and actually required antigen testing of source plasma donors.
As we have seen, actually, there continues to be yield in the source plasma industry, but not in the whole blood sector.  So, with that background, if you would turn on the slides, please.
[Slide.]
As we saw from Sue Stramer's data, the yield has actually more in the range of one to two per year rather than the five to 10 per year predicted, and we wondered why that is.  One possibility is that actually, the modeling that we use to estimate yield assumes that the incidence rate in the donor population, the rate of seroconversions or new infections is constant over time, and also that when a donor is giving, that they are giving in a steady‑state rate throughout the evolution of seroconversion, and the models estimate the duration of each of these windows, and then multiplying by the incidence, project the rate at which people may give during that brief window phase here, the antigenemic phase.
So, one assumption is that the rate at which people seroconvert overall can be assumed to be predictive of the rate at which they would give during that very transient antigenemic window.
So, as we realized that the yield wasn't coming toward what we had projected, we began to wonder, one, whether the incidence rates had dropped; two, the question of whether the donations may not be consistently given during the antigenemic phase either due to people's self‑deferring due to recent risk or to symptoms or deferral at the time of blood donation because we take people's temperature and ask them about things like recent night sweats, and as most of you know, HIV primary infection, particularly during the antigenemic phase, is associated with an elevated temperature and with symptoms, and in addition, these people may be aware of recent risk.
[Slide.]
So, to look at these issues, a couple of analyses.  One is actually REDS has continued to monitor incidence.  The incidence rates that we use to project the yield of antigen were an incidence rate about 4 per 100,000 per year based on data from this '91 to '93 time period.
As we have continued to monitor incidence, you can see there has been a small, although insignificant, drop in incidence rates, and we are really running these days more in the range of 1 per 100,000 person years, so, indeed, the incidence of HIV has declined in the donor pool, which may partly explain the lower than projected yield.
[Slide.]
Another clue actually comes from the panels that were actually studied in generating the original model data that led to antigen introduction, and this slide was actually made back in probably '94 and before we had any consideration of this, just selecting four of the seroconverting plasma donor panels from BBI that were representative of the panels, just to illustrate the ramp‑up of RNA, the increase in antigen levels, and then the appearance of antibody.
What I want to point here is something that is frequently seen in these panels, and specifically, it is actually the X axis.  What you see here are data points corresponding to when these donors were giving, and you see that these donors were giving at essentially a twice a week frequency, which is the rate that they are allowed to give, and then they don't give for a week.  They give it twice a week, twice a week, and they don't give, twice a week, twice a week, and then they skip a week.  Over here, this person skipped several weeks.
What you can see is the weeks they skip are fairly consistently when they would have the peak antigenemic titer.  So, what we suspect is going on is a fair bit of self‑deferral, attributable organ donor center deferral.  We actually looked back at donors who didn't give to see if they had come to the center and perhaps were deferred due to temperature, things like that, and there was no evidence of that.
So, what we actually think is many people, because they are sick, may not come in to give blood during that week they are maximally antigenemic.
[Slide.]
This is the plasma donor sector, and we have looked at this in the whole blood donor sector, as well, in the REDS study, and this is an analysis that George Schreiber did, where we looked at our seroconverters to all of the viruses, and we looked at their interdonation intervals, the time between their first positive donation and their prior negative donation, and this was based on antibody testing, and we did this in HbsAg for the four major agents.
Just to make a long story short, what we observed was that the HIV seroconverters had significantly longer interdonational intervals in their immediate pre‑seroconversion donation than the general donor pool, and specifically, most powerfully, is donors who were giving serially, when we looked at their interdonation interval immediately prior to seroconversion, it was much longer, 388 days, compared to these very same donors' usual pattern of donation, which was about 140 days, and that was highly significant.
This observation was true for HIV, but not true for any of the other viruses.  So, it really does look as if HIV seroconverters, both in the whole blood and plasma sector selectively defer immediately prior to seroconversion either due to some awareness of risk behaviors or because of this symptom issue.
[Slide.]
One last slide, which is to lead us into the newer data.  This is data again that was generated from panels immediately before the licensure of HIV antigen testing when we were trying to understand the durations of the RNA and antigen window characterizing lots of panels, and now we are focused back on these because the real issue we are focused on today is whether we can comfortably discontinue antigen testing given the availability of direct nucleic acid screening.
What this slide shows is what is termed at box and whisker plot showing the distribution of RNA among donations in these plasma panels that were detected only by RNA versus by p24 antigen during the pre‑antibody window period.  It is this kind of data that I will go into in more detail with newer analyses in the overhead.
[Slide.]
The first slide is actually the same data as was in those first two box and whiskers on that earlier plot, just directly comparing the RNA distribution.  Now, this was from approximately about 80 samples from 50 seroconversion panels.  Again, these were archived panels that had been identified in the period of like '85 through '95, and then testing back, we identified these RNA only or p24 antigen positive samples.
What you can see from this analysis is that there is a highly significant difference with the RNA‑only samples having a much lower viral load on average.  This, by the way, is Roche quantitative monitor PCR data versus Abbott p24 antigen results.  We can see that the RNA‑only had a average copy number of about 1,000, whereas, the p24 antigen had an average copy number of about 200,000.
[Slide.]
On this slide there are actually just some sort of scribbled statistics from this distribution plot focused on the antigen positive donations, and the critical point here is again the average copy number of these antigen positive, antigen negative donations is over 200,000, and the lower 95 percent confidence bound is about 25,000.
So, in other words, if you had an RNA assay that could detect samples with 25,000 copies based on this data set, you would detect 95 percent of the antigenemic donations.  You would detect 97.5 percent if you had an RNA assay that had about 2,000 copy sensitivity.  You would detect 99 percent with an RNA assay of about 1,000 copies.
[Slide.]
Then, one can look at these samples again from this earlier historical data set, plotting out the log of concentration of RNA versus the p24 antigen reactivity, and you can see that there is a moderate number of samples down here that are antigen nonreactive that were RNA positive, very similar to what Sue Stramer showed, and then once you get into the samples that are antigenemic, you see a very close relationship between the levels of RNA and the levels of antigen.
[Slide.]
If one does a regression analysis on this data,  you can then begin to try to estimate what the RNA load is at the point of the antigen cutoff, and this is focused on the antigen positive, RNA positive samples, and based on this analysis, the estimated intercept is around‑‑I think it was around 30,000 copies.
But this was very old data, so what we wanted to do was to really update and expand this analysis, and fortunately, Sue Preston and Andy Conrad from Alpha and NGI were comfortable with sharing their newer data, which is much more exhaustive.
[Slide.]
This slide summarizes a similar analytical approach to get an understanding of the distribution of the antigen positive units and the cutoff value at which the antigen test becomes reactive, so that we can ask the question of at what level of RNA would we be comfortable discontinuing antigen.
I think this very same data is actually the data that is the basis for defining the cutoff that we want NAT to perform at.  We want NAT to clearly be a substantial improvement relative to RNA, and interdict most of these RNA‑only samples that are detected by single donation testing.  So, these kind of analyses are the kind of data that yield the 5,000 recommendation.
But to focus first on the antigen‑only phase, there were 85 specimens in this data set that were negative on the third generation antibody Combi test, specifically Abbott's HIV 1/2 Combi test that were positive on p24 antigen.  In this case, it was the Coulter p24 antigen assay.
This slide then shows the distribution with the median copy number of about 100,000‑‑we will look at those statistics in a moment‑‑and the vast majority of samples having copy numbers well over 10,000 copies, really with only a single outlier specimen.
In contrast, the RNA‑only samples have a much lower copy number, an average copy number of around 20,000 with samples detected as low as 100 copies or less.
[Slide.]
This is statistics again not for people to see.  If you actually push that up.  This is basically for me to just comment.  The same kind of analyses, then focusing on the antigen‑only samples, would tell us that an assay sensitivity of 10,000 would pick up 95 percent of the antigen‑positive samples that Alpha and NGI detected.
As you want to pick up 97.5 percent, an assay would have to have a sensitivity on an individual donation of 7,000 RNA copies, and if you wanted to pick up 99 percent of the antigenemic specimens, the assay would have to be able to pick up around 2,400 copies per mL in the individual donation samples.
[Slide.]
Then next thing we wanted to understand was more precisely what the RNA load is at the cutoff of the antigen assay.  The data that Sue Preston presented, extremely positive reassuring, essentially, every single positive antigen sample was detected by RNA at a pool of 512, and empirically, as I just showed, if you take a cross‑section of samples picked up as antigen only, the lower 95 percent confidence found on that distribution is around 10,000 copies.  So, you would pick up 95 percent of real world samples with an assay of 10,000 copies.
But we wanted to go a little further and try to really understand the antigen intercept, meaning at what concentration of RNA did the antigen assay become reactive.
Based on this regression analysis, we could estimate almost exactly 10,000 copies is where the antigen test first becomes reactive.  So, clearly, setting a cutoff at or below the limit of sensitivity of the antigen assay would be a very reasonable and conservative strategy to allow discontinuation of this assay.
[Slide.]
This just shows confidence intervals analyses around that cutoff, but again, the bottom line is that virtually all the samples are detected at 10,000.  You will note this one outlier sample that actually had a copy number of only 500, and yet was detected at on the antigen assay.
[Slide.]
This is a similar plot of the distribution, but now this is limited to 32 of these approximately 45 seroconverters where we had 3 samples that were RNA positive prior to antibody.  This then distributes their individual subject RNA versus antigen reactivity.
The point I want to make here is that virtually all of these people, all of their antigen RNA data is consistent with a very tight cutoff sensitivity of the antigen test at 10,000 copies.  So, almost all of these people crossed this antigen cutoff line right at that 10,000 copy sensitivity.  So, very reassuring that a 10,000 sensitivity assay would comfortably detect all of the samples even if they were diluted down to the cutoff of the assay.  But there was this one sample, and interestingly, this one person is actually represented three times in a panel, and all three samples from this person showed a low RNA copy number on this assay relative to the antigen in single intensity.
So, the point here, this is one out of 32 people.  There may be rare individuals who, on a particular RNA assay, may give you relatively low RNA antigen load, but why that is, is under investigation, but these are extremely rare, and again, this sample was picked up at a 512 pool, but my bottom line message here is that based on the analysis we have been doing, we would be very comfortable that a cutoff as high as 10,000 should allow discontinuation of p24 antigen testing, and certainly setting a cutoff half that, at 5,000, would be an even more conservative and appropriate position.
Thank you.
DR. HOLLINGER:  Thank you, Mike.
Any questions of Dr. Busch?
[No response.]
DR. HOLLINGER:  The final speaker in this session is Dr. Schochetman from Abbott Laboratories.
Abbott Laboratories
DR. SCHOCHETMAN:  Thank you.
I think my role here is to sort of provide the counterpoint to this and to provide possibly a cautionary note about premature termination of antigen testing, and thereby probably sending a disincentive message to manufacturers to not bring forth new and more sensitive antigen tests.
[Slide.]
What I hope to be able to do today is to convince you that the gap in detection between individual antigen testing, using a new and more sensitive assay with broad HIV variant detection, and NAT testing of pooled samples may not be as significant as we may have originally thought.
[Slide.]
Before I begin with that part of it, I would like to come back to the HIV variant issue.  I am sure most of you are aware of the fact that HIV variants are rapidly spreading into developed countries.  If you are not aware, currently, only at 1/30th of the global infections in the world are due to HIV‑1 group M subtype.
In Europe now, it is estimated that up to 25 percent of new infections are due to non‑subtype B HIV‑1 group M infections, and in the U.S., that number of non‑subtype B HIV infections is also increasing, and according to the CDC, there may be in excess of 3,200 cases that were actually detected that were non‑subtype B.
[Slide.]
I think the challenge to manufacturers certainly is to develop sensitive assays with broad HIV variant detection.  In particular, for NAT assays, they must be able to detect all HIV variants efficiently, and must have adequate sensitivity to address dilution factor due to pooling.
[Slide.]
What I would like to do now is address all HIV variants efficiently.  What I have provided you here is a comparison of two assays, two quantitative assays, the LCx assay from Abbott and the test of record assay here in the United States, the FDA‑licensed test.
What I would like to do is point out really the upper lefthand quadrant here, that there are 71 samples out of a total of 278 that we actually looked at, which were positive in the LCx assay and negative in the test of record here in the United States including at least five Group O specimens shown in red here.
[Slide.]
I think you can see here that those 71, when you break them down, you find out that in terms of HIV subtypes, that they run the gamut of subtypes from all the A through G, HIV‑1 group M subtypes and including the Group O.  The mosaics would be either mosaic or recombinant viruses.
I think when one looks at which assay you are using, I think it is imperative that actually one pay attention to and realize the broadness of the cross‑reactivity of the assays that are being used and whether they can detect all subtypes.
[Slide.]
What about the issue adequate sensitivity to address the dilution factor due to pooling?
I have just taken three examples here of actual specimens.  These happen to be mosaic viruses A/G/A, and these are specimens with low copy number.  In this case, the copy number is just over 1,000, again here over 1,000, and this one is actually less than 1,000.
You can see here as we begin to dilute, certainly, if you are looking at 50 copies per mL, that as you reach about 1 to 50 in a pool of 128, you actually would be negative, and if you are looking at a sensitivity of 100 copies per mL, you would actually lose your sensitivity more like 1 in 20.
[Slide.]
What about antigen testing?  Well, we have gone ahead and actually developed a new and more sensitive antigen test, and you can see here the sensitivity begins to approach about a picogram/mL for p24.
When you look at the ability of this assay to actually detect a variety of subtypes, the group M subtypes A through G, and including O, you can see that this assay is very sensitive and can efficiently quantitate really all the variants, and not just simply the HIV group M subtype B.
So, here, we have an assay that actually is very sensitive and has very broad detection.
[Slide.]
Well, what about the comparison between a sensitive antigen assay and genetic testing?  A lot of data we heard today was really with the currently licensed tests which have been around for a while.
If you talk about the sensitivity of an antigen assay, such as the one I showed, which is about a picogram of p24, you are talking about somewhere in the neighborhood of around 10,000 copies of viral RNA.
So, even at a sensitivity of 50 copies per mL for a NAT test, and you are talking about a pool of 128, the sample must have at least 6,400 copies of viral RNA.  I think there can be variability as much as half a log between assays and maybe between runs, so that the difference of 10,000 copies picked up by a more sensitive antigen assay and 6,400 copies may really not be all that significant.
[Slide.]
In terms of the advantages of individual testing in pooled versus NAT testing, I think certainly the antigen testing is a fully automated system.  It provides rapid results, and as I show you, can actually provide very efficient detection of all HIV variants including the group O, really does not have issues related to sample preparation, contamination issues.  We heard this morning issues of possible transportation, temperature controls, et cetera, et cetera.  The assay has the ability to be confirmed using a neutralization test, and in terms of simplicity for implementation, there would be no pools needed to dilute the sensitivity, and there would be no dissection of pools.
I think I would leave you with the comment that although we now have an assay that can get us down to about a picogram of p24, I think that by no means is that the theoretical limit, and we feel that we can actually go more sensitive, and I will come back to my original point, that is, that I think if we decide to send a message that nucleic acid testing should be removed, then, we may send a disincentive to the development of new technology, and I will leave it at that.
DR. HOLLINGER:  Thank you, Dr. Schochetman.
Any questions on this presentation for now?
[No response.]
DR. HOLLINGER:  In the open public hearing, we have one person who stated he wanted to speak, and that is Dr. Kleinman from the AABB.
Open Public Hearing
DR. KLEINMAN:  The AABB commends the FDA for initiating open public discussions about the potential elimination of the p24 antigen assay.  The major requirement for establishing that the HIV‑1 p24 antigen assay can be safely discontinued is to demonstrate that it elimination would not introduce additional HIV infectious units into the blood supply.  The AABB would like to take this opportunity to present a proposed approach to acquiring the data necessary to evaluate this issue.
The AABB recognizes that elimination of the p24 antigen assay will not be possible until all donated units are screened by an assay that is of equivalent or greater sensitivity for detecting window period infection.
In the case of pooled NAT, this would mean that NAT would need to be completed prior to component release.  Furthermore, the AABB believes that pooled NAT would need to demonstrate satisfactory performance characteristics in routine operational settings before it can be considered as a replacement for the p24 antigen test.
It is unclear exactly what requirements would need to be met to fulfill this criterion; at a minimum, the pooled NAT system would need to have the required level of sensitivity, as determined by previous studies comparing p24 antigen results with quantitative viral nucleic acid assays.
In the view of the FDA, satisfactory performance may require that a pooled HIV NAT system be licensed prior to considering replacing the p24 antigen assay.  However, other approaches to demonstrating satisfactory performance, such as compiling performance data over an extended time frame while still under IND, for example, 6 to 12 months, should also be considered.
The rationale for the introduction of p24 antigen testing was based on modeled data from plasma seroconversion panels that demonstrated the ability of the assay to shorten the window period for HIV infection by approximately six days relative to the estimated 22‑day window with the most sensitive antibody assays.
Data from the same seroconversion panels have indicated that all HIV‑1 p24 antigen positive window period units also were positive by research RNA PCR assays and that these assays further shorten the window period by an additional three to five days.
Furthermore, quantitative PCR assays indicate that p24 antigen positive units contain at least 10,000 copies per ml of HIV RNA.  These combined data suggest that pooled NAT programs using assays with 50 copy/ml sensitivity and pool sizes of less than or equal to 128, which is the maximum pool size proposed by the volunteer blood sector, will be able to detect all window period units that are p24 antigen positive.
As you heard today, using the incidence window period model developed by the REDS, it was projected that up to eight HIV p24 antigen positive, antibody negative units would be detected annually in the U.S.
Actual experience over the past three years has demonstrated that fewer than two units per year have been detected in volunteer donors.  This low yield indicates that it would take many years to accumulate a sufficient number of p24 antigen positive window period units to substantiate that pooled NAT will detect all such units.
The AABB believes that an alternative approach for data acquisition is needed.  We suggest that test performance on commercial plasma donor seroconversion panels and on samples obtained from HIV screening performed by the commercial plasma donor sector serve as the basis of assessing the performance of a pooled HIV NAT system versus the p24 antigen assay.
Satisfactory performance of a pooled NAT system relative to p24 antigen testing could first be demonstrated in a research laboratory  and then could be validated by the testing of blinded seroconversion panel samples in clinical trial protocols conducted by the operational NAT laboratories.
The number of antigen positive window period units needed should be determined by statistical evaluation and agreed upon in advance by FDA and the testing laboratories.  Such an approach would yield data that should duplicate prospective blood donor screening performance, but in a very much shorter time frame.
This approach would permit rapid evaluation of the feasibility of replacing the p24 antigen assay without increasing risk to recipients.  If the data support such an approach, rapid elimination of an unnecessary test would have the benefits of simplifying the blood donor screening process and reducing the costs of supplying blood components.
Thank you.
DR. HOLLINGER:  Thank you, Steve.
Any questions of Dr. Kleinman?
[No response.]
DR. HOLLINGER:  Is there anyone in the audience also then during the open public hearing that would like to make a presentation?
Yes, please state your name and organization.
DR. HEALEY:  Yes.  Good afternoon.  My name is Chris Healey, and I am the Director of Government Affairs for ABRA, which represents the source plasma collection industry.
We are encouraged by the fact that FDA has initiated the dialogue about discontinuation of p24 antigen testing, and we concur that the time is right to begin discussing the specifics of discontinuation criteria.
Of course, first among them must be that p24 antigen testing is discontinued only if there is no sacrifice in the safety of source plasma, which means that the NAT testing must be demonstrated to be equal to or better than the current p24 antigen testing.
Other key issues to the industry must be addressed early on in this dialogue, and among them are included the implementation of discontinuation of p24 antigen testing.  What I mean by that is that industry believes it should be done industrywide, and not piecemeal.  That is to say, we believe that FDA should consider withdrawing its policy industrywide, and not according to specific manufacturers or specific collectors.
To that end, we think that discontinuation should not be linked to specific IND amendments, and the perspective here is that the logistics associated with tracking specific units of plasma as to whether they should be p24 tested or tested according to NAT is just overburdensome and would basically eliminate this good work or discontinuation.  It would make it unworkable essentially.
We believe that FDA can take a perspective of looking at the aggregate data.  We believe that industry working together with the agency can collect data over some period of time, six months, a year, and that based on the aggregate industry data, industry and FDA can agree that the time is right to withdraw the policy industrywide.
Other issues pertain to the development of the seroconversion panel.  Primary among them is that the panel ought to be internationally recognized.  We believe that we should be working with European and Japanese partners to make sure that whatever seroconversion panel is developed to assess NAT testing is recognized by our foreign counterparts.
Finally, we believe that whatever panel is developed, that it should be used only as a reference panel, and shouldn't be used at all to evaluate sensitivity of current NAT tests.
We look forward to working with the agency on this initiative, and look forward to reporting back to the BPAC.
DR. HOLLINGER:  Thank you.
DR. EPSTEIN:  Jay Epstein, FDA.
I understand at a practical level why it would be easier to just have a blanket removal of antigen for the fractionation industry, but the reality is that if different testing systems are going to be used, we can only get to that point once we are assured that all of the ones in use are adequately sensitive to replace antigen.  That is just a logical requirement.  So, you know, if we were to have a blanket policy and we looked at it your way, we would have to wait until all assays available met that standard.
DR. HOLLINGER:  Other comments?
[No response.]
DR. HOLLINGER:  I think then we will close the open public hearing.
Now, we will open it for the committee for their discussions.  Anyone would like to make some comments about the issue on p24 antigen testing, the potential criteria for discontinuation or continuation?
Yes, Dr. Fitzpatrick.
Committee Discussion
DR. FITZPATRICK:  Abbott has raised a point here that I think needs to be considered, and that is that the focus is on elimination of p24 antigen in deference to PCR testing, but if they can demonstrate equal sensitivity and narrowing of the window by detecting p24 antigen, now you have two equivalent tests, and it is a matter of economics and selection as to which test you are going to use to select and test for HIV.
I didn't hear that argument presented by anybody, but I think that needs to be considered.
DR. HOLLINGER:  Does that pose a problem if there are comparable sensitivities and it can be demonstrated either that the comparable sensitivities or that one picks up some that are positive by antigen and negative by RNA, and vice versa?
DR. EPSTEIN:  I guess we will have to cross that bridge when we come to it.  The question that will arise is whether if you have two different assays and they each pick up the same number of antibody negative infectious samples, should they coexist and be used as alternatives or should they both be used versus the simple case where they pick up the same samples.
If they pick up the same samples, the question is easy because you could easily allow alternative use, but if they pick up the same number or approximately so, but they are not the same sample, then, it is difficult, and I think that the logic would tend to drive us to keep both tests.
DR. HOLLINGER:  Jay, while you are here, in Europe they require p24 antigen testing, so it is not an issue, a regulatory issue at all.
DR. EPSTEIN:  They have not introduced it in Europe to my knowledge.
DR. HOLLINGER:  And not into other countries?  Does Canada require it?
DR. EPSTEIN:  I believe Canada followed the U.S. model.  I believe that Canada followed the U.S. recommendation, but to my knowledge, no European country is testing for p24.
DR. HOLLINGER:  Other questions?  Yes, Dr. Nelson.
DR. NELSON:  The data seem to indicate that under most circumstances, the window period is shorter with the PCR testing, but I am still disturbed by the data showing negative PCR with other than non‑group B viruses.
The Abbott presented those data, and there seems to be some disagreement on that.
DR. HOLLINGER:  Is there any other way of knowing whether those samples are infectious or not either by culture or other‑‑possibly not by culture, but other ways of knowing that?  Gerald.
DR. SCHOCHETMAN:  Well, certainly the specimens are isolated from HIV‑infected individuals, and as we sequence across the genome, we don't see any premature termination signals, so our assumption is that these are probably viruses that would be infectious.
DR. HOLLINGER:  Say it again, that what?
DR. SCHOCHETMAN:  These would in essence be infectious viruses.  We have no indication that they are not infectious.  The evidence would probably be the other way.  They are isolated from people who replicating virus, and as we sequence across the genome, we see no premature termination, and we see only open reading frames, so we are assuming that these are infectious agents.
DR. HOLLINGER:  I am sorry, these are antigen positive, but RNA negative?
DR. SCHOCHETMAN:  No.
DR. HOLLINGER:  They are low level.
DR. SCHOCHETMAN:  They are picked up by the Abbott assay, they are missed by the other assay.
DR. HOLLINGER:  But low level PCR positive?
DR. SCHOCHETMAN:  Well, they are not necessarily low level.  They are pretty good level.  It is just the other assay doesn't have the variant detection capability.  The broadness of the detection is more limited.
DR. HOLLINGER:  Did you present also some information, though, that suggested that some were very low level?
DR. SCHOCHETMAN:  I also presented some additional data on three samples that were low copy number to start with.  What I was suggesting was that if you start diluting those, even at a 1 to 20 dilution with a sensitivity of 100 copies per ml, which is what we heard today, is that those would go negative.
DR. HOLLINGER:  Did you do that?
DR. SCHOCHETMAN:  I presented the data.
DR. HOLLINGER:  No, but did you dilute them and then test them?
DR. SCHOCHETMAN:  Yes.
DR. HOLLINGER:  And they were negative?
DR. SCHOCHETMAN:  Yes.
DR. HOLLINGER:  Thank you.
DR. SCHOCHETMAN:  I mean they were positive in the assay, but negative if you assume a cutoff of 100 copies per ml.
DR. HOLLINGER:  I guess my question is did you specifically dilute them.
DR. SCHOCHETMAN:  We specifically diluted them and did the experiment.
DR. HOLLINGER:  And retested them and they were negative.
DR. SCHOCHETMAN:  Yes.
DR. HOLLINGER:  Thank you.
DR. NELSON:  Could I ask Dr. Schochetman one additional question?  You used the Roche monitor.  Was that Version 1 or Version 1.5 that was used, because we have had experience in Thailand that subtype e, the Version 1 doesn't work very well, but 1.5 does.
Which assay was used for that determination?
DR. SCHOCHETMAN:  Specifically, in this case, used the 1.0 because it is the licensed kit here in the United States, and the reason the E is missing is because in the GAG region it is A.
DR. HOLLINGER:  Do you want to respond to these issues, Mike?  Yes, and then Andy.
DR. BUSCH:  I think we have really got an apples to oranges.  The data you saw was LCx, which is the Abbott noncommercially available at this point amplification assay versus the Roche 1.0 monitor assay.
We did not see p24 antigen data versus the 1.0 monitor assay.  I wouldn't doubt that they would have false negatives on the 1.0 monitor test because, as Ken indicated, that test had serious subtype sensitivity problems which have been fixed with the commercially not yet available, but I believe submitted 1.5 or 2.0 monitor, which is the quantitative assay, and certainly all the data I have seen from both Roche and Gen‑Probe looking at a large number of subtype‑defined specimens has indicated 100 percent sensitivity of the assays that are in development and being implemented in donor screening.
So, these samples that we saw were all Abbott source samples, and I think it is a beautiful panel and would be outstanding to be able to apply that panel to the assays we are talking about, but until that is done, I have never seen a single contemporary antigen positive sample that is missed by either the Gen‑Probe or the Roche systems.
DR. CONRAD:  Andy Conrad from NGI.
I just wanted to echo what Dr. Busch said, that that slide was again the Abbott LCx amplification system versus Amplicore 1.0, I think it is not exactly what we have been talking about here.  In our clinical experience, looking at thousands and millions of donations, we have never seen a case when the antigen was positive and the PCR was not, and I think that is a much more telling thing.
As far as subtype detection, most of the manufacturers who are using nucleic acid‑based detection systems now are very, very comfortable detecting, and have tremendous specificity and sensitivity throughout the entire genomic range of subtypes, and I think that would obviously be forwarded in the submissions.
DR. HOLLINGER:  And both you and Dr. Busch would indicate that the levels are such in those antigen positives that they would be detected with a pool system?
DR. CONRAD:  Even with the 1 picogram thing that we saw here, it is 10,000 copies, and the NAT, we will show you the sensitivities that nucleic acid systems are getting, that would be easily detected even in larger pools than the ones proposed.
DR. HOLLINGER:  Thank you.
DR. NELSON:  Our experience in Thailand in testing people with Version 1, we found a fair number of negatives that went up 3 or 4 logs with the 1.5.  So, they had high levels of virus, it was just the wrong primer.
DR. HOLLINGER:  David, you had a question?
DR. STRONCEK:  A question for Jay.  The topic of this was criteria for discontinuation of the antigen test.  I assume when companies do comparison to show the NAT test is equivalent or better than antigen testing, they are going to have to test all samples, they can't exclude some that were positive for HCV or something like that.
The other issue is the first NAT test that shows it can detect, you know, in a rigorous study with a licensed test, that shows it can detect everything and additional viruses that p24 can't, will that open up the category for all assays or all NAT testing tests approved have to show that.
So, I guess what I am asking for is, if we get to a time where p24 testing is eliminated, does that go in all cases or is it going to be only for one licensed NAT test at a time?
DR. EPSTEIN:  I don't know the answer.  I just think that we have to validate each test system.  Now, if we have a validated test system and any such system should be able to detect all p24 positives, but if we have a single, say, first validated system, we will then have a choice.
We will have a choice whether to go ahead and label it such that if you screen with that system, you do not need additionally to do p24, or we will have the choice to wait until we think that there are enough such systems to satisfy the entire blood collection industry and then recommend it uniformly, assuming that only validated systems would be used for that purpose.
We would probably bring that very question back to the Advisory Committee, because there will be a choice available there.  But my own thinking is that probably the decisionmaking would be driven by the individual test systems and their validation.  We are not going to deny the use of validated systems as they become available.
But again, we don't have to make that decision today.  Let's see the data first.  We will be back with that question, I am sure.
DR. HOLLINGER:  Not seeing any other responses from the committee, we will take 20 minutes for a break, and we will start at 3:30, the appointed time.
[Recess.]
DR. HOLLINGER:  This session is on validation of donor history questions.  It is an important issue.  Any of you who have recently gone to donate blood and found all the questions that are being asked of you, and sometimes how they are different from different centers, I think this is an important topic.
We are going to start out.  Captain Mary Gustafson is going to introduce the topic, and then we will move forward with the other presenters.  We have two presentations and one person who has asked to speak in the open public hearing.
III.  VALIDATION OF DONOR HISTORY QUESTIONS
Introduction
CPT GUSTAFSON:  Thank you.  Actually since we were running so far behind, I apologize to the committee because I am not going to go in the order of the slides that I gave you, but I am going to abbreviate my presentation, so that we can spend the time listening to our invited guests and the interested public, as well as leaving time for some committee discussion.
I will skip the background that is in your presentation on exactly what donor history questioning is and where it fits within the overlapping layers of safety that protect the blood supply.
But to cut to the chase, why are we bringing this topic before you today?  There is a couple of reasons.  You were provided a copy of the American Association of Blood Bank's Uniform Donor History Questionnaire in your mailing.
This form is approved by us as suitable for use by blood establishments, but we do not mandate its use or any other standardized form, and as Dr. Hollinger said, there are variations.  We have standards, we have regulations, we have recommendations that people need to abide by in making up their donor history questionnaire, but we do allow a great deal of variability.
Another reason for bringing this topic to you is that a fairly recent oversight report faulted us, the agency, for not requiring the Uniform Donor History Questionnaire.
This was one of the deficiencies noted by the General Accounting Office in its February 1997 Report to the Ranking Minority Member of the Committee on Commerce in the House of Representatives, entitled "Blood Supply, FDA Oversight and Remaining Issues of Safety."
Although this observation was not included in the list of the GAO recommendations to the Secretary of the Health and Human Services, it is an issue that has been discussed before and merits further discussion.
The other reason for presenting this topic is that we know that not all information obtained from donors at the time of donation is accurate.  The 1997 JAMA article that was in your mailing discusses data from the REDS survey, which will likely be discussed more by Dr. Williams in his presentation, but it showed that nearly 2 percent of donors provided inaccurate information at donation.
[Slide.]
We in the FDA also know from our own error and accident reporting system that donors fail to give accurate information at donation, but may make information available  at a later date.  These reports are called Post‑Donation Reports.
In 1998, 61 percent of all error and accident reports received in the Center for Biologics were Post‑Donation Reports.  Slightly less than 80 percent of these involved information picked up at subsequent donation that was not revealed in an earlier donation.
About 15 percent are donor callbacks and the rest are third‑party reports.  Again, nearly 80 percent, it's 78.4 percent of the reports are concerning information that was known to the donor or should have been known to the donor at the time of the earlier donation, and include such things as having had a tattoo or ear or body piercing within a year of donation.
These are types of data that indicate that there is room for improvement in the donor screening process.  One of the problems is that we often find that these types of reports are not fully investigated.  There is always oops factor or, if I could embarrass Andy Conrad if he is still around, there is the idea that the donors lie, and it is just one of those things that we really can't do much about.
So, the follow up is usually incomplete whereby they could look at their processes, is it particular questions that donors are missing or is it particular screeners, is it the day of the week, certain donor demographics, fixed site versus mobile sites, maybe an issue of privacy, or even other issues within the donor behavior that we, as regulators, and also I think in blood bank, you know, are just not comfortable with.
Let's face it, we are far more interested in discussing the types of things that we discussed earlier today, where there is real, real scientific data rather than donor behavior, and we are really excited that we got Dr. Jane Piliavin back today to sit with the BPAC, because she is a behavioral scientist and can help much in the discussion of these areas.
[Slide.]
As background, I am going to briefly discuss donor studies that were sponsored by FDA in the past.  In the late 1980s and early 1990s, FDA sponsored two donor studies with the purposes of intercepting the at‑risk donors and increasing and improving donor screening effectiveness.
Both of these studies were performed under contract by the American Institute for Research.
[Slide.]
The first study was entitled "Intercepting Potential Donors as Risk for AIDS or Other Infections," which was completed in 1990.  The purpose of this study was to get at‑risk donors to not donate or prevent their donations from being used by using the confidential unit exclusion and to study methods to communicate more effectively with donors.
[Slide.]
The study involved testing five types of screening material to improve the effectiveness of screening donors for risk behaviors at different points in the process.
These materials included AIDS information brochures designed specifically for men or women, utilizing line drawings of risk behaviors and simple tests, and AIDS information video incorporating motivational material in the form of testimonials from persons who have correctly decided not to donate, behavior questions asked orally and answered with paper and pencil about a donor's participation in specific risk behaviors, comprehension questions asked and answered orally that ask donors if they understand that they should not donate blood if they have engaged in specific risk behaviors, and a revised Confidential Unit Exclusion form containing pictures to emphasize the ramifications of the choice the donor makes.
[Slide.]
In the study, the interventions were compared to one another and to existing materials in terms of the numbers of at‑risk persons who did or did not donate for transfusion, the amount of attention paid to materials, the scores on a comprehension test, and the self‑reports by the subjects of attitudes toward the various behaviors.
To summarize, investigators found that people responded well to the pictures, and they were able to score higher on the comprehension test after exposure to the brochures.
[Slide.]
However, increased comprehension related to the materials did not affect their behavior in terms of making the correct decision to donate or not.
Likewise, it was demonstrated that even if people stated orally that they understood that they should not donate if they engaged in risk behaviors, this did not affect whether or not they decided to give blood.
The only intervention that seemed to make a difference in screening out at‑risk donors was the very direct behavior questions.
Another observation from the study is that people don't read information provided, and even when the donor claims to have read the material, observation of the donor during the process did not support the donor's self‑reporting of having read the material.
The results of this study were the basis for FDA's December 5th, 1990 recommendation to blood establishments that donor screening include the list of direct questions to be asked of the donor orally if possible.
These recommendations were later combined in a comprehensive April 23rd, 1992 revised recommendations for the prevention of human immunodeficiency virus transmission by blood and blood product.  This was the first time that FDA had provided the exact wording for questions to be asked during the interview process, and the first time that questions were actually field‑tested prior to general use for comprehension and effect on donor deferral.
[Slide.]
In the early 1990s, the American Institute for Research performed another study under contract with FDA, this study, optimistically entitled "Increasing the Safety of the Blood Supply by Screening Donors More Effectively."
The study was completed in 1993, and was the subject of BPAC discussions in 1993 and 1994.  The goal of the study was to improve donor screening by developing new processes that would hopefully increase the validity of the donor interview process, provide for the different needs of the first‑time donor versus the repeat donor as one complaint from donors since adding length to the donor questionnaire with the addition of the direct, high‑risk questions has been the amount of time required to donate blood, an increased knowledge of both the donor and the health historian via educational materials and training.
[Slide.]
The material studied during the contract included a computer‑assisted donor interview, an abbreviated donor history for repeat donors, prototype donor information cards for per‑ and post‑donations, and a curriculum for health history training.
The study was conducted at blood centers and a plasma center, and included over 7,000 donors.  At the end of the study, the results did not support the title of the study, that is, there was no demonstration that use of any of the materials could increase the safety of the blood supply by screening methods.
[Slide.]
However, the study did demonstrate the feasibility of using a computer‑assisted donor interview and provided materials that could be used by blood centers in developing their own procedures for a computer‑assisted donor interview, abbreviated donor history for repeat donors, donor educational materials, and a curriculum for training health history technicians.
In retrospect, neither study fully met FDA's expectations.  Particularly with the second study, there were problems in study design, randomization, definition of endpoints and statistical methods.  However, the greatest obstacle in performing donor studies is that the risk of infectivity in the blood donor population is extremely low.
I am sure one would like to see a study that links the effectiveness of donor screening to recipient outcome, that is, infections in recipients or even a less dragged out deferral of donors who have positive markers, however, the blood donor population currently is a very healthy, low‑risk population.
You can tell from the numbers of samples tested this morning in the NAT testing, we were talking about hundreds of thousands to a million donors to get that type of data, and behavioral data is even more difficult to come by.
Therefore, to design a study to test the effect of any screening method based on outcome measures requires a prohibitively large number of donors.  But like I said before, we know that there is room for improvement nevertheless.  We know from REDS data that nearly 2 percent of donors interviewed provided incorrect information at the time of donation, and we know from our own error and accident reporting that information obtained during the donor interview is not always complete and accurate.
Even so, as Dr. Hollinger pointed out earlier also, we keep adding to the donor interview process without removing anything.  Since the early 1990s when the amount of information presented to the donor and the length of the donation process were concerned, we have added additional questions to the form.
Among the questions added are questions about recent incarceration, questions about risk of CJD, and geographical questions to tease out risk of HIV‑1 group O infection.
Today's topic‑‑it is late in the day‑‑and this is an introductory discussion for the committee.  We are not going to ask the committee to provide a formal recommendation or vote on anything today.  However, as you listen to Dr. Williams' and Dr. Bianco's presentations, and as you prepare for committee discussion, I will show you a few questions that you might keep in mind.
[Slide.]
The first I mention with great trepidation.  Should FDA support a study or studies to validate the donor history questions?  Of course, the short answer would be yes.  This is akin to asking you if you support motherhood, apple pie, and white picket fences, and eternal youth.
However, as I mentioned earlier, blood donors are currently a very healthy population.  With the redundant layers of safety provided by blood centers today, the expectation that we can perform a study that truly links donor screening effectiveness with outcome measures in the recipient is probably not realistic.
So, with this in mind, given that efficacy studies based on final outcome, which would be infection in recipients, are impractical, what suggestions do the committee members have for appropriate areas of study?
Would the committee view a stratification of questions based on risk outcomes a useful exercise?  Are there ways to tease out questions that may no longer be useful, on one hand, and questions that are so critical that we need to study these questions linked to outcome in recipients?
Finally, does the committee view a mandated national donor questionnaire desirable?  I will share with you that in looking at the transcript from the BPAC in March of 1994, when the second AIR study was discussed, and there were materials for computer‑assisted donor interview and pre‑ and post‑donation information, one of the fears of both the committee members and of industry in public session was that FDA would actually mandate the use of these materials, and they felt that this would inhibit innovation in the field.
So, it will be interesting to see if things have changed in the past five years.
With that, I will turn this over to our invited speakers.  Thank you.
DR. HOLLINGER:  Thank you.
The first presentation will be by Alan Williams representing the American Association of Blood Banks.
American Association of Blood Banks
DR. WILLIAMS:  Thank you, Blaine.
[Slide.]
As Mary outlined, the topic is a challenging one.  Validation of a process is going to have many elements, and this is a particularly difficult one to look at.  Lack of outcome measures is only one of the difficulties.
I hope as I go through the talk, I will be able to point out some other inherent problems of definition of the process which I think need to be resolved before one can really talk about validation, if that in fact is possible.
What I want to do is pitch my talk from a behavioral and research standpoint, and I think you will see some parallels between my presentation and Dr. Bianco's.  His is going to cover more the blood center perspective.
[Slide.]
As we move increasingly toward considering blood collection as a manufacturing process, I think it is worth reminding ourselves that blood donors aren't raw materials.  They are thinking, feeling, motivated individuals who don't always do what we anticipate they might do, and there are many aspects of our discipline which very much could be considered as having a large behavioral science component.
These include donor recruitment and retention, certainly a major issue for blood banking, pre‑donation education, donor qualification, which we are talking about today, confidential unit exclusion, test result notification, also a major issue, the whole issue of informed consent, and this has to do with donation, transfusion to recipients, and the research process, and again another major issue, risk education, public, patients, media, elected officials, and one could give examples from the HIV and HCV experiences, but I won't take time to go into that.
The reason I am going into this is the major take‑home points that I want to leave is that with all this behavioral science interaction, there really are very few behavioral scientists involved in the blood banking discipline.
There have been consultants along the way, individuals who have had blood banking association, but no one working full time in our field, and I think that is probably resulting in some of the difficulties that we have right now.
[Slide.]
So, to move into donor qualification, why is accurate donor qualification important?  Some of these are certainly very self‑evident.  To maximize blood safety is the big one, both for known agents which have a laboratory screen, it serves as another layer of protection, as you all know.
Probably looking toward the future, one of the major reasons to optimize our screening process by donor questioning is to face unknown threats in the future which have no laboratory screen.
CJD took us a few years ago by surprise as being an unconventional agent, and hopefully, there may be a test in the next few years.
From an operational perspective, certainly you want to minimize donor loss due to inappropriate deferrals.  You want to minimize negative operational impact.  Mary showed some of the statistics for contribution of the questionnaire process to post‑donation information and market withdrawals and recalls, an important issue for center operations.
One that often gets passed over is to minimize staff exposure to infectious donations.  Although you can certainly test out donations, you don't necessarily want hepatitis infectious and HIV infectious materials collected in the first place and handled by staff members.
[Slide.]
There have been a lot of discussions about some of these areas.  I put some of the major ones down because I am going to base some of my comments on some of the proceedings that have taken place.
There has been a major study of HIV seropositive donors sponsored by the CDC.  That started in 1988 and still is occurring, and has produced a lot of epidemiologic data about HIV seropositive blood donors.
As you know, REDS has conducted donor survey research since 1990, getting at risk factors and other characteristics of the blood supply donors.
National Heart, Lung, and Blood Institute has sponsored two major activities.  There was a behavioral workshop in November of '97, which got together behavioral scientists and blood banking experts and regulators, and we all discussed some of these issues, and some of the points I am going to bring up today came out of that workshop.
FDA has held several BPAC sessions, as well as a donor suitability workshop at the end of last year, discussing some of the issues.
AABB, as the national blood banking organization, has ongoing review of the donor screening activities through its scientific and administrative coordinating committees, its Standards and TTD and other committees, and its professional staff and board.
In addition, they recently added a national blood data resource center, which collects information from blood centers, which is relevant to this subject and could be an important data collection element in the future as we go into some of these activities.
[Slide.]
What are some of the successes of behavioral screening?  I think it is fair to say donor screening has contributed to unprecedented safety in the blood supply in combination with other factors.
It has contributed to documented reduction over time of markers in accepted first‑time blood donors, and I think in some data that will be presented by Dr. Bianco, you can see that the prevalence of donor risk and infection is much lower than the general population, and this is documented.
[Slide.]
What are some of the deficiencies?  Interviews with seropositive donors reveal behavioral risks that should have prevented donation.  There have been a lot of case control studies done on seropositive donors.  They are relatively easy to conduct and through the years a lot have been done.
Two that I will mention specifically are both the NIH and the REDS study of HCV‑infected donors.  Both came to the same major conclusion that injecting drug use, a major, if not the major risk factor of HCV infection.
[Slide.]
Also, the CDC HIV positive donor interview study has produced data similarly showing that individuals who are interviewed and found to have risk factors should not have been accepted as blood donors, and something happened during that process where the appropriate information didn't come to light and result in that donor's either self‑deferral or staff‑based deferral.
These are risk factors from recent data from the CDC interview study.  Males found to be HIV seropositive, 38 percent on subsequent interview reported having a sexual contact with other male risk.  This is down proportionately from approximately 60 to 65 percent when these studies were first taking place in the late '80s.
These individuals should not have been accepted as blood donors, that is a clear deferral criteria.
A small proportion, similar to HCV‑infected donors, report injecting drug use.  Again, these individuals should not have been accepted as blood donors, the point being that there is some leakage of individuals at risk through the screening process, and that gives us a target to address.
[Slide.]
Another interesting bit of information about HIV seropositive donors, and I give credit to Ken Clark who put these data and these slides together.  Although the overall number of positives enrolled in the study, 1990 versus 1997, is much lower, 129 in 1990 and 29 in 1997, those who report male contact with other males in the previous year is higher, 90 percent of those with the risk factor had recent activity, and I think that is an important consideration.
[Slide.]
From the REDS study, we have been conducting surveys.  The first major study was in 1993, ran a smaller pilot in 1995, and again a major survey last year.  The data from the '98 survey have not yet been extensively analyzed, but we have some preliminary analysis, and I will show them in a comparative basis with the 1993 study.
[Slide.]
In 1998, we studied 104,000 sampled donors at eight different sites, seven monthly waves, April through October, and one of the main reasons we ran the study was to update the 1993 survey data, which was the JAMA publication, and see how the deferrable risk variable identified in that survey held in 1998 time period compared to other donation variables get at some aspects why donors didn't reveal risk and importantly, we wanted to, in a major way, look at donation incentives and see if we could bring some answers to the question as to whether incentives do or do not increase risk in a blood donor population, and also got additional information on HIV test‑seeking.
[Slide.]
Prevalence of reported behavioral risks, the overall cumulative prevalence of risk that should have resulted in deferral, as Mary mentioned, was 1.9 percent in 1993.  It is about the same value, actually closer to 2 percent in 1998, but because there are a few additional centers and we have a few more questions involved, I think it is going to take further analysis to see if there is any change over time, so we can address that.
You can see here in 1993 data, the final data, half percent of individuals accepted as donors in responding to the survey admitted drug use ever in their lifetime, and that is a deferral criteria.
A little lower in the preliminary data for 1998, but I think we need to look at the final data and complete that analysis.
The bottom line here is some of the risk factors observed in '93 are still there in the 1998 data.  I think as we look at the data over time, we will be able to determine if there are any trends present.
One that we are watching in particular is the apparent possible higher trend in donors who have sexual contact with other males.
[Slide.]
Donors report insufficient privacy at screening.  Privacy is one thing that can potentially compromise the donor history.  All donors in the '98 survey, 4 percent reported that they had some concerns about the privacy at the time of the screening at the blood center.
These vary according to donors who report different risk factors, and the highest are those who had sexual contact either with another male since '77 or sex with CSWs, commercial sex worker or a prostitute, 12.8 percent reported that they had concerns about privacy.
So, you see some association is going on there between risk and some of the operational processes that we have.
[Slide.]
Similar data in terms of donors who reported that they donated either ever or in the past year to receive the results of an HIV test.  The data for 1993, we had I believe 6.2 percent who reported ever donating blood to receive an HIV test, and 3.5 percent in the past year.
This number appears to be reduced somewhat in 1998.  We will have to see if that holds as the data are finalized.  One thing to keep in mind is that some of the home HIV tests became available, so this potentially could have contributed to a drop in this figure.
But again you see variation, again some of the risk factors that were also reported in the survey, and you can see again the same three groups here that reported sexual contact and might have been worried about something at the time of donation report significantly higher rates of HIV test‑seeking.
[Slide.]
What are some of the deficiencies as well from the donor perspective?  I think it is pretty clear that donors tend to make their own judgments about their personal risk.  Some of it might be an inherent tendency, denial that you don't really mean me, and I feel fine, and this person really couldn't have had any problems that I was with.  So, it might be an inherent tendency to make your own judgment.
In addition, I think another thing of potentially a factor is that the scientific basis of screening questions either may not be understood by the individual being screened or they might tend to make their own judgments about risk if they feel that the scientific basis of screening is not accurate because it is politically motivated or discriminatory in some way.
I think in some elements of the donor population, this might be coming into play that individuals feel that there is no scientific basis for certain questions and they don't take them seriously.  We don't have direct data for that, but I think some of the indirect data points in that direction.
[Slide.]
What are some of the other elements from the donor side?  Donors seek to gain or preserve something of value by proceeding with donation.  Here, we get into the test‑seeking issue, blood centers are a free, confidential, reliable source of HIV testing.
Certainly, donors get a healthy feeling and an altruistic feeling from the donation itself.  It is something that we use to encourage donation, and certainly there is some motivation attached to it for all donors, even those who have risk.
There is an element of saving face in a peer environment, particularly in a work site type collection where your supervisor is rounding up donors.  That factor is also well known.
I put other possibilities here because there are some areas that are charged with controversy and emotion, but very little data.  Here, I would classify elements like incentives, donation for therapeutic phlebotomy, directed donation, some of those areas where what is the donor perspective, what is the value of the donation, and does it supersede their perspective of making risk known at the time of donor screening.
These are areas that need further data collection.  As I mentioned, the REDS study is really concentrated on incentive use and for the HHS Safety and Availability meeting in April, we are trying to put together a major analysis of the 1998 to address the issue.
[Slide.]
From a donor perspective, our questionnaires are complex and lengthy.  There are undoubtedly some educational barriers for some of the wording that is used.  There are cultural differences.  As Donna Mayo mentioned in her publication to the AIR study, people don't read, they don't like to read, and for repeat donors there is a certain redundancy when they come to the blood center multiple times and have to go through this long questionnaire and oral history each time.
[Slide.]
Also, screening deficiencies here looking from the blood center's perspective.  To measure the parameters of performance of anything, you have to compare it to a gold standard whether you are looking at predictive accuracy, sensitivity, specificity, you need a gold standard for comparison, and I think some of the gold standards for some of the screening questions are a little ambiguous.
Are we looking for the true existence of a defined risk factor or are we looking for the ability to transmit a seronegative infection to a recipient?  The first one is reasonably easy to validate, the second one is almost impossible to validate, but what is the gold standard that we are looking at?
Just as an example, I used history of syphilis as one indication, and I think you can recognize the possibilities for different interpretations, why that question might be asked.
In a sense, we are relying on surrogate value of questions.  Just the surrogate value of testing got a bad name with respect to non‑A, non‑B hepatitis.  I think we are doing a little bit of that in terms of questioning of donors.  It complicates scientific credibility and also may be viewed as political or discriminatory.
One example of this might be the consideration of deferring males who have had sexual contact with other males since 1977.  I am not aware of any window period for HIV infection that exceeds or even comes close to one year.  Why the deferral should go back to '77, there has been a lot of discussion about it, but it is not based on the window period of HIV, because scientific data argues against that.
[Slide.]
From a behavioral perspective, I just wanted to mention that this is a major problem in the field of AIDS‑related research.  Getting information about personal risk is inherently difficult.  Response rates tend to be low.  Missing data happens frequently.  Even if you get someone to complete a questionnaire, often there is about 20 percent missing data, and internal inconsistencies are frequent.
[Slide.]
I wanted to say something about the AIR study, but Mary covered it quite well.  I think particularly the first AIR contract, there is some valuable information there, and as I say later, I hope some of that, that was not published, can be made available, because I think that first contract was pretty well done.  There was a lot of meat in the data that emerged from that.
Out of the NHLBI discussion, there were some discussions of current research going on.  Charles Turner was at that meeting and described the use of what is known as Audio‑CASI.  CASI stands for computer‑assisted self‑interview.  This is increasingly being used for risk behavior data collection in HIV‑related studies that has the advantage of being fully private, does not require literacy.  It can be standardized, so there is no interviewer variability.  It can be done in any language.  It can have visual aids, and the respondent, in essence, is in control rather than having an interviewer who is controlling the situation.
This work was published just about a year ago in Science.  Those of you who are interested, I think it is really good to see the detailed write‑up of how that works somewhat better in collecting risk‑related information.
[Slide.]
Also at the meeting was Dr. Catalina from UCSF, the Center for AIDS Prevention Studies, who went into some of the more behavioral aspects of designing questions and proposed that pre‑identifying some of the threats that a question might have to an interviewee and trying to preempt those in way you introduce the question can have a big impact in terms of relaxing the individual and getting them to give you an answer or the correct answer.
He also brought forward the idea of using enhanced questions which give a little background before asking the basic question that you want to have answered, and showed some data, I am not sure if it is published yet, that in an HIV risk situation, not with blood donors, but with other subjects, that they get more reliable and better information completion by doing this.
One of the areas that we can validate key questions is through the structure, content, and comprehension of current blood donor screening questions.
[Slide.]
Again, getting back to the recall and market withdrawal importance of questions, within Red Cross there has been an effort in our department to do some of this with a key set of questions.  This has been spearheaded by Sharyn Orton, who is in the audience here.  Victoria Virvos is a facilitator for the focus groups that we used.
[Slide.]
The idea was to use focus group discussions with individuals in this case who have never donated blood to evaluate the structure, content and comprehension of seven selected questions.  These weren't AIDS risk related questions, but they were seven questions which made the major contribution to Red Cross recalls and market withdrawals, and had PDI information concerns.
[Slide.]
What are the goals?  The introduction to this session was participants were asked what is the question asking, are all of the terms and the way the question is written clear, if not, would they ask for more information, if more information needs to be given, where and how should it be provided, and what interviewer techniques would make them most comfortable with the interview process.
[Slide.]
There are five focus groups that have been held so far, various demographic groups.  This was done both using a facilitator who was good at getting people to speak up and address the questions at hand, as well as the Red Cross volunteer who kind of explained the background of the process and provided scientific input.
The participants were familiarized with the donation environment and the materials.  The questions they were to answer were available on a flip chart, and background and facilitation was provided, as I mentioned.
[Slide.]
The results, interestingly, recommendations were really pretty consistent between the groups, and we got useful comments and recommendations, and I think on a path toward restructuring some of these questions which hopefully can then be validated again prior to making a permanent change, but I think the main conclusion here is these types of focus groups are doable.  They are relatively inexpensive, and I think it is worth considering doing some of this work before implementing new questions.
[Slide.]
So, some general recommendations that I will end with, the first one is consider establishing programs to attract more behavioral science professionals into the transfusion medicine arena.  It is important.
Second, establish mechanisms to evaluate the understanding and impact of new questions prior to implementation.  It is difficult to do if you are not prepared.  One way to prepare would be to have a set of rapid response blood centers where you could get this done, because they have training and some funding to be a rapid response network.
REDS has served this role in the lab side, and not necessarily the same centers, but I think a small network of centers could easily do some of the questionnaire work.
[Slide.]
One comment made to me earlier today was what should we do with the screening process.  We should basically take the whole thing apart and put it back together again.
That is not exactly what I wrote here, but it's a thought.  I think perhaps as we move toward NAT testing, it is an opportunity to look hard at the questions that we are asking, consider streamlining, and asking what we really want to ask in a way that we really need to do it.
[Slide.]
I think there might be some consideration of asking IOM of another independent sponsorship of a consensus conference for two major issues:  establish an agreed rationale for current and future questions including cost considerations, which FDA by law doesn't consider.
The second thing is we need mechanisms through which new screening procedures can be evaluated within a regulated blood collection operation, a very difficult issue, and Mary went into that in some detail.
[Slide.]
Fourth, investigate the feasibility of a standardized, validated national screening questionnaire.  I think there are issues where some local options are appropriate, but I think there should be an approval process, so that a handful of regions which decide to ask a question that they feel might be important doesn't snowball the country into asking this at all blood centers.  I think that is an unfortunate circumstance if that happens.
Fifth, fund research to define specificity and predictive accuracy of key screening questions, a very difficult challenge, but I think it is doable.
[Slide.]
Finally back to the AIR study, there was a publication in Transfusion in '91, about the major results from the first AIR contract.  There is also some additional information like interviewer training materials and some details about their short‑track screening for regular donors.
I would hope that if it is not currently available, public or the field, that FDA would consider making this available in some form, because I think there is some really good information there.
I will stop here.  Thank you.
DR. HOLLINGER:  Thank you.
The final presentation, Dr. Bianco, from the New York Blood Center.
New York Blood Center
DR. BIANCO:  I think that Alan Williams gave a very nice presentation of several high‑level issues related to validation or to donor history questions.  What I am going to try to do is to take a somewhat more practical view of medical history.
[Slide.]
Looking at it, in the past, in the early days of blood transfusion, medical history was it.  We had no basis for selecting donors except through medical history.  We shouldn't forget that only in the late sixties, early seventies, that we came, except for syphilis that was introduced in the forties, that we came with the came with the first test that really started addressing the major problems of blood transfusion, that was hepatitis B.
There were no screening assays except for blood typing, and the history of infectious diseases focused on hepatitis.
In the 1950's, in New York City, in a study that was published by the New York Academy of Medicine, 25 percent of the people that received multiple blood transfusions had clinical evidence of hepatitis.
[Slide.]
This left us with a heritage that I think affects very much our thinking today.  It is the extreme desire that we have, and because of that need to rely on medical history, and the success of the change from paid donors to volunteer donors created unrealistic expectations in terms of medical history, and it perpetuated a number of assumptions that are not based on data.
Those assumptions obviously are all questions are understood by all donors, all donors are truthful in their answers, and the more questions we ask, the better.
[Slide.]
Medical history today is one of several layers of safety, and is a major focus.  It has its major focus, one, as Dr. Williams presented very well in diseases for which there are no screening assays; two, in known limitations of the screening assays, windows, HIV‑O, CJD.
Together with all the pre‑donation procedures it improves blood safety, but there are ways by which we can measure the efficacy.
[Slide.]
If we compare the population prevalence before and after medical history, at least from data that are published from the Public Health system, and from data that we have from our own organizations, there is a substantial contribution to education and medical history, and the knowledge, and all the things that are done to the safety of the donors when we look at this prevalence.
We do not have specific studies that will really compare what the prevalence is in the population of donors that show at our door, and we will talk a little bit more about that.
[Slide.]
We defer donors based on medical history, and we defer donors on questions and activities that have very different meaning for the different donors.  It may be questions that require interpretation.  It may be questions about risk behavior in which the donor is very uncomfortable with the questions, but one thing that I am very sure is that the interviewer, the historian is as uncomfortable as the donor or more uncomfortable as the donor asking those questions.
I see when I go to donate blood the discomfort of the technician that is collecting the blood and asking myself, the boss, these types of questions.
[Slide.]
Now, donors, despite all that, reveal risk behavior in medical history.  If we take a summary of some of our medical history, donors will tell us that they had sex with another man, that they had taken drugs, and the ratios are on the right side of the column that I call Prevalence, so about 1 in 1,100 donors or 1,200 donors told us that they have used drugs in the past, and 1 in the CSW, people that have given money for sex, 1 in 35,000 donors.
[Slide.]
I put in the charts that you have one set of deferral reasons and numbers.  I used this in a presentation that I made at the Donor Suitability Workshop, and I was very concerned with this 23 percent of all deferrals, of all donors that presented being deferred.
I did a lot of work in our computers, and that other table was not really real, because included all the test deferrals and all the other reasons for which people in the past would have been in our computer as deferred donors.
So, a more accurate figure taken for the year of 1998 is that among the study group, among 480,000 donors, 62,000 were deferred, about 13 percent of them; 25,000 by something very objective like hemoglobin or blood pressure, but 15,000 by the general questions regarding medication, 15,000 about questions on infectious diseases.
[Slide.]
Other things that donors used to do, but they changed their behavior, was the Confidential Unit Exclusion.  Here, we are telling a donor the risk may affect the person that is receiving a unit of blood from you, and if you did any of those things that are listed here, if you did not say that you do it, but you have done it, use this label, and we will not transfuse your blood.
But the effectiveness of the process has diminished substantially.  Today, very rarely in the last four or five years, we will find an individual that used the self‑exclusion and that is positive on an HIV test.
[Slide.]
It is true that the total numbers got diminished substantially, but this is due probably, and that is a graphic form of the same thing, this is due probably to the changes of characteristics of the donors as revealed in the HIV positive donor studies in which in the early days were mostly males who had sex with males, sophisticated, understanding the crisis of HIV and AIDS, and today, many, about half of them, women, and that really do not understand, about half of them cannot identify clearly what is the risk that led them to become positive for HIV.
[Slide.]
So, CUE was effective in the eighties.  Today, only a small proportion of donors use it, very few are positive, and probably is associated with the changes in the donor population.
[Slide.]
But even like that, about 0.4 percent of our donors still select CUE, and many of them for the wrong reasons, and who will note it is for the wrong reasons when they do it in the process of giving a directed donation for their child or for a relative, and they will use that label, and then later they will scream why can't you release that unit of blood, it was for my child, and that they did not understand the process.
[Slide.]
However, there were things that came from the AIR study that were very important, and these encouraged at that time with the memo on April 23, '92, encouraged us to introduce direct questions about behavior to our donors.
We were very scared.  We have volunteers here.  We were afraid that we were going to violate their privacies, we were offending them, but until the process happened, and a substantial number, as we compared between '90 and '91, when we did not ask those questions, and when we started asking direct questions to the donors, that HIV risk questions increased substantially, while other types of deferrals did not increase.
[Slide.]
More recently, we had a similar experience in small numbers to affect the total donations with a donor base of about 400 in 1,000 donations, but we saw a 12‑fold increase in the number of people that were deferred the moment that we asked, not only injection drugs, but snorting cocaine.
[Slide.]
So, donors reveal risk behavior.  Donors who are deferred, but we should say that donors who are referred up front do not donate.  We do not have a sample, we do not test those donors.
Consequently, we do not know what is the specificity, the sensitivity, the positive predictive value of those questions.  We do not know if anybody that we deferred because of a history of hepatitis has actually had hepatitis ever.  Certainly, I would like to encourage, together with Dr. Williams, that these studies should be carried out.
They are very, very important because of the number of people that are affected, because of the consequences of donor deferral both for the system, for the recipient, we do not have the unit of blood available, and for the donor who is extremely upset.  He tried or she tried to do something good, and they were told that because of something like a history of hepatitis or something else, they cannot do something good.
[Slide.]
What else do we know?  That many donors, yes, review risk, but donors who review risk behavior do not present risk to the system.  They are deferred, so they are not going to donate.
The people that do not change as we add questions, as we change deferral periods, are people who denied risk behaviors even when they have risk behavior.  We have to realize that whatever changes we make only affect people that are truthful in their answers, and we know that 1.9 percent of the donors from the studies that Dr. Williams mentioned will for some reason, and I don't think that it is a question of lying, but for some reason not be able to come up with the right answer at the right time.
[Slide.]
However, we continue to add complexity to the system.  There are too many questions involving too many events in the life of the donor.
The complexity of the questions interferes with the accuracy of the answers.
The perception of discrimination, the one‑year deferral versus lifetime deferral that Dr. Williams mentioned, and the fact that we have no effective means of validation of those changes.
[Slide.]
When we talk validation, that scares me working in a blood center.  If I go through the process validation documents from 1987, it says that we have to establish documented evidence with a high degree of assurance.
[Slide.]
We can make medical history more effective.  We cannot treat it as a device.  We can maintain the know effectiveness of medical history by repeating the REDS surveys at regular intervals, by measuring the prevalence of markers among donors who are not deferred, and we can measure sensitivity and specificity of medical history questions by carrying out studies of deferred donors that include testing for determination of marker prevalence.
[Slide.]
In my opinion there are many questions in medical history for which my answer is no.  One of them is I don't think that all layers of safety carry the same weight, and we cannot treat them in exactly the same way.
Medical history is not device.  I don't think that all questions should be identical.  I think that uniformity, you lose that sensitivity that we have, that we have despite being a very homogeneous country and having the same holder in New York and in San Francisco, people are different, and people respond differently, and I think that locally, we have much more contact with the population, must more sensitivity to the ways they understand the questions.
[Slide.]
I think that medical history will have to be placed in the context of the technologies that we have, particularly now implementation of NAT, the weight of medical history will decrease for the tests for which we are using NAT.
Computer‑based interviews were very well discussed by Dr. Williams.
[Slide.]
Just to end with a few points.  I don't think that we can validate medical history because it is not a device, but we can apply validation principles, for instance, for the computer system that we use for medical history.
We think that we should change the character of medical history, particularly at NAT implementation, and I think that we could eliminate questions that are better covered by screening technologies, and we could focus on diseases and risks for which we have no screening test.  I think we would be much more effective in selecting our donor base.
Thank you.
DR. HOLLINGER:  Thank you, Celso.
This concludes the formal presentations.  We have one person who has asked to speak in the open public hearing.  I think that is Paul Cumming.
Open Public Hearing
DR. CUMMING:  My name is Paul Cumming.  I work with Dr. Thomas Zook and the staff of the Hocksworth Blood Center under a grant from the National Institutes of Health, and also with Dr. Edward Wallace out of the Center for Management Systems.  I am here to report, give the first results from implementation of the Hocksworth's Quality Donor System, which is an automated multimedia donor interviewing system.
You heard all of the potential advantages and the reasons why the screening may be important, so I won't bore you with those.  In terms of those of you who were at the Donor Suitability Conference, you got pretty much of a full introduction to the system in terms of what it was by Dr. Zook.
Basically, the thing that makes it different than the other systems including Turner's study with audio‑CASI is it adds color and photographs.  The reason for the photographs is as much as the old adage "A picture is worth a thousand words," and so we can emphasize particular parts of the questions.
It provides the same confidentiality or the audio confidentiality by putting sound through the earphones.  We have a lot of different validation criteria for the system, but the primary one that we are interested in at the moment or had the most discrepancy among or discussion among the staff was the issue of donor acceptability, truthfulness, things we can get from a survey.
The results we just got in, I just got the material this Tuesday from the first stuff.  We implemented February 22nd, and we are implementing at the Hocksworth Blood Center, and we are doing it slowly to make sure we know what we are doing, and so that we don't do any harm and just good.
[Slide.]
The questionnaire, I will cover this briefly since I have got three minutes, and you can come back and ask questions.  The questionnaire we are using, this is an exit questionnaire, and it attempts to get at whether or not the user of the system sees the presentation as clear, how satisfied they were with the time it took for the interview, were they comfortable with the privacy and the degree to which they were comfortable, do they believe the computer or the nurse interview will generate more honest answers from donors, and some information on their familiarity with computers.
That was given to everyone that used the system, that part of it, and I will give you the results on that in a moment.  The other part was only completed by repeat donors which were most of the group that we looked at.
As Dr. Zook noted in his presentation at the Donor Suitability Conference, a big difference here is that we are comparing the same donor interview with the automated people as with the manual system.  It is an identical questionnaire.  Basically, the output of the system is that it prints the donor questionnaire and looks very much the same as the one that is used with the manual system.
The ones that were asked of all donors is whether or not they prefer the video or they prefer the personal nurse interview, whether it was more understandable or less understandable with the Donor Quality System, the automated system, and what their likelihood of return was, the object being to make sure that we get a maximum number of return donors and don't scare them away.
[Slide.]
This was a summary provided by Hocksworth staff Tuesday of the questions.  I took it this morning and reduced it to some bar charts that I think make it easier to see.  In terms of the demographics of the group, they are not, at least from my perspective, atypical of a group in the Midwest of donors.  They seem to be in some parts slightly older than what I recall, but that just may be the Hocksworth Blood Center.
The respondents were almost all whole blood donors as that is where we decided to start, a few platelet donors.
[Slide.]
We also collected comments on the bottom of the form, as you saw, 17 of that 28, by the way, got complaining about the length of the interview.  The interview is roughly a 10 to 12‑minute interview by the computer, mandatory audio for any first‑time donor and for most questions for second‑time donors.
That compares to an interview of three to five with the original system that was approved by FDA for marketing in December of '97 and at your last meeting they commented that we were finally‑‑or they were approving a system which was the Hocksworth system.
[Slide.]
Again, this is a small sample, very preliminary, but to the best of my knowledge, no one else has ever had any data like this which is so comparable of putting an automated process into an existing system.
Across the top, the only program I could find rapidly this morning that would give me some graphics, and hope to get the patterns out of it.  You can see as to whether or not the Hocksworth Quality Donor System was clear, very clear to unclear.
Generally speaking, something like 87 percent of the donors saw it as very clear, an issue there being that‑‑assuming that the questions the donor asked are right‑‑then, is it clear to the donor, do they understand what the question is, and we were asking that.
In general, for the slides you will see‑‑and this group is different than the next set‑‑the 1 and the 2 answers are favorable to the Hocksworth system, and the 4 and the 5 are unfavorable or, in some cases, in comparison to the nurse system, they refer to that.  Three is a neutral response in general.
If you look at the time‑‑and I couldn't find anything that would hold these scales the same, so I am going from 100 percent scale to a 60 percent scale‑‑if you look at the time and their satisfaction with it, you will see that the most dissatisfaction, only 40 percent of the donors were satisfied with the time, but it was not as bad as I thought it would be.  I thought it would be much worse for that long of an interview.  Dr. Zook, on the other hand, didn't think it would bother them.  It turns out he was correct.
On privacy, the results are what I expected, you know, how comfortable were they, very comfortable, again 87 percent of the donors gave it a very comfortable ranking.
As to whether or not they would be more truthful with a nurse or a computer, the weight there clearly is into to the 1 and 2 category as opposed to into the 4 and 5 category, which is the nurse.  Most of the donors said the bulk of them‑‑I have forgotten what the number is‑‑that they would be most truthful with the computer than they would with a nurse.
[Slide.]
These are the comparative responses, the second part, the repeat donors only.  Again, the percentages are at the top.  I reversed the axes, I was having trouble finding something that would show things up.  Now, you have got the numbers on the bottom and the size of the percentage along the side.  But the convention holds.
The 1's and the 2's are favorable to the system, and the 5 to something else, the alternative or a manual system, a nurse, and the 1 in this case they prefer the automated system, the 5 they prefer the nurse system, 3 being neutral.  You can see there that much against the common wisdom of the blood industry, the automated system is at least as preferred or more preferred than the nurse system by these donors, with the larger single number of percentages, something like 32, 33, being ambivalent as to which way it is done, which was somewhat of a surprise, as well.
Looking to what they saw as most understandable, another one of these clarity issues, you have to understand the question before you can answer it, most of them again were indifferent.  Basically, the 3 there, they said that they didn't see it as either clear or less clear or understandable rather, but you can see, of the people who added opinion, the bulk of them saw the computer as providing a more understandable presentation with only, I think it was 2 percent or something like that, that saw the nurses as providing a better understanding of what the questions were about.
As to whether or not they would return, the last slide on the bottom there, you can see that the bulk of them were indifferent essentially, however to the extent they had an opinion, they thought that the computer system would have a favorable impact on their return.
What we concluded from that basically was that, in general, repeat donors favor or were neutral toward the automated system as compared with the prior personnel system.
DR. HOLLINGER:  Thank you
Is there anyone else for the public hearing before we turn it over to the committee, anybody else who wants to make a comment?
[No response.]
DR. HOLLINGER:  If not, then, we will close the public session and move into the committee discussions.  I will open it up to any comments from the committee.
Yes, Dr. Boyle.
Committee Discussion
DR. BOYLE:  I am just going to make an observation.  I do surveys for a living, and looking at the current state of your screening questionnaire, I think before you mandate anything, people ought to do a lot more research on that questionnaire, a lot more thought about what it is supposed to be accomplishing.
I mean one of the issues is are you just trying to scare people away or are you trying to get honest answers.  If you are trying to get honest answers, then, there is at least three issues you have to deal with.
Number one is attention.  If you put 50, 60, 80 questions, you lose people's attention, so you have to decide what you are going to focus on.  Also, the way you format it is going to be of great interest.
Next to the issue of attention, you have got to get to understanding, and some of the work that was being done by the Red Cross was trying to get at what people heard and understood from those questions to decide whether those are good or bad questions, but you have doing this for 20‑some or more years, and it is certainly time to do more than five focus groups.  You need a lot of cognitive testing to get at that type of stuff.
The final issue is the honesty, and I don't know how to tell you to get to honesty.  In my personal experience, some people lie on surveys, but an awful lot of people prefer to misunderstand the question, and what you want to do is define the question in such a way that they can understand and answer it, and I think it is striking the fact that if you ask very direct behavioral questions, you get better answers than if you try to fudge around it.
So, my only comment to maybe open this thing is before you move forward to decide there needs to be a standard form or what is in that standard form, you need to spend a lot more time because you have defined this screening as one of the main pieces of the safety net, of the multi‑tiered safety net, so I would suggest you use the same level of science on that, that you have done on some of the other levels.
DR. HOLLINGER:  Thank you, John.
Jane, would you, since this is why you are here, would you comment about all of this, please, from a behavioral standpoint, or any other comment that you might have?
DR. PILIAVIN:  First, I have to agree with Dr. Boyle that there is a science to asking questions.  One of the presenters earlier was making a distinction between behavioral science‑‑and they didn't say it this way‑‑real science.
It is I think in some ways more complex to try to do behavioral science, but certainly doing some very systematic things about the question, and having focus groups is a good start, trying to find out what people actually think the question is asking.  You can get some really surprising answers when you actually are honest enough and gutsy enough to ask people what they really think you are doing.
A lot of you are familiar with my perspective on the whole donor recruitment process including the screening, and I find it very difficult to separate out this piece of what we do with donors from the whole process that starts with whatever kinds of education people get in general about the health system and then the recruitment process which ends up bringing a certain set of people into the actual donation place.
It is obvious from the statistics that are shown of the prevalence of viral markers in donor populations and the prevalence in the total population that however we are doing it, we are doing an excellent job of getting a very, very, very safe group of people.
But I think that before you start, well, maybe at the same time you are worrying about the questions per se, you need to be worrying about how the people get to the donation session.
If you look the REDS data, there are a number of clues in there, one of which is coercion, another of which is incentives.  As a recall the REDS study, reasonable numbers of people who were not truthful at the time of being questioned say that they were either pressured in the recruitment setting or were given what strikes some of us as incentives that are kind of an offer you can't refuse sort of thing, and I think we have to seriously consider those issues along with the issues of what are we asking them, because if you induce someone to come into a situation on a basis that is probably inappropriate, you can hardly then be surprised if they are less than truthful with you because they are there for a reason that is somewhat different from the reason that you want them to be there.  So, there is that issue.
One of the things that struck me in one of the previous presentations, the one about the post‑donation reports just struck me with something that I had never actually thought about before.  It was well over half of the actual problem reports were donors who call in and say, oh, you know, I just remembered I got a tattoo or whatever.
Do people ever give donors the whole set of questions that they are going to be asked at the time they are being recruited, because what I was sitting her wondering, not as a social scientist, but as a person who used to give blood, what did the donor do when the donor went home, did the donor say, you know, they asked me this question‑‑to their husband or their wife or went back to work and said something to a colleague‑‑they asked me a question about whether I had had my ears pierced, why do you suppose they wanted to know that.
Maybe in discussing things with the people in this personal setting, they have come to the realization of why this might be important and they then call the donation center.  I think it would be really instructive to find out what the social process is by which donors come to that post‑donation report.
So, there is a couple of things that I think you need to think about, is how much do donors really know about what they are going to be asked when they get into the setting, and is there some way you can short‑circuit those people and have them not show up, so that you don't have to worry about then are they lying in the setting, do they then feel somewhat constrained because everybody is looking at them, and they feel like they can follow through.
I also noticed from the reading I did that you sent me in this FDA oversight and remaining issues of safety, the '97 report of the donor survey, that there are specific demographic groups who tend to show up over and over as the ones who are not answering truthfully or are not understanding or are being unwilling to talk to whoever it is that is interviewing them.
Those, I offer as three alternative interpretations of why the answer that you get in the survey is different from the answer they gave in the donation setting.
I am wondering if that is a clue that there is something different in the donation setting as a social situation as far as the members of these groups are concerned.  It was specifically African‑American men as I recall who are the ones that tend to show up in that statistic.
It was mentioned that there are some political aspects possibly.  I think that was referring to men who have sex with men as a group that feels like they are being discriminated against, but it may also be the case that African‑American men in this setting, as in most settings, feel that they are being discriminated against in some way.
It, of course, is also a group that tends to have on the average less education, so those things may be working together.  I am thinking here very much as a social psychologist who thinks about the interaction setting itself.
Now, this is where the questions are being asked, but it isn't specifically the questions themselves.  Dr. Bianco said he notices his technicians being uncomfortable when they are talking to the boss.  Well, of course, they are uncomfortable talking to the boss.  I mean that is a status reversal here, it is usually the high status person that is asking questions of the low status person, and so even if you weren't their boss, if you were known to be them as an M.D. in some other setting, they would be uncomfortable.
But we also have a great deal of discomfort in this society in interactions in which the status varies, different statuses of people in a conversational setting are different, blacks talking with whites, men talking with women, older people talking with younger people, and I am just wondering if anyone has ever thought about looking at‑‑here, I am reminded, a number of years ago I proposed that a conversational analyst be employed by people to do some research.  I have a person in mind actually.
A conversational analyst is a person who really sits down and very, very closely analyzes what goes on when people talk to each other from the level of pauses in speech and sideways glances through to everything else that goes on in that situation.
I suspect, for example, that when your technician is asking you questions, she usually does not look you in the eye.  Is that true?
DR. BIANCO:  Yes.
DR. PILIAVIN:  Okay.  I suspect that when white interviewers, white female interviewers are talking to black male potential donors, they do not look them in the eye either, because there is a kind of discomfort that we have in this culture in interracial interactions.
You can get an awful lot of nonverbal cues from someone when you actually look at them in the face that you don't get by keeping your head buried in your form and writing things down.
This, of course, is probably a major issue for untruthfulness in general or the inability of the person who is doing the interview to pick up discomfort that might indicate potential untruthfulness.  As long as we are doing things face to face and not doing it with computer‑assisted devices, we are going to have to think about the fact that this is a social situation.
It is a situation in which two people who don't know each other are having an extremely intimate interaction, and that is bound to extremely uncomfortable, and people tend to do it as quickly as possible to get out of there as fast as they can. This is why it is probably good that the computer takes longer.
So, all of these things argue for a close evaluation of what is actually going on in the situation.  I think it is probably more important than the actual wording of the questions although, as I said, I think that is something that needs looking at.
So, if we are going to stay with these kinds of interactions that are nurse on potential donor, we need, first of all, to study what goes on there.  Once we know a little better what goes on there, although I think if you just think about it a little bit, you have a pretty good idea right now what goes on there, a little bit of sensitivity training to how you do this in a way that is best designed to pick up people's discomforts rather than try to avoid them, because the discomforts are teaching you something, again, nondiscriminatory ways of dealing with people who are different from you, that that is really critical.
Another thing I picked up from one of the presentations before is the privacy issue.  I have never yet been in a blood donation center‑‑and I have given blood in lots of different places in various countries in the world‑‑ and never found one yet that I thought was sufficiently private except in Poland, and that was a long time ago.
In Poland, they actually have a doctor sit and talk to you in a private room.  I don't know why Poland did that, but it is really my only experience, and particularly on mobile drives where I believe 80 percent of the blood used to come from‑‑maybe still does‑‑cramped quarters, not even partitions most places, in high schools, kids sitting cheek by jowl with other kids, and you have all of these kinds of issues just confounded in mobile drives.
I guess that was kind of a stream of consciousness, and it is at this point all I have to say, but I will sit and listen to the rest of it.  I will probably think of something else.
DR. HOLLINGER:  Thank you, Jane.
Other comments?  Yes, Dr. Fitzpatrick.
DR. FITZPATRICK:  We have used standardized donor forms in DoD since Vietnam, and it is not essentially the questions in our setting that creates the errors.  It is the skill of the interviewer and the person asking the question or the skill of the person asking the donor to explain the yes answer to the question that was supposed to get a no answer, and I think that is a big part of the equation that is left out here.
I have observed people in a fair number of donor centers in the military over the past 24 years, and the interviewer has a conflicting goal.  Their goal is to collect as much blood as possible, but also to maintain the safety of the blood supply by screening out the donors that should be screened out.
So, depending on the skill of the interviewer and the integrity and sometimes you might say integrity or purpose of the screener, if you get a quick answer from the donor that meets your need in getting them to donate blood, you may not pursue that answer further, and I think in a number of the cases where I have reviewed accident reports, and a donor has been accepted that should have been deferred, some additional questioning by the screener would have deferred the donor.
They just didn't understand completely why that question was important or why they should provide more information or why the time frame was important, why is it important that your tattoo was within the past year, you know, they got a tattoo, they can't remember exactly when, that sort of thing.
So, I think as we move forward, those are the two parts of the equation.  One is simplifying the questions, and I agree with everything that was just said, we need to know what the donors think about the question when they read it and what they think we are actually asking, and the other is to look at our screeners and our interviewers, so that their purpose in life is the correct one and they are asking the right questions to find out why the donor answered it that way.
DR. HOLLINGER:  Thank you.  Yes, Dr. Nelson.
DR. NELSON:  I can't remember all the data from the REDS and the other study when they have looked at donors who had markers that might have been screened out, but it would be interesting to see in what setting they gave blood.
Alan, is that part of it in terms of a blood drive at a church with large numbers of other people or individual donors?  My wife has the job of recruiting donors for the church, and I have heard her talk to people over the phone, and she doesn't read the questions that they are going to be asked, I will tell you.  She tries to get‑‑and I am not sure how she thinks about whether or not they might have had a risk or not‑‑but I can see where different donors, the process of recruiting even before you get to the blood bank, that they may be very different.
I wonder, have you looked at that, is that part of the equation?
DR. WILLIAMS:  The data are available in the questionnaire in terms of both the site the blood was collected and what motivated the donor to come to the blood bank in the first place, but we haven't look at it in that context.  It is something that could be done.
DR. HOLLINGER:  Yes, Dr. Mitchell.
DR. MITCHELL:  In the REDS study, it did show that a lot of people who did not defer themselves that should have were black and latino men, and I have done recruiting and actually blood drives targeted at black and latino men.
I think that one of the reasons is sort of that people aren't as truthful is because of the social pressures, you know, we talked about the job location.  Another, I think is that people need to understand why you are asking those questions, and it is not clear, but I think that also the cultural sensitivity, as has been said before, about the interviewer plays a big part in that.
There are a lot of questions, for example, about people from African countries, and so on.  My experience is that people don't mind if they understand why you are asking those questions and if you know sort of in advance that there is an issue, that people don't feel badly, but if you are there at a site, and, you know, people want to give once they have made that commitment to come, people want to give.
At times we talked about having a donor pool, a low‑risk donor pool, and sort of developing a low‑risk donor pool, and I think that that would be the best way to go, and do it in such a way that you might say that these people are preferred donors, but not to exclude others who don't fit a certain profile.
I also had a technical question.  One is about the snorting of cocaine and the risk factors associated with that, and what is an ISU.
DR. HOLLINGER:  Well, question about cocaine I think was primarily put in because of some studies that suggested that there may be an association with transmission based on the fact that the nasal membranes are quite avascular and on using either a tube or a dollar bill, or whatever is used for snorting the cocaine, goes and usually passes into a person's nose, and then is passed on to the next person.  There is often blood around that tube.
In fact, there are some interesting aspects of that alone.  Often, women are at the bottom of the chain when that is done, and so they are much more likely to be at risk because it usually goes from the males, if there is a group of people doing this, often passes from the males who maybe will snort the cocaine, passed to the next person, and then finally to the women at the end of the chain, so there are some even enhanced risks with that group, so there is a little subtlety, but that was really why that question was asked.
DR. MITCHELL:  Is that a theoretical?
DR. HOLLINGER:  No, the data that Dr. Catalina in the NIH blood center, published in The New England Journal of Medicine a couple of years ago I guess it was, maybe three years now, looked at that and suggested that there were some data.
Now, there have been some other studies that have not supported that, and so that is an important issue is whether it really is or not, but when you think about it epidemiologically, I think it makes some real sense, and you talk to the patients who do it, I think it would make some sense.
DR. PILIAVIN:  He asked another question, which is what is ISU, and I was wondering that, too.
DR. WILLIAMS:  I am not sure exactly what materials the committee was sent, but we may be responsible for that.  In the 1998 donor survey, we separated out injecting drug use in terms of other illegal use from injecting steroid use, and we now commonly refer to steroid injection as ISU.
DR. HOLLINGER:  We thought it was Iowa State University, but we weren't sure about that.  That is why you got no answers to it.
Corey.
MR. DUBIN:  I think from our perspective we have always conceptualized the donor pool, at least our experience since we came to the table is that the donor pool in this country has never really been tapped to its greatest degree, so every time we seem to get in trouble, we seem to either want to relax the regulations or figure out why we can't get more out of the people we are getting it out of already.
In our own discussions internally, we like keep banging our head against the wall because we wonder if we are just naive, more naive than we understand, or if people just don't seem to get it or what drives the equation.
We have said this here many times, and we are going to keep saying it, I think, because I think there is something to be said.  The administration and the Congress I think can be used to our advantage, the majority leader, speaker, President, in ways that President Carter attacked energy in the 1970s, when he went to the nation.
I thought it was interesting when we had that weather‑related shortage of blood in the Northeast.  On the cover of USA Today, I believe it was the next day or a couple of days later showed all these farmers in Iowa with their arms out, rolling their sleeves up.
There was a message there, at least we saw a message there, but that message only got communicated to those farmers in Iowa in a critical situation, and it seems to me we need to start reconceptualizing what the donor pool is in this country, because I don't think we have begun to tap what is really out there.
Every time we hear in this committee, and the ones that have been around a long time have seen this, you know, sometimes you hear out of us this is deja vu, every time we hear we have got a back‑up on standards or we are going to change something because we have got a problem, to us it is the same old problem, why do we keep going back to (a) risky populations, or (b) the same people we are taking it from now.
How much analysis can we do on drawing blood out of people we have already drawn blood, when there is all kinds of people in this country we are not touching?  I don't think that is necessarily, I am not saying it is FDA's responsibility, because clearly it is not, but clearly, the government in a broader construction of that, i.e., the administration and the Congress, could be brought to bear, and I think the cover of USA Today was a very good example of that.
The second part we would raise, which is FDA, is we do think MSM is a problem, and we think it is a problem for two reasons.  One, obviously, it is discriminatory, and from our perspective, either equally as important or more, it is not getting the job done because it is too narrow, because it is about a population, and it is not specifically listing the risk behaviors that are associated with the transmission of AIDS or any other pathogen, so people are getting through that shouldn't if the policy was targeted on risk behavior, and we have been making that point for some time, as well.
DR. HOLLINGER:  Dr. Bianco.
DR. BIANCO:  Corey, I agree with the two things that you have said, but I have a challenge for you.  The best experience that we have in recruitment is when we can link a donor with a recipient, when we have a picture of a baby or we have a mother that said my life was saved because I received blood that was given to me by the community is when things happen.
Your community could help tremendously our ability to recruit donors.
MR. DUBIN:  I think it is very interesting.  For four years I have been sitting in this chair talking, and nobody has approached us until right now.  Nobody has approached us and said‑‑we have even told people we would be glad to help, and again it is the same point, what is in this equation that we are missing, because there is clearly something we don't understand, because we are prepared to do that obviously.
There is no real effort in doing that for us.  We do benefit intensely from the nation's blood supply, but what is missing, and I don't have any answer.  Clearly, on one level, Celso, we would be glad to help, we have offered many times, but I really think that donating blood has to be put back in the equation as a part of good citizenship, and we ought to do some good thinking about how to convince families rather than convince individual donors to keep coming back, how do we convince families that X amount of time here, the family ought to go down to the local blood bank.
Are there social engineering techniques we can use there?  I don't know, but we certainly feel like we just keep focus on the same crew, and sometimes that is a risky crew, and we get real nervous when that happens.
DR. HOLLINGER:  Jane, I would like to ask a question.  Dr. Fitzpatrick and Dr. Mitchell brought up some very important questions also, ideas about that the explanations of why things are not done or not given.
I mean I could perceive of groups of donors, potential donors first coming in with an informed individual explaining to them all the questions, why they are being asked, what they mean, and so on, might probably give you a pretty good donor population if that were done.
But how do you go about doing something like that, is it possible, is it just daydreaming or what, can you comment?  Then, any other comments you have, please.
DR. PILIAVIN:  Well, one of the things that some donor centers do a little, but I never understood why more donor centers don't do it more, is using committed regular donors to do some of their recruitment, and it certainly would be relatively easy to program such people who have answered these questions multi, multi‑times themselves and understand why they are being asked, to be those kinds of educators and ambassadors to new donors, and they would be free, just like they are free when they come and give blood, they would be free to do this.
I even think that people like me, who gave many gallons of blood and then can't anymore for health reasons, would be an idea population for this because we are feeling bad that we can't do it anymore, we were hooked on this activity, and so there is that.
I also think that we are in a climate now, at least I perceive it this way being on a college campus, where college students are starting to get excited about the idea of volunteering and doing things for the community.  It has gotten to be kind of the thing to do, I mean let's not be cynical about it, I hope it is really something that these kids will keep doing.
But giving blood is volunteering, and I don't think this general ethos about volunteering has included blood donation as one of those things they have talked about.  They are always talking about going down to the local food pantry or soup kitchen or helping with the homeless, reading to children, tutoring children, all of these things that are one on one person kinds of things, because I think they think that is what appeals to these kids, but I think there could be something involved in orientations on college campuses.
Also, and I wrote this in my book nine years ago or whenever that book came out, we really need to think about including discussions of blood donations and uses of blood in health curriculums as young as grade school with children.  I mean we are teaching children things about health all along the line including sex education, and so on.
I don't see any reason why units couldn't be put together that have blood donation as part of a general discussion of community health, but that, of course, is a very long‑range project and would involve huge organizational and governmental cooperation, which I just find unlikely in this day and age.
DR. HOLLINGER:  Marion.
DR. KOERPER:  Something you said sort of struck a bell with me in terms of getting to want to come and donate without the sense of coercion, or, you know, everybody else at work is doing it, so I had better go do it, too, or they will think that I am doing something I shouldn't do.
When we are trying to recruit patients for various studies that we have ongoing, we actually send out a letter and a copy of the consent form, and say if you are interested, call us back, so that it is not like they are sitting in the room with the doctor, and I say, gee, would you like to participate, and they feel like how can I say no to my child's doctor.
I don't know how you would come up with a list of potential donors although, for instance, my son's high school does have a donor day at high school, and my son's college does, so one might have a list of students or what have you, but rather than that initial contact being another person, the church member, for instance, for whom it is hard to say no, to send out a letter of explanation and a copy of all those questions, because you said people may not really understand the questions, but if they could read them in advance, so send a letter explaining the reasons for donating, but who shouldn't donate, and the questionnaire or the questions with why these questions are important, and then inviting people, if they would like to donate, to call to make an appointment, have a number for them to call.
DR. PILIAVIN:  Of course, the reason that coercion is used is because it works, but I think young people are where the idealism is, and we keep seeing all these danger signals about the baby boom generation who have been the blood donors are aging, and we are going to need to replace them.  Well, the boomer babies are here, that is the young people now.  These are the boomer's babies.
So, we have got the echo boom is what the demographers call it.  it is not quite as big as the first boom, but it is pretty big.  It seems to be to me the time to do this kind of intensive education at the high school and college level partly because if you establish a habit at that age, it is likely to stick.
We all know that is the problem with cigarettes, right?  I mean you start it young, that is when you have got trouble.  I happen to be hopeful that positive habits can work the same way.
I am afraid I really have to go.  I have got a plane at 7 o'clock out of National, and there is a van that leaves at 5:30 that will take me to the Metro, and then I will get there.
DR. HOLLINGER:  Thank you for your comments, appreciate your coming.
DR. PILIAVIN:  Thank you.
DR. HOLLINGER:  Corey?
MR. DUBIN:  I think we have to reinfuse, kind of get away from the cynicism that won't work, look, folks, we got the Speaker of the House, Newt Gingrich, to back us in legislation that we passed the Congress unanimously.  We were able to do that.
Everybody said you have got to be kidding, that is not possible.  I think those things can be done, and in some of our discussions with some of the Republican leadership who we were working with on the legislation, we raised this issue, you know, because we were there, we had time with them ‑ John McCain, Porter Goss, some very influential Republicans, Democrats, as well.
We got a positive response from them.  Some of them told us they had never been approached.  We again felt like are we missing something, is something going on that we don't know about.  I mean I wonder if the blood bank in Illinois where Hastert is from, the new speaker, has ever approached him or if Porter in Chicago has ever been approached or Barbara Boxer or, you know, Lois Capps in California, who I guarantee would do it because I know Lois.
I mean I think there is ways that we have got to kind of reinvigorate this thing, because the negative side is, like I said before and I am going to say it again, we get very nervous when you all start looking at the risky people, because we have been down this path once already, and we are still in some ways partly the canaries of the blood supply, but as we move into recombinant, you have got the immune deficient people who are hanging out there and the alpha‑1 people, and they are the ones even at more risk now than we are, and we don't want to see a repeat performance.
If we are talking to a Senator McCain or Senator Leahy, and we raise this issue, they say, sure, but we have never been approached, what does that mean, what is missing?
DR. HOLLINGER:  I take it, Corey, you would feel that with the new tests coming down the line, the NAT technology and other things, it doesn't sound like you would be willing to have many of these questions removed from the system that are currently being asked.
Is that correct or incorrect?  Do you think that there is a possibility that these questions can be removed as not being very helpful with the new technology that is there, it is really picking up additional risks?
MR. DUBIN:  You have to separate derivative.  You know, in terms of our area, I mean certainly as recombinant technology becomes more and more on line, but for people who are still using human plasma derivative products, I think the GAO summed it up, the viral inactivation technologies work, the tests work, but there is serious GMP problems out there, and there are serious problems in the operation of the system.
We ratchet up the system nice and tight, absolutely, we are a lot safer than we have been, and the technology is there, but you have got to have a system where people are meeting GMP and the tests and the technologies being applied are being done and applied correctly with the kind of in‑service training that is needed for it to work.
DR. HOLLINGER:  Mark.
DR. MITCHELL:  I have a couple of things.  One is that I still think that it is important not to have a national standardized format because I think that there are so many variables locally, I mean from language to culture and understanding of the questions.  I think that there should be national guidelines, but not a requirement for that.
Another question I have I guess is about CJD, if it is going to be taken out, if it is no longer going to be a deferral, then, why ask questions about it.
DR. HOLLINGER:  There are some reasons.  Go ahead, Jay.
DR. EPSTEIN:  We do still defer donors either for CJD or CJD risk including classic CJD risk.  It is just that we do not now routinely and automatically withdraw plasma derivatives, so we have limited the conditions under which there is a derivative withdrawal.  We do still screen the donors and retrieve components if they were donated when we get post‑donation information.
DR. HOLLINGER:  Gail.
DR. MACIK:  I just wanted to comment the same as far as what you are going to do with our questionnaire.  I do believe there has to be mandated questions to be asked, but then leave it to the regions to decide how they ask the question.  So, you want to make sure that all the same things are asked, that you put it in the right language, in the right culture, and in that case, if somebody walks in, you offer them do you want to speak with someone, do you want to watch a video, do you want to use a computer screen, so that they feel comfortable with whatever media they pick, because a grandmother who has never seen a computer doesn't like to sit in front of a computer and try to figure out what button to push.  She is going to be more likely wanting to talk to a real person.
So, I think it comes down to, yes, mandating what has to be asked, but not how you ask it, and then have individual areas think of who they are serving, are you primarily urban, are you primarily rural, are you from the country of Texas.  You know, there is various things that you have to think about when you put these together.
Then, also, to get into how do you recruit people.  There has to be a civic duty that comes up and getting people to come forward, but I think better effort at educating before they show up, putting out quick little snippets even on television, you know, if they get repeatedly in front of them like, you know, if you have a tattoo, it might do this, so you want to be careful when you donate your blood or just things that you wouldn't otherwise think about, ear piercing, you know, and things like this that you wouldn't necessarily think about, but you made all the effort to get over to the blood bank after being cajoled by your neighbor or church group, and then you are going to be thrown out because you had your ears pierced and you can't remember if it was nine months ago or it was six months ago or whatever.
You know, there needs to be just kind of some thinking about this, and I would go a little bit with Corey, really trying to get a defined donating group probably makes more sense than really relying on the blast of civic duty going out and trying to get donors that come together as a group.
DR. HOLLINGER:  Dr. Fitzpatrick.
DR. FITZPATRICK:  Even though we use a standard form in DoD, I wouldn't advocate a national standard form.  I agree with Corey and Dr. Bianco that different communities need different things, and our form is designed differently from, say, from the Red Cross form, because our population is different, and we try to make the questions understood.  I am not sure we do so well with that, but we try.
Then, for the need, you know, in times of national emergency or national disaster, the population responds very well, and we have never had a problem with a blood shortage during a period of a national disaster or emergency, but we do need to target increasing the number and the supply, and so maybe if we reduce the number of questions or eliminate questions, we may affect the fact that we have a very safe population.
We showed by the statistics that our donor population is different from the general population.  If we eliminate the questions, we may invite many of those people back because as time goes on, it won't be so well known that you shouldn't donate if you have done those things or had your ears pierced or tattoo or whatever, and now we become a screener by testing, and we increase the expense of the product by doing that instead of screening out those donors before we take all the effort to draw the blood, test them, and put it on the shelf.
DR. HOLLINGER:  Just a question for one of the blood banking people here.  Are the questions in most blood banks shorter for repeat donors or are they exactly the same?
DR. BIANCO:  Exactly the same.
DR. HOLLINGER:  Exactly the same.  Okay.
DR. BIANCO:  And 80 percent of the donors in the majority of the centers in the country are repeat donors, so, Corey, there is a core donor population.  The problem that we have is that it is not enough, and that population is aging.
DR. HOLLINGER:  John.
DR. BOYLE:  I have learned a lot since I began by just criticizing the questionnaire.  All I would like to say is that once again, I don't know what the purpose of the screening is or the questionnaire is.  You could have a lot of different purposes.
But if I went to a federal agency and described a survey that I was going to do, that was going to be on sensitive topics, however, we were going to do the interviewing in person, under conditions that were less than private, that we were going to let different regions‑‑we will give them the same list of topics, but they can ask the questions differently, we are not going to train the interviewers or we are going to let them be trained locally, and we are not going to deal with the issues of how they interact with people of different social caliber or various things, and yet I was going to come back and say I had some kind of standardized result or at least I had some sense of what I was bringing back and that it was relatively uniform, I certainly wouldn't get that contract.
So, the only question that I would pose is when we think of the things that we want to do that we may be limited, and once again I don't know how limited we are in terms of the privacy, but clearly if you ask sensitive questions under non‑private conditions, the likelihood that you are going to get really valid responses from those people who are doing the things that are less usual is questionable.
Similarly, with all the nicks of we want to do it our own way, you know, probably what needs to be thought through is what is the purpose of the screening phase and then how best can it be done, but right now I can just describe it as extraordinary.
DR. HOLLINGER:  Yes, Jeanne.
DR. LINDEN:  I just wanted to bring up the issue of repeat donors.  I know Dr. McCurdy has in previous meetings talked about the fact if we could just get the donors that we have to come back more often‑‑I agree it is an aging group and we do need to expand the donor base, but if we could get people to donate twice a year instead of once, then, we would have a lot better blood supply, and it is people who have been prescreened.
I would think that if we could do something about the questionnaire process that recognizes that they are former donors and looks at changes from the previous, and not every single "ever" question all over again, and that just gives them some recognition, it's like, gee, you have been here before, and we are going to treat you in a special way, would be a little bit positive in giving them a more beneficial experience.
The other problem with that, though, is I know that a lot of people don't donate more frequently simply because it isn't convenient for them.  My O‑negative husband is the perfect example.  He will donate when it is convenient, otherwise, forget it.
Just as an example, the blood collection agency in our area does the recruitment from 300 miles away, and people have no clue of geography.  I talked to somebody the other night who tried to get us to go to a bloodmobile that was two counties away.
I think that the blood banks can do a better job with perhaps more local involvement for recruitment to make things convenient for people, and there is lots of different aspects to this, but we need to make it a more positive experience for people, and then we can maybe retain them to come back a second time.
I think the questionnaire is part of that, but there are other aspects, as well.
DR. HOLLINGER:  Captain Gustafson.
CPT GUSTAFSON:  I will correct something on the abbreviated donor history.  We have approved it for primarily serial plasma donations when the donor comes back as many times as twice a week, and they will be asked.  The high‑risk questions are all asked orally, but some of the other things as has your history changed or has anything happened since you were in last, have you seen a doctor, those types of questions that might tell the screener that they should delve a little bit deeper into it.
Also, for autologous donations when the donor is giving maybe for a surgery that is planned in a month or two, and they give repeated donations, and those are given.
I think there is one or two blood centers who have been approved for an abbreviated donor history form, otherwise, I don't know if they actually use it.  There is the issue with the allogeneic blood donor, that they only give once every eight weeks, so the span of time, then, between donations is greater, but we do have some donations now that are approved for the abbreviated history form.
DR. HOLLINGER:  Dr. McCurdy.
DR. McCURDY:  It seems to me that what we are hearing about it that there are a lot of different things and a lot of different opinions about how blood donors should or are or are not recruited, and I suspect that what may be needed is a relatively innovative start‑from‑scratch look at the whole process to see where we are going.
I think that although only 20 percent or less of donors are first‑time donors, of those that are left, as Jeanne said, the vast majority of them donate once a year, and if you could get them to donate a second time, you might have an awful lot more blood or at least half of them to donate a second time.
We are drawing blood now pretty much the way we did 15, 20, 30, 40 years ago.  Most of it is on mobiles.  Mobile is relatively easy as far as the recruiting staff is concerned, it is relatively expensive as far as the collecting staff is concerned.
A few blood centers have moved toward fixed sites that are open periodically.  They may have staff that rotate from one fixed site to another, but I think there are a lot of things that could be looked at in relatively basic and innovative fashion, and I think that if somebody were to come up with a well‑planned, careful study, I think the NHLBI would be happy to discuss what might be done further to understand better what we are doing and how.
DR. HOLLINGER:  We are at 5:30.  Does anybody else have any particular burning questions?  Yes, Paul.
DR. McCURDY:  One other thing.  There was a rather extensive study done in the late seventies by Alvin Drake from MIT as to why donors who were donating stopped donating, and there were a number of reasons, but they all boil down to essentially what Corey said earlier today, nobody asked me.
DR. HOLLINGER:  Just to remind the committee and others who are going to come tomorrow, the session will start at 8:00 tomorrow.  It will be an update first on tick‑borne diseases workshop, then, there will be a session on IGIV, and then a session again, a reintroduction of inadvertent contamination of plasma pools for fractionation with the probability of completing this at 2:30 or 3 o'clock tomorrow afternoon.
We will see you all then at 8 o'clock in the morning.
[Whereupon, at 5:35 p.m., the proceedings were recessed, to resume at 8:00 a.m., Friday, March 26, 1999.]