ELWDEPARTMENT OF HEALTH AND HUMAN SERVICES

FOOD AND DRUG ADMINISTRATION

CENTER FOR BIOLOGICS EVALUATION AND RESEARCH

BLOOD PRODUCTS ADVISORY COMMITTEE

SIXTY‑FIFTH MEETING

OPEN SESSION ‑ VOLUME II

Friday, March 17, 2000

8:00 a.m.

Kennedy Ballroom
Holiday Inn Silver Spring
8777 Georgia Avenue
Silver Spring, Maryland

Voting Members

F. Blaine Hollinger, M.D., Chairman

Mary E. Chamberland, M.D.

G. Michael Fitzpatrick, Ph.D.

Marion A. Koerper, M.D.

Jeanne V. Linden, M.D.

B. Gail Macik, M.D.

Mark A. Mitchell, M.D.

Terry V. Rice

Paul J. Schmidt, M.D.

David F. Stroncek, M.D.

Temporary Voting Members

Paul R. McCurdy, M.D.

Carmelita U. Tuazon, M.D.

Jonathan S. Allan, D.V.M.

Non‑Voting Consumer Representative

Katherine E. Knowles

Non‑Voting Industry Representative

Toby L. Simon, M.D.

Guest of the Committee

Louisa E. Chapman, M.D.

Executive Secretary

Linda A. Smallwood, Ph.D.

C O N T E N T S

Page

Opening Remarks

     F. Blaine Hollinger, M.D., Chairman	5

Committee Updates

     Summary of January 2000 PHS Advisory Committee
     Meeting on Blood Safety and Availability
     Stephen Nightingale, M.D.	5

     CJD Policy
     Dorothy Scott, M.D.	16

     HCV Lookback Guidance
     Paul Mied, Ph.D.	20

     Post Donation Information Algorithm
     Edward Tabor, M.D.	38

     IGIV Clinical Endpoints
     Basil Golding, M.D.	50

Open Public Hearing

     Jason Bablack
     Plasma Protein Therapeutics Association	57

     Miriam O'Day
     Immune Deficiency Foundation	86

     Robert Sandhaus, M.D.
     Alpha One Foundation	88

     Al Smith, M.D.
     Calicivirus studies	91

     Patrick L. Iversen, Ph.D.
     AVI Biopharma	94

Open Committee Discussion

     Blood Action Plan:  Supply Issues
     Captain Mary Gustafson	98

C O N T E N T S

Open Committee Discussion

     Donor Deferral Issues Relating to
     Xenotransplantation

Introduction and Background
Andrew Dayton, M.D., Ph.D.	107

Open Public Hearing

     Louis Katz, M.D.
     American Association of Blood Banks
     America's Blood Centers	126

     Ariel Shapiro, M.D.
     Life Service Blood Services, Chicago, Ill.	131

     Linda Chambers, M.D.
     Senior Medical Officer, Red Cross	132

     Chris Healey
     Director of Government Affairs, ABRA	135

Open Committee Discussion

     Questions for the Committee, Committee
     Discussion and Recommendations	137

Report of Intramural Site Visit:  Laboratory
of Plasma Derivatives, Division of Hematology

     Introduction and Overview:

Neil Goldman, Ph.D.
Associate Director for Research, CBER	177

John Finlayson, Ph.D.
Associate Director for Science, OBRR	188

Mark Weinstein, Ph.D.
Director, Division of Hematology	191

     Summary of Laboratory of Plasma 	Derivatives
     Basil Golding, M.D.	195

Presentation by Dr. Alayash	198

Presentation by Dr. Scott	204

Adjournment	211

P R O C E E D I N G S
DR. SMALLWOOD:  Good morning, and welcome to the second day's deliberations of the 65th Meeting of the Blood Products Advisory Committee.  I am Linda Smallwood, the Executive Secretary.
On yesterday I read the meeting statement that pertains to both days' deliberations.  If there is anyone that needs to make any declarations regarding any discussion of the topics for today, please do so at this time.  This would also include any of the committee members.  We would ask that anyone speaking before the committee, if they would please identify themselves by giving their name and their affiliation, and please speak into the mike.
If there are no declarations at this time, then I will turn over the meeting proceedings to the chairperson, Dr. Blaine Hollinger.  Dr. Hollinger?
DR. HOLLINGER:  Yes, thank you, Dr. Smallwood.
We are going to start the session this morning on the committee updates, and the first one will be given by Dr. Stephen Nightingale on the summary of the January 2000 PHS Advisory Committee Meeting on Blood Safety and Availability.
DR. NIGHTINGALE:  Good morning.  I am Steve Nightingale, and the meeting that I wish to review was held on January 26th and 27th, and the subject of that meeting was Errors and Accidents in Blood Administration:  What Can Be Done to Reduce Their Occurrence?  The meeting was scheduled to begin at 8:00 o'clock on January 26th, but unfortunately there was a snowstorm.  This is Connecticut Avenue, looking south, about 10:00 a.m.
And we were faced with actually something that I think was of relevance to the committee, which is, what do you do if you are the executive secretary of a committee and the government is closed officially?  This is not in fact a trivial question.  There was a meeting of the Committee on Alternative Medicine at NIH that was actually held a couple of hours earlier, and there were congressional inquiries that resulted from the decision to continue to have the meeting.
We did persevere.  When we sought advice of counsel, this was all that we found, was "Each advisory committee meeting is to be held at a reasonable time and in a place reasonably accessible to the public."  Federal law is actually very explicit about when a meeting can be closed, but it is silent on when a meeting should be open.
So we made the decision to open, and I'm pleased to say that this was the attendance score:  17 out of 18 public members, whereas 4 out of 6 ex‑officio members.  By Fisher's exact test the P is .14, which is not significant.  However, if only one of the members had not been there and it had been three and three, the P would have been .03 and highly significant.  So I thank my ex‑officio members.
The quote of the day was by the Surgeon General, who said "It's amazing how much is getting done while the government is officially closed."  This was one of the things.
There is actually a substantive point, believe it or not, that I'm going to be making about these slides in a minute, but at the moment let me get to the meat of the meeting, to bring up what we did.
The first speaker was Dr. Kevin Shine, the president of the Institute of Medicine, who presented their report on errors and accidents in medicine.  It is in fact not the only initiative.  Ours and several others were developed in parallel, but his is certainly the one that has gotten the greatest amount of ink, and I guess electrons as well.
We did have a presentation by Bob Francis, who is the immediate past Vice Chairman of the National Transportation Safety Board.  We opened our discussion of the issue with Mr. Francis because there have been substantial advances in aviation safety in the last decade.  He provided a perspective on it.
Dr. Bosk, who has written the classic text called "Forgive and Remember:  Managing Medical Failure" gave a historical perspective on this.  And I am reviewing these quickly because the interested parties can find them at our web site, which is www.dhhs.gov\partner\bloodsafety.  I am hopeful that by close of business today our web site will have been substantially upgraded, and if it is not, I apologize for the delay.
Dr. Westrum provided a sociologic perspective, and Dr. Linden of the Blood Products Advisory Committee to my right here, very generously agreed to come and describe the experience of New York State's medical error reporting system.
We had the perspective of a clinic manager, of a transfusion service manager, Ms. Reardon, who is the director of the Carle Clinic in Urbana. Sharon, Ms. O'Callaghan, of Food and Drug, who is also in the room here, described FDA's current procedures and the regulations on which they are based.
And we concluded with a discussion by Dr. Battles and Dr. Kaplan of the Medical Event Reporting System for Transfusion Medicine that they have developed with the support of the National Heart, Lung and Blood Institute.  We also did just very briefly have presentations on the hep C update from Dr. Alter and the Blood Action Plan from Captain Gustafson, who will be presenting I believe shortly after I am.  And we had representatives of Hema‑Quebec, Canadian Blood Services, and Dr. Gerry Sandler at Georgetown spoke about patient identification services.
So I think the focus of what I wanted to present to you in the 15 minutes that I have was on where we are as an advisory committee with the issues of errors in management, and this is simply to note that we had relatively broad and generally, I think overall highly supportive comment from the public interest groups and from individuals of the public.  What I wanted to get to, then, was this, in this context.
I have summarized the recommendations.  They are, again, posted on the web.  In a nutshell, what we said, first of all, was "all"‑‑and the italics were the key words‑‑"all" blood establishments should have a quality assurance program that includes an effective, confidential, non‑punitive system for the management of errors and accidents not subject to regulatory review.
The substantive issues were, first, I have italicized "all" because, as you know, the Food and Drug Administration plans to issue a final rule that would require this.  The question was raised at the meeting, since it has been announced that this is coming, was this superfluous.  And the answer was, well, it probably was, but given the delays that can happen to a final rule on its final passage to the Federal Register, the committee supported the FDA in this.
Probably the most difficult word for the committee to come up with was "effective."  "Effective" was perhaps not a compromise, but the word that was chosen in lieu of "mandatory," and I have italicized it here because the committee really did not achieve final consensus on what should be mandatory.
Although "confidential" was not something that we spent a lot of time debating in the system, there were definitely concerns raised within the committee, particularly by the patients, those who have ties to the patient community, about protection of potentially discoverable facts.  And that is an unresolved issue, at least at the committee level, and I think well beyond the level of our committee.
And, finally, the language "not subject to regulatory review" was the language that was chosen after substantial discussion.  I think the issue here is, for those of us who are in the blood business, in the case of blood those actions that are not subject to regulatory review are, I don't want to say few and far between, but blood is I think a bellwether for some parts of the industry because the regulatory review is‑‑perhaps because of the subject and its history‑‑is quite broad.
These, then, are the issues that remained at the conclusion of the meeting, and that is‑‑I have rephrased them.  In the document that is being prepared for the Secretary's signature, the language will look something like this.  We have, I think, three very legitimate interests here, which is the right to be informed, and I have put the duty to inform.
I think both this committee and our own have heard from our British colleagues about the duty to inform in the British common law and jurisprudence.  The status of that duty to inform is less clear in American jurisprudence, and I hope to have some discussion of that at our next meeting.
Very clearly, the middle is the baseline, which is the need of the regulator for information necessary to perform its statutory responsibilities.  This is something that will not go away.  What we are hoping is that the aviation industry, where the FAA has a similar need for information, will be perhaps able to, if not give us guidance, give us a historical perspective.  And that is going to happen in the next meeting.
And, finally, the issue which I think is not quite yet well developed in the public mind outside of the aviation community is just exactly what are the benefits to society of protecting information so that it can be analyzed and the conclusions of that analysis acted on.  These are the three things that I think need further work.
One possible direction of the advisory committee's deliberation might take this particular form, although this is by no means settled.  I am not a lawyer but have been talking to them recently, which is where I picked up the word "hypotheticalS".  And things to consider:
An A positive patient receives an O positive unit of blood and nothing else happens.  Is this reportable?  Many people would say yes.  Many people would say it should be.  There are two sides to this question, and I hope the advisory committee will explore this.
The other, the contrary hypothetical, an A positive patient almost receives a unit of O positive blood.  Again, I think you can look at this from the perspective of the patient, you can look at from the perspective of the regulator, and you need to look at it from the perspective of society, and in fact one also needs to look at from the perspective of the provider because they are also stakeholders.
So the folks that we have lined up for the meeting on the 25th, Dr. Westrum, who spoke at the last meeting on his own research, will discuss in a little bit more detail the scientific basis of current error management strategies.  He will talk about the work of Dr. James Reason, "Managing Errors of Organizations," a 1997 book.  He will also give his own spin on it.
I am delighted that Ms. Linda Connell, who is the Executive Director of the NASA/Ames, the Aviation Safety Reporting System, and Captain Scott Griffith, who is the chief pilot of American Airlines, have agreed to be present at the meeting.  I have asked both of them to discuss, to answer the following questions:  Could you describe the development of your system?  Could you describe its accomplishments to date?  Could you describe the problems that still remain to be overcome?  And, finally, what advice would you give us, based on your experience.  And this would be the perspective, first of the regulator, which would be Ms. Connell, and the regulated, which would be Captain Griffith.
After the 10 o'clock break that all committees have, Dr. Helmreich, who really was the pioneer of adapting the ideas of aviation safety‑‑not only the psychology to aviation safety, but adapting them to the operating room.  Dr. Helmreich was on the far end of the mountain that I showed earlier and did not make it to the previous meeting.
Dr. Small is a mid‑career investigator at Harvard University, is moving to the University of Chicago, and I used "mid‑career" because he I hope will represent the second generation of error management investigators in clinical medicine.  And what I am hoping from him is to get his perspective on what do you do after the pioneers have hung up their parachute, I guess.
I do have a legal scholar in mind.  I do not have the commitment from that scholar at this point in time.  I have asked Dr. Linden and Dr. Kaplan to conclude the morning and lead the afternoon discussion by summarizing their views on where they feel the committee's guidance has come and where they feel the committee could provide further guidance.  One of those areas where I am sure there will be further guidance is in the source of the funding that will be necessary to implement any effective error management system.
And in the afternoon‑‑I'm sorry‑‑on the following day, the 26th, we will discuss the issue of how advances in blood safety should be reimbursed.  This will be a follow‑up of our August 26th and 27th advisory committee meeting, mating numbers, suggestions.  There was a letter from the President on October 19th, I believe, to Senator Roth, that discussed some changes that the Health Care Financing Administration would be making in the outpatient prospective payment system.
This slide is a little thin here, obviously, because the Health Care Financing Administration's final rule has not yet been published.  The deadline that I believe will obtain is April the 10th.  There is a legal issue with which I am not familiar, but again, as I said, I have been talking to lawyers a lot recently, and I have reason to believe that the final rule will be published in the Federal Register on or before April 9th.  It is in the final stages of clearance right now.
And I believe that that final rule will quite certainly not be the last word on this issue which has come before your committee, of course, yesterday and before.  I do believe, however, that it will provide a constructive foundation for future discussion of this issue.
And with that, again, obviously this will be a short time line for people, and I have taken the last of my 15 minutes here to try and explain why it will be a short time line.  I really don't think that discussion would be really productive until the HCFA final rule is out, and from the 10th to the 26th is enough time for those who have had it.
This, finally‑‑I'm sorry, I got my son to scan this in for me‑‑but if you didn't see last week's New Yorker, there is a doctor there and he is saying‑‑I will use my pointer here‑‑on my way out the door, here, medical school equivalency diploma, "To err is human.  That's why they put erasers on pencils.  Mistakes happen."  And the nurse is saying to the doctor, "Some guys from the State Board of Medicine are here to see you."
And that's the context in which we are operating today.  Thank you.
DR. HOLLINGER:  Thank you, Steve.
Any questions of Dr. Nightingale?
[No response.]
DR. HOLLINGER:  Okay.  Thanks, Steve.
The second presenter today is Dorothy Scott, and she will talk to us about the CJD policy.
DR. SCOTT:  Good morning.  I'm just going to summarize for you what's new in CJD since this committee last met, but I'm going to start off with what's now old.
As you recall, FDA published a revised guidance on November 23, 1999, entitled "Revised Precautionary Measures to Reduce the Possible Risk of Transmission of CJD and New Variant CJD by Blood and Blood Products."  Implementation was recommended by April 17, 2000, if not before.  And just to remind you, this guidance formalized the recommendation that plasma derivative containing material from donors with CJD or CJD risk not be withdrawn, and it summarizes the scientific rationale supporting this decision.
Linked to this was a recommendation that all blood products have labeling which mentions the theoretical risk of CJD transmission.  So we are in the process of receiving those labeling supplements for plasma derivatives.
In addition, this guidance contained a new donor deferral for people who have traveled to the United Kingdom or resided there for six months or more between 1980 and 1996, which were the peak years of the BSE epidemic.
Since release of this guidance, we have had a lot of questions about implementation.  In fact, they are coming faster now as April 17th arrives, and we have done our best to provide clarifications.
Other events in CJD:  We have formed a PHS interagency ad hoc working group on new variant CJD in blood.  This is in response to requests by the Surgeon General, David Satcher, that we set up a mechanism to regularly review the scientific basis of the United Kingdom donor deferral.
And the first meeting of this committee was on November 17, 1999.  It reviewed the current new variant CJD epidemiology, and it was also apprised of current lab experiments going on in new variant CJD which are concerned with the possibility of transmission by blood or blood products.  And the next meeting is scheduled for May of 2000.
Other current concerns that the FDA has are the cases of new variant CJD which have occurred in France‑‑there are now three such cases‑‑and also the extent of European surveillance for bovine spongiform encephalopathy.  And we expect that some of these issues are likely to be addressed at the next meeting of the TSE Advisory Committee, but the agenda is only tentatively planned at this point.  There should be a Federal Register notice coming out soon.
So that's all I have to say about CJD issues for now.  I will take any questions about the guidance or other events.
DR. HOLLINGER:  Any questions from the committee about CJD, nvCJD or otherwise?  Yes, Dr. Stroncek?
DR. STRONCEK:  Has anyone implemented this, and have they given us any information on how much, how many donors they have had to turn away or lost?
DR. SCOTT:  To my knowledge, this has not been implemented, but we have received a lot of questions in the past month about donors.  For example, there is one fairly large blood bank which has 300 donors that they are turning away, and they are concerned about this issue very much.
And we have been told, when this guidance came out and when the earlier guidance came out in August, that this could be a big problem.  But I think that it really hasn't generally been implemented yet, because of the questions we are receiving now about donor deferral.
DR. HOLLINGER:  Marion?  Dr. Koerper?
DR. KOERPER:  Could you elaborate a little bit about the three cases of new variant in France?
DR. SCOTT:  These are three cases that have been documented by brain biopsy or autopsy, and in terms of the amount of time that they resided in the United Kingdom, I don't have all of that information, but it's my understanding that there's also a French BSE problem and that France has received a lot of beef from the United Kingdom in the past, during their BSE epidemic.  We don't have the exact numbers on the time, if any, that they spent in the United Kingdom.  Jay might have some
DR. EPSTEIN:  What's important about the cases is that the individuals had not been to the United Kingdom, so that they were indigenous to France, suggesting that it was either due to imported beef from the U.K. or due to the BSE epidemic in France, and that's why there is additional concern.
DR. HOLLINGER:  Any cases of transfusion‑associated in the CJD?
DR. SCOTT:  No, none known.
DR. HOLLINGER:  Dr. Simon?
DR. SIMON:  One answer to Dr. Stroncek's question.  We implemented the first of the year and have been a little bit surprised by the numbers.  And it's larger than we anticipated and, as you might expect, particularly in centers located near Air Force bases.  So the warnings from our Air Force friends were appropriate.  They have a lot of people that have been there, to the U.K.
The other thing, for those who have not implemented it, as often occurs, the law of unintended consequences, besides the donor losses, the lookbacks have been a pretty significant issue and problem, and I think people who are yet to implement will be unpleasantly surprised by some of the situations with the lookbacks and how extensive they are, and the issues and questions of how far back you need to go with particular plasma products, and the variance among the manufacturers in terms of the amount of unpooled material they had.
The one question I was going to ask is, can you give us an update on the number of cases of new variant?  Is this beginning to show epidemic type proportions, or is it still running at a low level?
DR. SCOTT:  It's still running at a low level but, as you probably know, it's estimated that we won't have a good idea of whether this is going to rise for another three to five years.  But there is no startling increase in cases, number of cases, as of this point.
DR. HOLLINGER:  Thank you very much.
The next topic is on HCV lookback guidance, and Dr. Paul Mied will present this information.
DR. MIED:  Thank you, Dr. Hollinger.
Before I discuss the revised FDA guidance on HCV lookback, I have been asked to review for the committee exactly what is meant by HCV lookback and what FDA guidance on lookback is meant to accomplish.
Multiple layers of safety, as you know, including donor screening and testing, are used to reduce the risk of transmitting infection through blood transfusion.  However, a person may donate blood early in infection, during the period when a testable marker is not detectable by a screening test but the infectious agent is present in the donor's blood.  And that's what we have been referring to as the infectious window period.
Now, if a donor donates blood on a number of occasions and each donation tests negative for antibody to HCV, but the donor subsequently returns and tests repeatedly reactive for antibody to HCV at a later date, prior collections from such a donor would be at increased risk for transmitting HCV.  In addition, a recipient of a transfusion of blood or blood components collected from such a donor during the window period would not know that he or she may have become infected with HCV through the transfusion unless they were notified.  Furthermore, prior unscreened collections from donors who later were found to be repeatedly reactive when screened for antibodies to HCV since 1990, when screening began, may have been at increased risk for transmitting HCV due to a prevalent chronic infection in the donor.
Chronic hepatitis due to HCV is a major health problem in the U.S.  The infection is usually clinically silent until serious damage has been caused to the liver, and as a result, infected people are unaware of their disease until such damage has already occurred.  Advances in medical diagnosis and therapy have created opportunities for disease prevention or treatment many years after recipient exposure to a donor later determined to be at increased risk of HCV infection.
Now, although transfusion transmitted infections account for only a very small proportion of HCV infections, it is possible to identify and look back at prior donations that might have been collected during the window period.  FDA is recommending that blood establishments perform such lookback activity, and that this activity include, first of all, quarantine of any affected prior collections that remain in inventory; further testing of the repeatedly reactive donor; thirdly, notification of consignees that have received shipments of such blood or blood components; and notification of transfusion recipients who have received blood from a donor later determined to be infected with HCV.
FDA is recommending that blood establishments perform a retrospective review of testing records when a current donor tests repeatedly reactive for HCV.  Now, this records search is intended to identify prior to collections dating back to January 1, 1988, or back indefinitely for computerized electronic records.  In addition, FDA is recommending a historical record search to identify prior collections from donors who had tested repeatedly reactive for HCV in the past and were deferred from further donation, and the retrospective records search in this case should be of historical records, historical testing records extending back to January 1, 1988, or back indefinitely for computerized electronic records.
Now, FDA published this most recent guidance on HCV lookback, and the title of it is here, as a draft document for comment only on June 17, 1999.  This document contained proposed recommendations for extension of HCV lookback to address donor testing back to May 1990, using EIA 1.0, as recommended by the PHS Advisory Committee on Blood Safety and Availability at its January 1999 meeting.
The comment period for this guidance closed on August 23, 1999, although we are still receiving comments and are discussing them, considering them and incorporating them.  And these comments have been summarized and discussed in several public meetings:  First of all, the August 1999 meeting of the PHS Advisory Committee; the September 1999 meeting of the Blood Products Advisory Committee; and the November 1999 Annual Meeting of the American Association of Blood Banks.
This morning what I am going to do is provide a summary of the status of industry implementation of HCV lookback, including voluntary compliance with the June 1999 FDA guidance, and I'll also summarize the agency's current thinking regarding revisions to the June 1999 guidance that may be made when that revised guidance is issued in the near future for implementation.
The next couple of slides I will be showing you were prepared by Miriam Alter at CDC.  According to CDC's nationwide evaluation of the effectiveness of targeted notification for HCV infection, as of December 1999 nearly 80 percent, 59 plus 18, nearly 80 percent of blood collection establishments have completed at least 90 percent of their consignee notifications based on EIA 2.0 and EIA 3.0 multi‑antigen testing.  And American's Blood Centers or ABC has reported this week that all of their member blood centers who responded to their recent survey indicated that they had completed 100 percent of their consignee notifications for prior collections dating back to January 1, 1988.
Now, as stated in the June 1999 FDA guidance document, the deadline for completion of this notification of consignees for prior collections dating back to January 1, 1988 is March 23, 2000, so they are well on their way.  Approximately 20 percent of blood establishments, most of the smaller ones, have begun, 80 percent have not begun, and 15 percent have completed notification of consignees based on EIA 1.0 single antigen screening.
In addition, transfusion services have completed the notification process for 80 percent of recipients of components from EIA 2.0 and EIA 3.0 multi‑antigen tested donors.  According to the CDC survey respondents, the recipient notification process had been completed for 33,098 recipients, of whom 70 percent are deceased, 23 percent were actually notified, 12 percent were tested for HCV antibody, 2 percent were positive, and half of those recipients learned for the first time that they were positive.  Thus, the effectiveness of the targeted lookback for identifying HCV positive recipients is approximately 1 percent.
But what is the bottom line of this massive lookback effort?  If we were to project this yield from the respondents of this CDC survey to a nationwide level, it is estimated that as of December 1999, approximately 900 recipients have learned for the first time that they are HCV positive, as a result of the targeted HCV lookback effort.
Now, FDA's current thinking regarding revisions to the June 1999 guidance is that, first, the scope of the indefinite search of records prior to January 1, 1988, should be limited to computerized electronic records.  This would make the pre‑1900 lookback based on readily retrievable records, as FDA stated in the June 1999 guidance, meaningful, but it would limit it in a practical way.  All other records searches, such as microfiche and paper records, would extend back to January 1, 1988 for a current repeatedly reactive donation or for a repeatedly reactive donation found in the retrospective review of records.
Secondly, Nucleic Acid Testing or NAT as a trigger for lookback, both prospectively and retrospectively, should be included.  Use of NAT as an additional test to clarify other screening test results would be permitted, subject to certain limitations.  For example, a positive NAT can confirm a repeatedly reactive result and trigger lookback.  But considering that in many cases HCV viremia is intermittent or is resolved, a negative NAT cannot obviate lookback for a repeatedly reactive donation, and a supplemental test for antibody would still need to be performed as a basis for determining the actions to be taken with regard to lookback.
Also, as part of lookback based on EIA 1.0, consideration of supplemental test results of record for the RIBA 1.0 performed under IND or as an in‑house testing service by Chiron, and the Abbott neutralization peptide assay performed in‑house by Abbott, as possible indicators for recipient notification, should be added.
As I said, FDA plans to issue a draft revised guidance for industry on HCV lookback for implementation in the near future.
This table summarizes the time frames for beginning and completing consignee notification that would be included in the revised FDA guidance for industry document.  These dates are for notification of consignees by blood establishments.
In the June guidance it was recommended that for the records search extending back to January 1, 1988, pertaining to EIA 2.0 and EIA 3.0 repeatedly reactive donations, blood establishments should complete notification of consignees by March 23, 2000, which was actually unchanged from the September 1998 guidance.  That still represents one year from the date, March 23, 1999, by which blood establishments were to have begun consignee notification for EIA 2.0 and 3.0.
In the June guidance it was recommended that for the records search for EIA 2.0 and 3.0 extending back indefinitely, that is, prior to January 1, 1988, and this would now be for computerized electronic records only, blood establishments should begin notification of consignees as soon as feasible and should complete all consignee notifications based on EIA 2.0 and 3.0 by September 30, 2000.
Now, that was in the June 1999 guidance, and that was to be six months later than the completion date for consignee notification for the search of manual records going back to January 1, 1988.  However, since the revised FDA guidance has not yet issued, our current thinking is to recommend that consignee notification based on the search of computerized records for EIA 2.0 and 3.0 be completed within 12 months following the upcoming date of publication of the revised guidance for implementation.
In the June guidance, it was recommended that for implementation of retrospective HCV lookback pertaining to EIA 1.0 repeatedly reactive donations, blood establishments should begin notification of consignees by December 31, 1999 and complete all consignee notifications for EIA 1.0 by September 30, 2000.  However, due to concerns raised by the blood organizations about having adequate time to perform the record searches for EIA 1.0 and about needing to lessen the impact on EIA 2.0 and 3.0 lookback efforts that were already underway, as well as the fact that the revised guidance is not yet issued, FDA is considering extending the date for beginning notification of consignees for EIA 1.0 and the date for completing all notifications pertaining to EIA 1.0 to 6 months and 15 months, respectively, following the upcoming date of publication of the revised guidance for implementation.
Lastly, this table summarizes the time frames for transfusion services to begin and complete recipient notification that would be included in the revised FDA guidance for industry document.  In the June guidance, it was recommended that transfusion services begin notification of consignees‑‑I'm sorry‑‑begin notification of the recipient when notified by the blood establishment, and complete all notifications of transfusion recipients identified in the retrospective record searches by September 30, 2001; that is, within one year of the last of the notifications that they receive from blood establishments.
However, if the dates that I just mentioned for blood establishments to begin and complete consignee notification for EIA 1.0 lookback are extended to 6 months and 15 months, respectively, following the upcoming date of publication of the revised guidance for implementation, this date to complete all notifications of transfusion recipients would be extended to one year beyond the date for completion of consignee notifications, or 27 months following the upcoming date of publication of the revised guidance for implementation.
Thank you.
DR. HOLLINGER:  Thank you, Dr. Mied.
Questions?  Yes, Dr. Boyle?
DR. BOYLE:  Points of clarification:  Since half of those who were notified were not tested, what constitutes notification?  And, secondly, is there any plan to sample that group that has not been tested to see if they are different or why they are not being tested?
DR. MIED:  The first part of your question is?
DR. BOYLE:  What constitutes notification?
DR. MIED:  We recommend that three attempts be made to notify a recipient.  If the recipient is deceased, then the notification process does not extend to their family members.  So that, if three attempts have been made to accomplish the notification, that ends the process as far as the transfusion service is concerned.
Now, the second part of your question?
DR. BOYLE:  The second part was, since 50 percent of those who are notified are never tested, is there any plan to look at a sample of those people to see whether or not in fact they never received notification, or they know that they are positive so they don't feel they need a test, or exactly what's going on with that group?  Because if they have the same characteristics as the other group, you've got 900 more cases in that group.
DR. MIED:  That's an excellent question.  I'd like to address that to Miriam Alter if she were here today.  But Mary?
DR. CHAMBERLAND:  Obviously Miriam would be the ultimate source on this, but just a little bit more supplemental information.  Miriam presented a slightly updated version of the data at a recent meeting that was held here in Washington, I believe it was a couple of weeks ago, as part of the general notification effort.  There was a meeting with various groups who‑‑health care providers and patient groups‑‑who likely would fit in the category of having been transfused, and she presented some updated numbers at that meeting.
My understanding that of those individuals that were notified, it was found that about 25 percent of them were dead, so obviously it was next‑of‑kin that ended up being notified.  So some of those notifications were to people that were already deceased, and 50 of the‑‑as Paul said, 50 percent of those notified were tested for HCV, and according to the survey to date, 50 percent of those already knew they were positive, so I think that explains some reason why people may not have sought testing.
As part of the evaluation that CDC, in collaboration with ACPER and FDA, is doing on the lookback effort, besides these surveys of blood collection and transfusion centers, there is going to be an attempt to try and evaluate the effectiveness of the lookback from the perspective of individual persons.  And that, the methodology, as I understand it, as to how to go about doing that and sampling and all of that hasn't been‑‑is still in the process of being developed because it's going to be challenging, but I would like to think that there would be some information that we can try and glean from that kind of a further evaluation.
DR. HOLLINGER:  Yes, Dr. Koerper?
DR. KOERPER:  I am speaking from my own experience in dealing with our blood bank, our local blood bank, but the way the notification is happening is that our blood transfusion service is identifying the physician who was responsible for the transfusion, notifying the physician, and then leaving it up to the physician's discretion whether the individual is actually notified or not.
So, I mean, we have an elaborate form we have to fill out saying whether we notified them or not and whether we recommended testing or did the testing, what the result was, but there are certain physicians who feel that because it's an elderly person or someone who is dealing with a terminal illness, that it may not be in the best interest of the individual to physically get this notice that, "By the way, you've got one more thing to worry about."
So sometimes the physician is notified but the actual recipient is not notified.  And what I don't know from these statistics that both of you have mentioned is whether that, you know, the person being notified includes these situations where the physician was notified and made a decision not to actually inform the recipient.
DR. CHAMBERLAND:  Regarding this initial survey that CDC did, it was a very preliminary‑‑it was viewed as an interim preliminary survey to kind of get a quick snapshot of what was going on, and I don't believe that level of detailed information was being collected.  And there is, right now there is discussion as to whether this should be followed up with another interim survey at a later date.
I mean, I am delighted to hear that ABC did their own survey and found obviously a 100 percent completion rate for the lookback dating back to 1988.  But trying to balance the need to get some information on an interim basis without wanting to sort of try the patience of individuals that have to fill out these forms‑‑because ultimately, at the completion of this lookback, is when the very detailed series of evaluations will be planned, so I don't think we have that kind of information, but that's useful to know.
DR. HOLLINGER:  Yes, Dr. Katz?
DR. KATZ:  Louis Katz, Mississippi Valley Regional Blood Center.
I don't want‑‑the approaches to lookback vary in varying systems.  And, for example, my system, in cooperation with our hospital transfusion services, took a substantially more aggressive approach than it sounds like you've got.  So that's all over the board, I believe, and I don't know if there's anybody from the Red Cross that can address what they did.
But in my system, where we have completed that lookback, we find numbers essentially identical to what Miriam has presented from her national survey in terms of yield, just under 2 percent in our system that were newly discovered HCV infection.  So it is really quite variable, and some places have been very aggressive.
DR. HOLLINGER:  Yes.  I'm not sure one should always be a little pessimistic that you only got a 2 percent yield.  I mean, the fact is that there is a lot of education going on, a lot of information in the newspapers, and I will tell you from my standpoint that some patients that come to see me have been tested because of all the things in the news about lookback so they went and got tested.  So the fact that they were notified but then found to have already been tested I think is a good thing.
DR. KATZ:  And one other thing I just wanted to say is that sometimes the relationship of industry and FDA is contentious, and with regards to lookback, I think everybody in the industry or most people in the industry appreciate the approach that Paul and the agency have taken here, that this is doable and has not consumed the resources it might have under other circumstances.
DR. HOLLINGER:  Have you found it has been quite expensive to do?  And where have the resources come from to do this?  Who is footing the bill for this, Louis?
DR. KATZ:  Oh, we just put another $2 on a unit of red cells; it was easy.
A lot of person hours, enormous labor costs, and some of us are trying to figure out how many.  And within our system, we're guessing that for each individual that we in fact got to, notified and got tested, it was somewhere in the range of $700 or $800, but those numbers are not reliable yet.  Yes, it's pretty expensive.
DR. HOLLINGER:  Yes, Dr. Simon?
DR. SIMON:  Well, I was going to ask, and I know this is preliminary, I mean I was going to ask about the view from Mary and your point of view on the yield, which to someone like myself seems very low for all of the effort.  And I think you commented about all the publicity, but that could have all come from the non‑targeted lookback, which I think is another whole area, and one didn't necessarily need the targeted lookback to get the publicity and the public awareness.
Even though it's preliminary, is this considered a good yield for a public health effort of this dimension, in terms of what can be gained?
DR. CHAMBERLAND:  This is basically, the yield to date from this interim analysis is not unexpected.  I mean, based on previous experiences of doing lookback and whatever, this is‑‑I think there have been some surprises in terms of notifications being over or under estimated numbers of components that were involved, etcetera.  But in terms of the bottom line, in terms of the actual proportion of people that you reach who get tested, who otherwise wouldn't have, it really hasn't been too surprising.
Part of the final, if you will, or comprehensive evaluation of the lookback is going to include a cost‑benefit analysis, and so the final series of questionnaires that will go out to blood collection and transfusion services is actually going to attempt to collect information about costs, resources that were used, so that we can actually quantitate this better.  Which I think everybody thinks is a good thing to do, because I don't think any of us would be surprised if we would be on the cusp of facing a similar question with a new agent or a different agent down the road.  So I think people feel this is a very good opportunity to really try and quantitate this as best we can, and provide that information back.
DR. HOLLINGER:  Yes, Mr. Rice?
MR. RICE:  Well, I think that the yield‑‑about the yield, it would seem that we would probably try to find more people than 900 out of an effort of this magnitude, but I think if we had actually started to look back at an earlier point in time, the yield would have been much greater.  I think that this particular lookback demonstrates that the regulation which was in place in June of 1977, and I think my comments would be consistent with Mary Pendergast's comments a few years back, that there has been a requirement that we have some sort of process in place to do just this for 20 years.
And I wonder sometimes whether, because blood has traditionally been safe prior to that date, and unfortunately through HIV we learned some hard lessons, but have there ever really been resources set aside, just like if I had to plan, my heating system is going to go, I am planning for resources to replace that?  Was this really a budget item for 20 years, to basically say, you know, some day we're going to get something that we're going to have to actually perform a lookback and notify all consignees?  Which, if you look at the '77 regs, includes the individual.
So there has always been that problem of how we're going to do it, and with the record‑keeping now being electronic, it's much easier.  I think that it's been a great effort to basically identify the problems, even though the yield wasn't quite as great as perhaps the resources spent to find these people.  But I think that it may identify the problems that will definitely allow us to at least be in compliance, as I read the 1977 regs, on the next challenge.
DR. HOLLINGER:  Thank you.  If there are no further questions, thank you very much, Paul.
Oh, yes, Dr. Schmidt?
DR. SCHMIDT:  I think the expenditure Dr. Katz has given us is the blood center expenditure, and my recollection is, the American Hospital Association backed off the old HIV concept or looking at everybody who was ever transfused, when it was pointed out to them that the hospitals in the country would have to spend millions and millions that they didn't budget.  So when you're talking about costs, it's not at the blood center level.  That's a small part of the cost of getting to the patient.
MR. RICE:  Well, I think that now that we know this happens, we have to perform it, whatever the chain in that is actually involved in getting these notifications, that perhaps some planning for the future to have resources available, to make this not quite as difficult a task financially than it obviously has been for HCV.
DR. HOLLINGER:  Thank you.
The next update is on post‑donation information algorithm, and Dr. Tabor is going to give us that update.
DR. TABOR:  On previous occasions at BPAC when I have discussed post‑donation information algorithms, I used slides, and I was told afterwards that the slides were too detailed to be useful.  So this time we arranged to have the copies of the algorithms submitted to the committee ahead of time in your mailer, so you may want to pull those out and follow them.
We also had planned to have them at the front desk for the audience to pick up, but unfortunately they were not there the first thing this morning, but they will be there, I am told, at the break for you to obtain.  And the algorithm is also available on the web, that is, the draft algorithm.
Well, as you know, we have been discussing these algorithms at BPAC almost every meeting since 1997.  The topic was previously called "inadvertent contamination," and we searched far and wide for a replacement name for it, and it's not called "post‑donation information."  Let me remind you that so far these discussions have involved only those viruses for which serologic tests exist, and which can be inactivated and removed by procedures applied during the manufacturing process for plasma derivatives, namely hepatitis B virus, hepatitis C virus, and human immunodeficiency virus.
To summarize what BPAC has recommended, BPAC voted in March 1999 in support of the "test positive" algorithm; and in May of 1999 BPAC voted in support of the "risk factor" algorithm, with a proviso that footnote "i" be shortened because the number of risk factors that were listed there and that could activate the algorithm was so large that post‑donation information would affect every lot of every plasma derivative.
At the September 1999 BPAC, a revised algorithm was presented, along with additional suggestions for changes, based on the fact that by 1999 all units entering plasma pools would have been found to be negative for HCV and HIV by NAT testing of minipools.  The revised algorithm presented at September BPAC included the suggestion that if post‑donation information were received that a donor was in fact in a listed risk group, the pool itself would be tested, that is, the manufacturing pool would be tested, as an additional precaution, for HCV and HIV by a NAT test under an IND, and for HBV DNA by a NAT method validated under an IND.  If all of these tests were negative, the pool or products would be releasable.  And of course a positive test in one of these NAT tests would trigger a further GMP assessment.
We have made further modifications to the draft algorithm to reflect the BPAC discussion at the September meeting and to address issues related to prior donations by a donor with post‑donation information, so you might want to take a look at the draft algorithm.  Aside from several minor corrections to the algorithm, you will find that the main changes are located on the second page, which is titled "Risk Factor:  Plasma," as well as in some of the footnotes.
If post‑donation information is discovered prior to the pooling of a donation, the unit from that donor would be destroyed.  However, if the unit has already been pooled, NAT would be done on the manufacturing pool, and if NAT for HCV and HIV were negative on the manufacturing pool, as well of course as prior NAT on the minipool, and if a validated NAT were negative for HBV on the manufacturing pool, then the pool and/or the product could be released.
All pools or products containing prior donations by the same donor could be released, as well, provided that a recent donor sample were negative for all recommended serologic screening tests by NAT for HBV, HCV, and HIV, and serologic tests for anti‑HBc and anti‑HBs.
If any NAT on the manufacturing pool done after the receipt of post‑donation information were positive, or if a paper audit by the fractionator revealed that the minipool NAT done prior to pooling had in fact been positive and had incorrectly been reported as negative, or if NAT had for some reason not even been done on the minipool, then the pool and product would be quarantined and a GMP evaluation would be done.  The GMP evaluation would be the same type of evaluation that was endorsed by BPAC at a prior meeting, as described in footnote "d".
At a prior BPAC meeting, we had indicated that these algorithms, the "test positive" algorithm and the "risk factor" algorithm for post‑donation information, would not be developed into guidance documents until the approval of NAT tests under PLAs.  We are now near to the time when one or more PLAs will be submitted to FDA for NAT testing.  Therefore, it's safe to assume that the Office of Blood Research and Review will be working on a guidance document for these algorithms during the coming year in anticipation of the submission and approval of NAT tests for blood and plasma.
And I can take any questions that you have about the algorithm.
DR. HOLLINGER:  Any questions?  Yes, Dr. Chamberland?
DR. CHAMBERLAND:  Ed, thanks.  A couple questions.  In terms of the pieces, the parts of the algorithm that require NAT testing, I think they‑‑I was trying to reconcile the HBV NAT requirement with what we heard yesterday, because obviously it seems that certainly for minipool testing, HIV and hepatitis C NAT testing is much further along.  So I wondered if you could elaborate a little bit  more about how this algorithm plays out with respect to NAT testing for hepatitis B?
DR. TABOR:  Okay, let me try.
DR. CHAMBERLAND:  And I was also curious about the data that Sue Stramer presented from the Red Cross yesterday, that seemed to indicate that performance of a hepatitis B surface antigen test with increased sensitivity might even be a better way to go.  So I was wondering if you could just sort of help elaborate a little bit on that.
DR. TABOR:  Okay.  Well, let me first say that the algorithm we're talking about is an algorithm for plasma, and at least some of our discussion yesterday was about testing of whole blood.  In the case of plasma, we feel very confident, based on data presented to BPAC over the past two years, and that I subsequently published in a review in Transfusion that was also submitted with your packet, we feel confident, based on the accumulated data, that if all of the GMP requirements are met and appropriate inactivation or removal procedures are followed in the manufacturing of pooled plasma derivatives, that any residual HBV would be non‑infectious for the recipient of these products.  And we also feel that the HBsAg testing removes the vast majority of HBV‑infected units that could enter a pool.
Well, let me drop back to talk about HCV and HIV for just one minute.  Those are already being tested in minipools for plasma entering the manufacturing pools, and the addition to the algorithm of NAT testing for HCV and HIV on the manufacturing pool was essentially a back‑up method to allow the manufacturers not to have to do a GMP evaluation on every single lot of every single product based on information that a donor was in a high‑risk population.
You must remember that these are all donors, even if they are in high‑risk populations, they are all donors who tested negative on all the serologic tests as well as in the minipool testing for HCV and HIV.  So in this case the subsequent testing by NAT on the manufacturing pool was basically a sort of fail‑safe addition to the algorithm.
In the case of HBV, we don't have minipool testing at present, and as we heard yesterday, it's unclear whether we will have minipool testing or whether, when the technology is available, perhaps we'll go straight to single donor testing.  But at present there is no minipool testing on most of the plasma entering products manufactured in the United States.
Nevertheless, based on the serologic tests available, we do feel that there is very little HBV that would enter the pool, based on the testing that's available, and we feel that the evidence is that any HBV that entered the pool would be inactivated by the manufacturing procedures.  But it was felt also that adding NAT testing of the manufacturing pool would at least ensure that there was no detectable HBV DNA at a certain level, and that this too provided some measure of additional safety in a situation where we really don't feel there is any risk at all.
DR. HOLLINGER:  And I guess also, Ed, if I am not mistaken, with the plasma these are still anti‑core positive, probably anti‑HBs positive units also dumped into the pool, which should add an additional safety factor for the HBV.  That's correct, is it not?
DR. TABOR:  Right, that's correct, because‑‑
DR. HOLLINGER:  So there should be some neutralization going on potentially anyway in those pools.
DR. TABOR:  That's correct.
DR. HOLLINGER:  Yes, John?
DR. BOYLE:  I would just like to clarify this, because there are two options.  One is the audit trail of the GMPs and the other is the NAT testing.  The industry in the past seems to have said that they can't do the audit trail in 36 hours, so the only way to avoid that is to have universal NAT testing.  Is that not correct?
DR. TABOR:  Well, 36 hours wasn't the actual figure that we had somewhat arbitrarily selected.  It was, I think, 72 hours, but it was equally arbitrary, and what you're saying is correct.  I don't really buy the inability to do it in that amount of time if resources were focused on it, but it would be a great burden to have to do it on every lot of every product, and it would cause a bottleneck in the supply of these products.
You will be hearing later, probably in the open public session, from the Plasma Protein Therapeutics Association, previously IPPIA, about some further modifications of a plan they are proposing to precertify GMP measures, and we can discuss that when they talk about it.  But basically what you said is correct, that this type of NAT testing would be to bypass a reevaluation of GMPs.
But, you know, what it really boils down to is, the only situation in which a manufacturer would end up doing this type of GMP evaluation would be when they failed the testing or when minipool testing had not been properly done.  I think that's what it would boil down to.
DR. HOLLINGER:  One other question.  On page 2 of the things that you sent us, Ed, it says that "all pools or products containing prior donations could be released, provided that a recent donor sample were negative for," and it says "all recommended serologic screening tests, NAT for HBV, HCV, HIV, and serologic tests for anti‑HBc and anti‑HBs."  I guess I would come back again and say, but these are being released into the pool of plasma products anyway.
DR. TABOR:  Well, yes.  Yes, let me explain that.  That was added because of an actual situation that arose since the last time we discussed this with BPAC, and we realized we had to address the issue of prior donations by the donor that might not have been‑‑that might still be in stock or in the manufacturing line.  And what we want to do is make sure that the present donation is not infectious and that the prior donations are not infectious, if they are still in the process of manufacturing.
And let's just say you have a donor who said they were not in any of the risk groups, answered negatively to all the questions in the questionnaire, and then on a subsequent donation or after they went home realized they were, they had had a tattoo or something.  They called up and said that they really were in a risk group and had forgotten to tell you.
Well, you want to make sure they were not infectious at the time of the present donation, so you have got the minipool NAT and you have got NAT testing on the manufacturing pool as well as serologic testing on the donor sample.  You want to make sure, also, that any prior donations are not infectious.
Well, if you have all of these tests available on the donor, you know that‑‑if you have the tests available, you have serologic tests on the earlier samples, you have NAT testing on the current sample, you might not have NAT testing on the earlier samples, depending on when it was collected, but it is possible that they could have had, say, hepatitis B when they donated six months ago and now be anti‑HBc or anti‑HBs positive.  And that was why that was added.
But in general anti‑HBc and anti‑HBs positive units are entering the pool, but in this case you want to make sure they don't have any evidence of prior HBV infection.  Now, the one exception, if you noticed in the footnotes, was for plasma that's going into immune globulins, and it was felt necessary to make an exception for plasma that's going only into immune globulins.
DR. HOLLINGER:  Yes, Dr. Koerper?
DR. KOERPER:  I'm curious why you're testing for anti‑HBs, because this means that somebody who has been immunized for hepatitis B would turn up positive for that test only.
DR. TABOR:  That was brought up in our internal discussions.  What you're dealing with is a situation where a manufacturer wants to use material that they would not have been able to use if the donor questionnaire had been answered honestly and appropriately, and so the manufacturer has the option of evaluating their GMPs for that lot or any affected lots, and if they want to bypass that, they can do this testing.  And if the individual in that risk group happened to have been vaccinated, they still have the option of evaluating the GMPs for those lots.
But you're not going to be able to necessarily‑‑I mean, I guess it's something that we can address in the footnotes to the algorithm, but it seems to me that this pathway of additional testing is to enable the manufacturer not to have to do a GMP evaluation on those lots.
DR. KOERPER:  Right, but maybe Blaine can answer this.  How often does somebody have an infection with HBV and only be left with an anti‑HBs?
DR. HOLLINGER:  I have never seen that.
DR. KOERPER:  I have never seen that, either.  If you take all of our hemophilia patients that we have tested over 20 years, all the ones who were infected have anti‑HBc.  And the only ones who only have the anti‑HBs are the ones that we immunized, so that's why I'm questioning the need to do the anti‑HBs.
DR. TABOR:  What you're saying is that anti‑HBc would be enough.
DR. HOLLINGER:  Any other comments to Dr. Tabor?  You're very silent over there, Toby.
DR. SIMON:  I believe industry is making a presentation, and at the time‑‑is that correct?  Okay.
DR. TABOR:  Let me just emphasize that this is not final, that the guidance document will be prepared and made available for public comment, and we welcome suggestions, including the ones such as you made about anti‑HBc and anti‑HBs.
DR. HOLLINGER:  Will you still be in the FDA, Ed, by the time this is all completed?
DR. TABOR:  Well, if HCV lookback is any model, I'll probably be walking with a cane.
DR. HOLLINGER:  Okay.  Thanks, Ed.  Yes?  Oh, I'm sorry.
DR. MITCHELL:  I just wanted to comment that you had mentioned about tattoos, and I wanted to make it clear that that's not in‑‑
DR. TABOR:  I'm sorry.  Yes, I gave a bad example.  Thank you.
DR. HOLLINGER:  Okay.  The next update is on IGIV clinical endpoints, and Dr. Golding is going to give us an update on that.
DR. GOLDING:  Good morning.  Before we start with the slides, just a small comment.  Dr. Albert Ferrugia is here visiting from Australia.  He is the director of the equivalent Office of Blood in Australia, and when he came to our group he asked me how was my labyrinthitis.
I asked him, "How do you know that I had labyrinthitis?"  He said, "At the last BPAC, when you went up, you said you had a viral labyrinthitis and if you were disoriented, it was because the viral labyrinthitis."  "And how did you find that out?"  "It's on the transcript and that's on the web."
So I need to update my medical record that's on the web.  The diagnosis of viral labyrinthitis was incorrect.  I was taking non‑steroidal anti‑inflammatory drugs at the time, and that caused the dizziness.  When I stopped the drugs, the dizziness went away.  And I just wanted to be sure that that was clear and on the internet.
As for the IGIV update, could I have the first slide?  So what I'm going to be talking about is the Immune Globulin Intravenous (Human), a clinical trial proposal for primary immune deficiency, and what I'm going to tell you, this proposal is based on a consensus that was arrived at from discussions with the Clinical Review Branch at the Office of Blood, the senior management at the Office of Blood and CBER, and much help from Peter Lachenbruch and his group at CBER.
At the BPAC in March '99 I emphasized that the plasma fractionation process was complicated.  It's a multi‑step process.  Variations in the manufacture can have far‑reaching effects on safety and efficacy, and we regard each product as being unique, and that immune globulin should not be treated as a single generic biologic.
I also stated at that BPAC that we had come up with a proposal, and the proposal for study, for clinical study, was a prospective, double‑blinded, randomized Phase III study, in other words, a two‑arm study to evaluate the efficacy and safety of new IGIV products by comparing them to licensed IGIV products, and the sample size that was calculated at that time was approximately 80 patients, which was much less than most of the trials that were being proposed at the time.
So the problems with this trial design that we discovered were that there still were limited numbers of patients with the diagnosis of primary immune deficiency that could be recruited for these trials, and that multiple new IGIV products were in line to be tested, and that the critical shortage of IGIV persisted, which drives the need to seek other means to come to a proposal that would allow foster approval of these products in a safe and effective manner.
So the new proposal that we're proposing now‑‑and I would like to emphasize that this is only a proposal, it does not exclude other proposals that could be made by manufacturers‑‑so according to this proposal, discussion of possible trials that would reduce the sample size were arrived at from internal debate at the FDA, and formal and informal discussions with the Immune Deficiency Foundation, and the discussions centered around many different issues.  One was the possibility of using pharmacokinetic data as a basis for approval.  Another suggestion was the suggestion that we could use surrogate endpoints such as fever as the primary endpoint.
What we think we have come up with as being preferable to this is using historical controls to justify a single‑arm study, and this is based on the fact that IGIV products have been very successful in limiting infections in PID patients, and that acute bacterial infections per patient per year are as many as four or greater than four without treatment, and are in the region of .5 or fewer than .5 on treatment.  So this is at least an eight‑fold difference between patients receiving IGIV and patients not receiving IGIV.
So the study design that we came up with is a single‑arm study.  It would be a 12‑month open study, and we would be comparing the new product to historical controls for safety, PK data, and efficacy, using 80 percent power and 99 percent confidence level, in other words, an alpha of .01, and the increased rigor is partly to account for the single‑arm nature of the study and to do one‑sided testing of the data.
In terms of safety, the safety targets are again based on previous trials and historical data.  The historical control estimate is that 20 percent of adverse events occur per infusion of IGIV, and the trial target would be to exclude 40 percent or greater adverse events per infusion.  And the approximate sample size for this would be about 40 to 50 patients receiving 12 infusions sequentially, in other words, about a year of follow‑up for each patient because they receive these infusions every three to four weeks.
The clinical trial design would include PK studies, so there would be first a washout period.  The patients would still be receiving IGIV but after two or three months the data would be collected for the Cmax, the Tmax, the area under the curve clearance, and the half‑lives, and importantly also the trough levels, which are used almost universally by physicians to decide on dosage.  And the observed values should not be inferior to those concurrently or previously determined for approved products.
In terms of efficacy, the efficacy would be established using an objective, clinically meaningful endpoint.  The primary endpoint would be acute serious bacterial infections which would be predefined, and what we're talking about here are infections such as pneumonia, bacterial pneumonia, bacterial meningitis, bacteremia and septicemia, osteomyelitis.  Most of the acute serious bacterial infections are in fact pneumonias.  By the overwhelming majority are pneumonia, which can be diagnosed by x‑ray and which are responsive to antibiotics.
The secondary endpoints could include or should include serum immune globulin levels, other endpoints such as antibiotic treatment, numbers of hospitalizations, fever, and others.  The sample size should be sufficient to determine whether the infection rate for the new IGIV is at or below the "beltline", and the numbers that we came up with were approximately in the range of 40 to 50 patients.
The primary endpoint, as I said, would be acute serious bacterial infections, and this is based on historical controls that the infections per patient per year are less or equal to .5 using approved IGIV products, and the data with the new product must exclude an infection rate of 1 or greater than 1 per patient per year.
The trial would be considered a Phase III pivotal trial sufficient for licensure.  Submissions with six‑month interim data could be submitted six months after the trial onset to initiate review of the manufacturing, the PK data, and the initial safety data.  The efficacy and complete safety data would be submitted after termination of the trial, that is, each patient would be treated for a minimum of 12 months.  Initial FDA action is expected within six months of receipt of the completed data.
In conclusion, the number of patients per trial will be reduced, permitting concurrent trials of new products.  For approval, the new products will need to have acceptable safety, PK, and efficacy profiles when compared to historical controls.
And the data will be collected during the trials to validate additional surrogate markers, e.g., for example, antibodies against specific pathogens.  For example, we know that Haemophilus influenza and streptococcus pneumonia are the primary causes of pneumonia in these patients, and it seems reasonable to start collecting data to make sure that‑‑to determine whether we could use these as surrogate markers for subsequent trials.
Thank you.
DR. HOLLINGER:  Thank you, Dr. Golding.
Any questions for Dr. Golding?  Yes, Dr. Boyle?
DR. BOYLE:  It's not a question, it's just a congratulations to the FDA on a job well done.
DR. HOLLINGER:  Thank you.  If there are no further questions, then‑‑oh, yes.  Dr. Epstein
DR. EPSTEIN:  Yes, I just wanted to add a comment.  Well, first of all, thank you for your remark.  The central change here is shifting from the notion that we can't approve a new product without comparing it in a two‑arm trial to a previously approved product.  Instead, what we have done is, we have examined the historic data and established a standard for approval of any new product.  That's the central insight here.  The fact that we have also added a rolling type review is to expedite the process, but that's really the key point.
DR. HOLLINGER:  Thank you.
This completes the committee's updates this morning.  We're going to open this up now to the public hearing.  There are several people who have asked to speak to some of these issues.  So the first will be Jason Bablack from the PPTA.  Tell us about the new name, too, Jason.
MR. BABLACK:  Thank you.  With regards to the new name, it's the Plasma Protein Therapeutics Association, and it reflects a merger, if you will, with our European counterparts, which was the European Association of the Plasma Products Industry, and it is really focusing now of global issues, with a North American component, a European component, and we are expanding also to look at issues in Japan, as well.
With regards to the post‑donation information algorithm, I would like to make a few comments.  I have about 10 or 11 slides here, and then we would be happy to answer any questions that you have.
First of all, I would like to change the focus of this ever so slightly because we have been talking about post‑donation information reports, but I really want to get to what those stand for.  And what they stand for are undetectable window period units or the potential of an undetectable window period unit.  So we are going to just change the focus of the discussion ever so slightly to address that potential risk, and talk about a proposal that we have come up with that we hope will address that at least as good as what the FDA proposes, and hopefully a little better.
This is just an introduction slide, and in the past there has been a little confusion about what is currently done, what the FDA has suggested and what we want to do, so I just want to kind of summarize it, start off from that base and then go forward.  So currently, when we get information, post‑donation information for risk factors, for hepatitis B, C, or HIV risk factors, the units in inventory, and because we have a 60‑day inventory hold, all of those units are removed from further manufacture.  Non‑reactive units, and all of those that actually are in inventory are non‑reactive, that have been pooled, continue through normal processing.
So this is currently what is done.  It's in the company SOPs.  They have all been inspected and agreed to by the FDA.  That is what is currently done, and the rationale behind that is, basically there are very robust inactivation procedures, that if there is a potential window period that is below the level of detection, that would definitely be taken care of through viral inactivation methods.
FDA has developed an algorithm to address PDIRs, and it includes NAT testing options that Dr. Tabor discussed just a minute ago.  It also involves a potential of tracing and a retrospective review of viral inactivation data for those impacted lots.  And the industry alternative is a prospective supplemental review focused on viral reduction records for all lots, and it also includes NAT testing of minipools and/or manufacturing pools.
So just from the start, I think we are very close, and it's really a matter of do we want to go backwards and look at ones that are identified through PDIRs, or do we want to go forward and say for every lot?  Because there's a chance that any unit could actually at some point have a PDIR associated with it, do we want to have assurance for any unit going forward?
With the history of the issue, I think everyone agrees we have an excellent viral safety record profile for these products.  Dr. Tabor just recently published an article in Transfusion speaking to that, and I don't think there is any disagreement with that.  Nonetheless, there was a recommendation that we can and should continue to look at ways to further improve the margin of safety, and one way is to address any potential risks that would be associated with PDIRs.  And here again I want to take a step back from the actual post‑donation information report and say it's really the window period or potential that a unit is in the window period that we want to address the risk for.
I won't go through this in too much detail.  The FDA has developed an algorithm that we've gone through many times in recent BPAC meetings, and it's focused on post‑donation information reports.  That's the trigger to initiate some sort of review.  Either it's looking at the unit or the pool, or going back and looking at the actual products made from that pool.
The NAT testing was originally focused on the donor unit, with discussions today which sounded very promising to us.  It looked like NAT testing on the manufacturing pool might be sufficient, and one question we have for the FDA is, would a NAT test done prior to finding of the PDIR suffice, or would you have to go back and test retrospectively?
Currently, though, not all the manufacturers are testing for hepatitis B, so right now that is not an option that would exclude the GMP review.  So for the FDA algorithm, it would involve a retrospective tracing of each unit to identify all the impacted lots, and then going the comprehensive GMP evaluation.  And in the original algorithm, and I think it's still there, is the 72‑hour time frame for doing all of these.
Now, this is a slide I think I showed you last September, but I think it's important to kind of understand.  This is an example of a PDIR, and this was the example‑‑we collected many examples‑‑this was the one that had the least amount of impact.  There was one PDIR.  Of that, there were seven units collected from that individual prior to getting that information.  Six of those were removed from inventory, from the 60‑day hold.
One of them had been manufactured.  And you can see what happened to that one unit.  There were four Factor VIII lots; one Factor IX; eight albumin; and one IGIV lot; plus eight intermediates.  So there were intermediates that had not been manufactured to final products yet, and it's still unclear what would happen with those under the FDA algorithm.  But that's just to show you that one unit from one donor can have that effect on the number of final products, so this is a significant amount of reviews if you're doing it retrospectively.
We also have some additional concerns with the algorithm.  We believe it's inefficient in addressing what we're trying to get at, which is the potential risk associated with undetectable window period units.  While it can actually address some risk, if you look at the ones that are identified, there are still many that may not be identified, because really what we're talking about is the potential risk is based on the possibility of an undetectable window period unit entering the pool.
Now, these are random events that we believe are not accurate predictors of actual risk through a particular unit, and in the next slide I'll explain that a little bit further.  Also, we have the 60‑day inventory hold that reduces the risk already of pooling window period units, because as we get additional sampling from these donors, if one would happen to seroconvert, we can go back and pull out what would be window period units.  And then there is also the problem of most if not, many if not most lots are already released, and this requires a quarantine while we do these investigations, and obviously that causes some supply implications.
Now, this is, it doesn't look like it but it's actually a busy slide and I'm going to take a couple of minutes to go through it.  Assume that this is your typical plasma donor who would donate once a week, so he donated four times in January, four times in February, four times in March, three times in April, and he comes back in April and gives us some information.  Now, it's important to understand that all of these units are negative for all the serological tests and all NAT tests that are currently done by the manufacturer.
Now, if you go back to the first day in January, and I had a little mark on there but it looks like it came off, assuming that first unit in January is actually when the risk activity took place, what this does is, all of those units have an additional level of risk associated with them, that they could be potentially in the window period unit.  We don't know about that until you get down to April, and if you look at what happens then, we get that piece of information, we go back and take out all the units in inventory, so that takes out all of April and all of March, but there are still several units from February and from January that have been pooled and may have actually been manufactured.
Now, if you look at the FDA algorithm, what it does is, it waits until you get that PDIR and then you're going to go back and do some kind of retrospective review.  Even if you're just looking at the NAT tests on the manufacturing pool, even if you're going back and looking at all of these reviews, it's still retrospective, without addressing the risk that each of those units has going forward.
What we want to do is, for each of those units as they go through manufacturing, assume the worst, if you will, in that we are going to assume that each of these could potentially be in the window period.  And what we're going to do is, we're going to add not only the NAT testing, because we're doing that, but we're going to add the enhanced GMP review for viral inactivation records for every single one, because any of these could at any time have a PDIR associated with it.  And rather than wait to get that PDIR, we're going to go forward saying that any one could have it, and so therefore they should all be treated the same.
So, just quickly going through our proposal, it's a prospective supplemental review focused on the viral reduction records for all lots, and this is performed by staff who are specially trained in virological principles, product‑specific processes for viral inactivation and reduction steps, and critical operating parameters for each step.
Now, this is important because we have had some discussion about this, as well.  This is conducted as an additional review, so the normal manufacturing review is done, the normal QA review is done, and then this is an additional review by an additional set of eyes, if you will, to look one more time at what we think are very critical parts of the manufacturing process.  And the certification of this review is required for lot release, so in order to get the lot out the door, you have to have this additional review done.
In addition to that, we are currently NAT testing for hepatitis C and HIV at the minipool and/or the manufacturing pool, and the manufacturers have submitted INDs for hepatitis B NAT testing.  So in essence we're doing both; we're just going to do them up front.
Now, what are the benefits of this?  We believe this is an effective alternative to address potential viral risk associated with undetectable window period units, and it doesn't impact supply because we do it up front, we do it on a routine, regular basis that does not require us to quarantine products.  It applies to all lots of plasma derivatives, so it does not rely in a random event to trigger this review.
It's something that we do all the time.  It's prospective, so, if you will, it's preventative versus reactive.  It provides an additional assurance of viral reduction procedures.  Any potential safety issue related to PDIR or anything else, because you're not solely looking at PDIR's, are addressed before a lot goes out the door.  And, once again, it minimizes the impact of product supply.  And with the NAT testing, I think everyone agrees that this is state‑of‑the‑art, and it further reduces the window period, which basically makes this more effective.
Where are we?  This is the implementation phase.  The companies have all done the preparation of their viral record review documentation, so all the check sheets are made.  Revision of corporate SOPs for product release, so in order to get product out the door, this is part of that SOP now.  Employees have been trained on virology, the viral reduction processes for their particular steps, and the program SOPs, so that they understand that this review is required and how to perform the review.  And it is implemented for all currently manufactured products, so it is actually in place.
And after some discussions, both with consumer groups and the FDA, we felt that it was important to add this final piece to it.  And really what this is, we're going to have an independent third party audit the company's implementation of this program, and we will make those audits available to the FDA so they can say whether or not it's actually being done.
And I would be happy to answer any questions you have.
DR. HOLLINGER:  Any questions for Mr. Bablack?  Yes, Dr. Boyle?
DR. BOYLE:  Just a question on these PDIRs.  Are most of them coming from first‑time donors, as opposed to continuing donors?
MR. BABLACK:  No.  PDIRs, by their very nature, come from repeat donors, because if they were coming from a first‑time donor, they wouldn't have donated in the first place.  So they come back at some point in the future, and you can see from the example I gave that it was, for this first example where there were seven units drawn, it was done very early.  It is not always that way, and a lot of the examples we collected showed 20 or 30 units in manufacturing, not just the ones in inventory hold but in manufacturing, before we got that piece of information.
DR. BOYLE:  But looking at the five elements that are in the algorithm, and I'm thinking of your chart up there that shows the donations from January to April, and so at the end of April somebody says, "Oh, by the way, I was an IV drug user," or "Oh, by the way, I've been having sex with other men"?
MR. BABLACK:  Right.
DR. BOYLE:  That actually does happen?
MR. BABLACK:  That actually does happen.  Unfortunately, but it does.
DR. SIMON:  Well, it's usually a little bit more, you know, a little bit more below the surface, like, "You know, I had something in 1978 or '83."  So it's not usually the more overt sort of thing.  Or "I forgot that I lived as a child as a missionary in Nigeria."  That's the sort of thing we see.
DR. HOLLINGER:  Yes?
DR. FITZPATRICK:  So, to boil this down, what you're proposing is that if this program is successful, then if you get a PDIR, you would just ignore it essentially?
MR. BABLACK:  What you would do, to put it in a more positive spin, you would have already done what the FDA would like you to do, you would have done up front, and so it would obviate the need to do anything from that particular piece of information.  And don't forget, it's also important to understand that the collection center already sends an accident and error report to the FDA regarding that, so this is obviously done in addition to the FDA, understanding that that already happened.
DR. FITZPATRICK:  And this is currently being put in place by industry?
MR. BABLACK:  It is in place for all currently manufactured products.
DR. FITZPATRICK:  So I think we had this discussion a while back, so that I think the committee said that we endorsed what you were doing.  We wanted to see a track record before anyone made a recommendation to the FDA that they change their algorithm process, that your program was successful.
MR. BABLACK:  Right.  So where we are right now is, the program has been implemented and we are in the process of developing this third party audit that we can then share with the FDA and‑‑
DR. FITZPATRICK:  Yes.  It looks like a great program.  We just need to see that it works.
MR. BABLACK:  Thank you.
DR. HOLLINGER:  Thank you.  Yes, Mark?  Dr. Mitchell?
DR. MITCHELL:  I would expect, then, when a PDIR comes across, that there would be some kind of documentation of what has already been done.  Is that what you're proposing?
MR. BABLACK:  Actually we're not, and let me explain why.  Doing, basing it on the PDIR, one, it doesn't actually accomplish anything because the risk is either there or it's not.  So looking at that as a trigger, if that were a test, it would be very non‑sensitive and non‑specific.
So it doesn't really tell us anything that we don't already know about that unit, if we already assume that that unit could be in the window period.  So, therefore, basing any additional investigations on that particular piece of information I don't think provides us any additional assurance that anything has been done or needs to be done, as along as something has already been done for everything.
That's the way we are viewing this.  If we didn't have something in place, then there might be some suggestion that, yes, we should do something with that piece of information.  I think that's where the discussion has been in the past, is if you have an additional piece of information, do you need to do something additional?  What we are saying is, if we assume this for every single unit, then getting that piece of information is just‑‑it doesn't tell us anything else because we've already assumed it into the process.
I don't think that answered your question very well.
DR. HOLLINGER:  Dr. Macik?
DR. MACIK:  In looking at what you're doing, you could in essence call this kind of a universal precaution.  You assume every donation is a window unit donation, and you are working it up maximally.  And so you accept the risk that with the best possible tests that we have today, there are still going to be a few units in there that you can't find, that are before NAT testing.
In the plasma industry, for most of the processes, then you have the further fail‑safe of you're doing an inactivation process which should catch those rare window units that go through.  And so it would seem to me, acknowledging that we would like to see that it actually is in place and working as proposed, that this is probably a much safer way and a better way and a prospective way to look at this information, without spending manpower and dollars doing retrospective reviews that we have tended to get into, that really just look back and identify our errors, and not really making efforts to prospectively prevent errors.
So I would like to commend the industry on pulling this together.  It seems to me a good approach.  Hopefully some day we'll have a test that can give 100 percent window unit identification, but until that time I think, you know, this is probably about the best we can do.
DR. HOLLINGER:  I'm going to take one more question because we're getting a little bit behind.  Dr. Schmidt?
DR. SCHMIDT:  Well, I'm strongly opposed to the one question issue.  I've been on this committee for several times, and we've heard this before and we're hearing this in piecemeal.  I've said before that I'm strongly opposed to this, and I want to emphasize that to the FDA.  If they're looking for guidance, this is a lousy‑‑this proposal is okay for operations, but in place of the FDA proposal it's lousy.  If the FDA wants to take this under advisement, then we need to devote some time to it so we can hear the full story.
The implications of this is that we're negating all our health history questions.  You know, someone can say, "Well, what difference does it make to ask for HIV or HCV?  Because it doesn't make any difference, we're going to use that lot anyway."  So, you know, that has fundamental implications, and that merits a long discussion, not these piecemeal presentations every 15 minutes with little discussion.  I'm appalled at this.
DR. HOLLINGER:  Thank you, David.  We'll take one more question, then.  We'll take other questions, then.  That's all right.  Paul?
DR. McCURDY:  Well, I think that universal precautions example is not a bad one.  I don't know how it is now, but early on universal precautions were better when you knew the patient was infected than when you didn't know the patient was infected.
And I think a triggered lookback or a triggered review is going to be more thorough, almost certainly, than a routine review.  It is, again, axiomatic that if you have one person doing something and another person checking it, the first person better do it right because the second person will assume that he did, and will likely miss problems of one sort or another.
I think there also needs to be some thought given as to how the auditor is selected.  Again, if the auditor is not selected pretty independently, then again they may not pick up all of the potential problems.  I think it's a potentially reasonable approach, but I think there are some flaws.
I have one other question:  What proportion of the donors in the plasma industry donate once a week or twice week, and for how long?  Is this something that happens over a year or two?
MR. BABLACK:  I am not an expert on the donor issues, but I can tell you that typically donors come in and donate once or twice a week for a period of time and then usually drop out.  So there is an extended period of time that they donate on a very regular basis.
DR. McCURDY:  What's that period of time?  Do you have any idea?
MR. BABLACK:  I can't answer that question.  I'm sorry
DR. HOLLINGER:  Yes?  Toby Simon.
DR. SIMON:  I think one of the things that's been lost sight of during the discussion, and I want to make sure we don't, as I understand it, the PDIR is not being ignored.  When the report is received, all units that have not been pooled are removed and destroyed.  The issue is the units that have been pooled, and what kind of system can we have in place to protect the patient and at the same time not disrupt supply?
And I think one of the issues that industry‑‑that also may have been lost sight of has been a lot of discussion about whether the GMP review can be done in 72 hours.  I think what I got out of the presentation is, it's not so much that that's the time‑consuming problem, it's that each time that report is received, there has to be a tracing of every unit that was received.
So that obviously you'll get a list of units and a list of dates, and you start pulling the units in inventory and then you come to those unit that have been pooled, and you have to identify every pool of every product, multiple products made, and then you have to identify every pool from the intermediates that are made, and then go back and test this all.  And I think what industry is saying is that is logistically very difficult and problematic, and can we take the universal precautions approach and, given that, assume that each pool will have a PDI in it at this point, and do this prospectively?
So I think, in answer to Dr. McCurdy's question, there is a little bit of division between specialty and non‑specialty.  For example, in the ladies with anti‑D donating FRH immune globulin, it's not uncommon for them to donate 100 units a year, year after year after year.  We have donors that go back 20 and 30 years.  Thirty years may be too much.  Yes, almost 30 now, getting close to that.
In the non‑specialty, I think what Jason described is the most common, but there are donors who stick in there once or twice a week, year after year.  Most donors come for a period of time and then either move or for some other reason, become too busy or whatever.  So it's a highly variable situation.
I think 10 or 20 units in a PDIR would be common.  Of course, the donors who give you a PDIR tend to be somewhat less reliable donors compared to those who donate a long period of time, but still there will be cases in which a post‑donation information report will come in with 50, 60, 100 units, and so forth.
DR. HOLLINGER:  Mr. Rice?
MR. RICE:  Yes, I just had a couple of questions.  The PDIR I would hope would pick up due to some of the questions, the behavioral characteristics of the individual, perhaps.  I am more concerned about emerging threats than the ones we know about.
Frankly, there are certain behaviors that the questionnaires tries to elicit, which are the types of things that are what I believe the real threat to the blood supply, in that I believe testing and our review procedures, the GMPs are so tight that I think pretty much that the risk of what we know about is dealt with fairly aggressively and completely.  I'm more concerned about the things that we don't know about, where that questionnaire trigger may elicit, as we're developing and moving and finding new bugs and new types of threats to the blood supply.
Now, you could say that we can't be concerned about everything all the time, and you have to deal with what you've got.  But ultimately the mention there was, the risk of this proposal is not borne by the industry; ultimately the risk is borne by the recipient of these products.
DR. HOLLINGER:  Thank you.
Yes, Dr. Finlayson?
DR. FINLAYSON:  I think apropos of Dr. Macik's comments, it's very important to clarify something.  And unlike Dr. Golding, I can't take refuge in saying that I'm taking steroids, so I have just plain forgotten which of your four and five letter codes you are under.  But I seem to remember that your entire membership would be doing minipool testing for HIV and HCV NAT by now, and on your slide you said minipool or the manufacturing pool.  Could you clarify that, please?
MR. BABLACK:  That was basically an and/or.  I think some‑‑they are all doing minipool testing.
DR. FINLAYSON:  Well, do you propose they take this giant leap backwards in dilution and do just the manufacturing pool?
MR. BABLACK:  No, I don't think anyone is.
DR. FINLAYSON:  So, in other words, you would be willing to strike the "or"?
MR. BABLACK:  I don't see any problem with that.
DR. FINLAYSON:  Thank you.
MR. BABLACK:  Now, the reason we said and/or is because not everyone was doing the manufacturing pool.  There had been some discussions whether someone could do the manufacturing pool under the particular IND that they had submitted, and so we had and/or because everyone was doing at least the minipool; some were doing the minipool and the manufacturing pool.
DR. FINLAYSON:  So you would be willing to do a little rewording there?
MR. BABLACK:  If you can come up with a better way to say that, I'd be happy to take it.
DR. FINLAYSON:  I'm sure I can.  All right.  Point two:  I also seem to remember at one of these gatherings that you said that your membership would, by the end of calendar 2000, be doing minipool testing on HBV.
MR. BABLACK:  Correct.
DR. FINLAYSON:  Is that also correct?
MR. BABLACK:  That is correct, and it is still true.  It is my understanding that all the INDs have been filed and are in the process of beginning implementing that at the sites.
DR. FINLAYSON:  Thank you.
DR. HOLLINGER:  Yes, Dr. Fitzpatrick?
DR. FITZPATRICK:  Well, with what Mr. Rice has said and the universal precautions, I think I'm distressed by what Dr. Simon said, because we've talked a number of times to the industry about they need to be able to quickly identify where the blood products from these donors go, and it should be automated and readily available and easy to do.  And there still is that need for these emerging agents.  Something's going to happen, that you're going to have to do a lookback.  It's unavoidable.  And so to say that that's an undue stress upon the industry to have to do that is, I don't think, acceptable.
MR. BABLACK:  If I could address that, I don't think that's what we're saying.  In fact, that's currently done for many types of failure investigations.  For example, if you have inadvertently put in a positive unit, that actually would be done, where you would trace that unit through the manufacturing process, find out all the intermediates, all the final product lots that went to, and do an investigation on those, as well as the typical failure investigation as to how this happened in the first place.
What we're saying, on an ongoing basis, because of the sheer number of final product lots that will be implicated by the number of PDIRs, doing that on a routine basis is not the most efficient way of manufacturing product and getting it out the door.  What we're trying to do is develop a system that allows us to have the same or greater levels of safety to what the FDA has required, but doing it in a systematic approach that prevents the types of errors that you get from ad hoc types of investigations that you're trying to do in a finite period of time so that you don't have to quarantine product that's already been released in the field.
DR. HOLLINGER:  Yes?  Oh, yes, Kathy Knowles?
MS. KNOWLES:  I think there have been several times at this committee meeting where also we have discussed the problems with the donor history questionnaire, and at some point in time I think it's really important to get an update, because I know there have been workshops on that issue.  I'd like to see what has happened and what kind of progress is being made to streamline that, to help people give the most honest answers possible.
DR. HOLLINGER:  Thank you, Kathy.
Yes, Dr. Boyle?
DR. BOYLE:  Jason, if you could just clarify, at some level it seems like we're reasonably close, because your industry is going to do universal NAT testing.  Universal NAT testing would allow us to deal with the issue of errors and omissions or the PDIRs, but the problem is, is the linkage in terms of being able to document a specific case has gone through a specific process.  And I guess the question that I'm raising, I've raised before, others have raised is why, going forward prospectively, can't you set up the system so that you can identify automatically the numbers of the lots and how they get‑‑where they go to, so that all you have to do is pull it up on a computer and be able to demonstrate that that in fact has gone through the proper gate?
MR. BABLACK:  I don't think that is unrealistic.  The problem we have with that is, having done it for every lot, having assumed that every unit was in the window period, I don't think it actually gets you any additional pieces of information that you don't have without that.  And, two, what do you do with that information once you find it?  I mean, if all you're going to do is take that and hold it somewhere, I don't think it accomplishes anything.
There has been some talk in the past that the FDA might want some of these reported to them, and that would be one way to accomplish that.  But the question is, does the FDA have the staff and the time to review all of these, because there will be a significant number of reviews that are done.  Even, as you see, from one unit you had almost 20 final product lots that would have these reviews, and therefore that would be documentation then sent to the FDA, requiring them to review it.
If you're just going to sit on it, isn't it better to just assume that every lot was in the window period and have that associated with every final product lot, that you have done this review?  Which is what is incorporated in our program.  So as part of the batch record review and the documentation for a particular lot, you have this enhanced second review accompanying that, so it's attached to every single lot going forward.
DR. HOLLINGER:  Dr. Stroncek?
DR. STRONCEK:  I'd like to follow up on Mr. Rice's point.  These questions are very important.  They not only screen for HCV, HIV and hepatitis B virus, but they probably screen for other agents we can't test for, and they will likely screen out people at high risk for new problems coming along that may or may not be inactivated.  So these post‑donation inquiries I still consider a serious matter, even with all the testing we have and with all the inactivation.
I think the FDA proposal provides more oversight, and I'm in favor of that.  Quite honestly, you know, I don't trust any industry as a whole to just say that they're going to handle this all on their own.  I think that's the FDA's role.  I want to point out that you represent an association of a number of companies.  Some of these may deserve trust and may be able to make this work, but I don't think all of them will.  I know that companies come and go.  I know many companies are for profit and they're going to cut corners.  And I just think this is too important, and the safety of our recipients is too great to put this much trust in these organizations.
DR. HOLLINGER:  Dr. Macik?
DR. MACIK:  Just to readdress a couple of issues, one, what Mr. Rice has brought out is that ultimately it is the receivers who bear the ultimate burden.  It is also the receivers who bear the burden of not having a product available, if you're busy quarantining every unit that goes through and they can't get product.
So what we're really looking at is ways to balance this in the safest possible way, so if you use universal, you accept everything is at risk, one.  And I'm not a statistician, and so please don't jump on me too hard, but in some ways screening for and ruling out the hepatitis C, because those units are all going to be thrown out, in some ways those are linked also to those individuals who have the at‑risk behaviors.  It's not 100 percent, I realize, but you are in some ways impacting those who may have the at‑risk behaviors and throwing those bloods out up front.
And so you've done now, you've looked‑‑and what I would agree with is, you need a way that you know where every single unit went at any given time, so when we find that we now have a "mad rabbit" disease and people were exposed to it, and we have to pull that unit, then you go in and you grab it.  You know where everything went and you know who got every unit.  But not to put the restrictive‑‑if we've done everything we possibly can up front, that we don't restrict the flow of supply as much as possible.
And again, I totally agree also that this isn't an issue that‑‑maybe this requires an entire discussion a little bit more on where we're going, instead of just as part of the industry hour.  Thanks.
DR. HOLLINGER:  Yes, Mr. Rice?
MR. RICE:  Just a quick point, is that that was my point, is that the PDIRs would‑‑I'm looking for the fact that we're going to do the same checks that they're going to do, prospectively, and ultimately the lots would be released anyway.  But if a new virus comes down the pike, we have some sort of record‑keeping that says we've identified this behavior, and if we hadn't had this particular pathogen associated with this behavior, we now know that it is.
And do we keep a track?  And we still need that trigger mechanism to be able to go back and find everyone, so when the PDIR comes in, not only do we just check to see if this prospective mechanism suffices or is equal to the current standard the FDA has, but also that we need to keep the information or some sort of tagging so we can respond through a lookback type provision more quickly than we currently do.  It took us 10 years to do HCV.  That's too long.
DR. HOLLINGER:  Yes, Dr. Simon?
DR. SIMON:  Just quickly in response to that, I think my earlier remarks were somewhat misunderstood about the industry needing to track this and the amount of time it would take.  I think we all agree, and the industry would also, I assume, that they need to know and be able to quickly determine where every unit went, and every lot.
So that could be quickly determined, but as part of the algorithm they would then have to go and verify all your pool and minipool testing, create a record, and this would take a certain amount of time to complete.  So that was the point I was trying to make there, though perhaps not that well.
But in response to Dr. Stroncek's comment about trust, I think in either plan, industry would carry it out.  I mean, industry would carry out the algorithm or industry would carry out the prospective review, and in either case it's subject to review by FDA, either inspection or otherwise on submitted.  So I don't see that as a difference between the two, in terms of that situation.
MR. JACKMAN:  May I make a comment, please?  Dennis Jackman with PPTA.  On the question of trust, there was a comment made by Dr. Stroncek about not wanting to trust any industry.  And setting that aside, I just want to point out that we're not counting just on trust here.  We have third party review and certification of adherence to the prospective review, and we would make those audit results available to the agency as well, and those would be attached to the lot.
So it's not just a matter of trust, but even saying that, I just want to make it clear that this industry is very committed to producing safe and quality products.  It's in our direct interest to do so, for patients and for the viability of the industry, as well.
DR. HOLLINGER:  Dr. Schmidt?
DR. SCHMIDT:  Supporting Mr. Rice's worry about who is holding the mortgage at the end, the situation in the hospitals, what happens to these products and who gets them, is absolutely chaotic compared to blood.  You have no way of finding out, when this is bought by a hospital, who got it.
DR. HOLLINGER:  David, my apologies for starting to cut down on the questions.  I think it was important, and I think the issues that have been raised here are critical.  Perhaps it needs some further elaboration, further discussion outside the update session here.  So, with that in mind, perhaps that's something we can perhaps put on the agenda in the future if it seems to be necessary.
We're going to go on with the other public hearings.  The next person that asked to speak was Miriam O'Day from the Immune Deficiency Foundation.
MS. O'DAY:  Thank you.  Good morning.  I'm Miriam O'Day and I'm Vice President of the Immune Deficiency Foundation, and we're making a comment on the IGIV clinical endpoints.
The Immune Deficiency Foundation is a patient advocacy group dedicated to improving the lives of individuals affected with primary immunodeficiency disease.  IDF has presented testimony and data documenting the depth of the IGIV shortage and its human consequences before BPAC on numerous occasions.
In addressing the ongoing shortage, IDF has recommended various strategies, a number of which are aimed at rationing the available supply of IGIV based on medical necessity.  In cooperation with IDF, the agency has supported and endorsed prioritization protocols and emergency supply programs such as the IDF Safety Net Program.
Since the fall of 1997, industry estimates have consistently projected that demand will continue to outstrip supply well into the foreseeable future.  It is estimated that the current annual supply gap for IGIV is approximately 5 million grams.  For this reason, the Foundation has encouraged additional strategies, such as expediting licensure of new IGIV products and processes to alleviate the shortage.
IDF and its medical advisors support the FDA's revised guidance on IGIV clinical trials.  The immunology community and immune deficient patients believe that the recommended revisions for IGIV licensure are a significant step towards improving the supply of this lifesaving therapeutic.  The IDF commends the agency for adapting endpoints which are measured using the standard of care in the practice of immunology, therefore avoiding undue diagnostic burdens on patients participating in clinical trials.
FDA policy revisions in IGIV licensure are an excellent representation of public and private collaboration, allowing physicians who treat immune deficient patients on a daily basis the opportunity to consult on an appropriate clinical trial design, while ensuring that patient safety has not been compromised.
In cooperation with FDA, IDF is conducting a retrospective data collection project to determine the incidence of serious infection for patients with common variable immunodeficiencies.  The data obtained in this study, in conjunction with the published literature, will further assist in substantiating a historical control group of untreated patients.
And, in conclusion, I would just like to say thank you for your ongoing efforts, thank you to the agency, in efforts to help resolve this crisis in health care for immune deficient patients.
DR. HOLLINGER:  Thank you.
The next person who asked to speak was Robert Sandhaus from Alpha One Foundation.
DR. SANDHAUS:  Thank you very much for letting me take a few minutes to make a few brief comments.  Since this is the first time I have addressed this body, I would like to introduce myself.  I am Dr. Sandy Sandhaus, Executive Vice President and Medical Director of the Alpha One Foundation, which is a not‑for‑profit foundation supporting research in and detection of alpha one antitrypsin deficiency, one of the most common life‑threatening genetic disorders in the U.S.  I have worked as a researcher and clinician in this area for the past 30 years, and in addition to my new position at the Alpha One Foundation, I currently direct the alpha one antitrypsin deficiency program at the National Jewish Medical and Research Center in Denver, and I co‑direct the University of Colorado's new Genetic Lung Disease Center.
I have three related points I would briefly like to cover.  First, I would like to thank the members of the Blood Products Advisory Committee and the Food and Drug Administration for the attention and support they have provided during the critical shortage of plasma‑derived augmentation therapy for alpha one antitrypsin deficient patients.  Unfortunately, the shortage still exists, and as detection efforts move forward, the shortage can be expected to intensify, since it is estimated that currently only about 5 percent of the alpha one antitrypsin deficient patients in the United States have been identified.
My second point relates to the IGIV clinical endpoints just discussed.  The Foundation applauds the work that has been accomplished in this area, and asks only that a similar effort be started in alpha one antitrypsin deficiency.
A major impediment to new drug development in alpha one antitrypsin deficiency is the requirement to demonstrate improvement in the rate of decline of pulmonary function and/or mortality, a clinical challenge and development program that can take many years to complete.  If more rapid but relevant clinical and surrogate endpoints, such as reduction in the number or duration of pulmonary exacerbations, could be identified and accepted, additional therapies could be developed for this condition.
Finally, and based on review of the previous iteration of the proposals, the Alpha One Foundation would like to express its support for the alternative post‑donation information algorithm proposed by the Plasma Protein Therapeutics Association.  While we note the high ideals of patient safety preservation that are the basis of all the proposed algorithms, we also see problems inherent in each.
The alpha one antitrypsin deficient patient population is most concerned at this time about access to safe augmentation therapy.  We see both the agency's proposal and that of the PPTA as leading to a safer product, but we see an advantage in the PPTA's proposal in preventing major product quarantines and providing for proactive rather than retroactive safety enhancements.  We see both proposals as being interim solutions while awaiting additional technological advances in unit and pool screening procedures.
And I suppose I should add that while we gratefully accept donations from any source, currently the Alpha One Foundation's budget is supported in less than 5 percent by industry donations.
I want to thank you for keeping patient safety and product availability as your guiding principles.  The Alpha One Foundation looks forward to working with you on these same goals into the future.
DR. HOLLINGER:  Thank you, Dr. Sandhaus?
Any questions?
[No response.]
DR. HOLLINGER:  The next person who asked to speak was Dr. Al Smith, Calicivirus studies.
DR. SMITH:  Well, first of all I would like to thank you for giving me just a couple of moments, and I think the things that I might be able to address here are relevant to some of the conversations I have heard just now and some that took place yesterday.  It seems that there is a 3 percent hepatitis rate out there that just seems to hang there and doesn't go away, and we have seen that alluded to yesterday by Ian Williams out of CDC.
And then there are a series of viruses that have chased that‑‑G, GB, C, G, and TT, and yesterday we heard about the SEN virus.  And all of these, although they may be very important agents, don't seem to dip into this 3 percent.  Then, just now, on four occasions, and I had not heard it at all in the last two days, we hear about concern for emerging diseases, which brings me to this particular agent, that is, Calicivirus.
Now, Calicivirus is, the family is divided into four genera, and one of them, vesivirus, is a peculiar virus in that its origins are in the ocean.  Primary reservoirs are in the ocean.  This virus amplifies in the ocean.  And it has been of considerable importance to our livestock regulatory people for nearly 70 years because it causes a foreign animal disease, but only recently has been found to be zoonotic.
So once we establish this concern for a zoonotic agent, then what do we do about it?  Well, we have some data here which, if you can see that, and we have a table to follow on behind, across the bottom, the first blood group we looked at were normal.  These were samples from a Red Cross testing lab.  There's about 400 sera in that sample, and the percentage of positives within that sample is 5 percent.  So we would say that a normal population might have 5 percent positives in it, and that, like we say, is a good large sample.  This is an ELISA test.
Now, let me stop here and tell you, we have these viruses in isolation.  We have cDNA primers or probes.  We have monoclonal antibodies.  We can replicate them in vitro.  They are plaque purified, plaque passaged.  I mean, we know what we're working with.  So we have good serologic tests.
The next thing we looked at was a group of donors who had elevated ALTs‑‑and a shopping trip, grant you, because these agents can cause an array of diseases, including encephalitis, myocarditis, abortion and so forth, and hepatitis‑‑but we had the opportunity to look at elevated ALTs.  We did that.  The percentage positives out of 200 samples bumps to about 8 percent.
Okay, so we went on a further patient shopping trip and we looked at whether these could be blood‑borne or a needle transmitted kind of thing.  The next thing we looked at were only a few people in that group, there were 16, and these were people who had clinical hepatitis, non‑A through wherever you want to go, G at the time, they said.  Okay, so now these are 12 percent positive.
If you could move that down just a little, the next group we looked at, and not many people in that group, there were 10, but once again high risk for needle or blood transmission.  These were people who were either hepatitis B or C positive, and small numbers, but the percent bumps to 20 percent.
The last group we looked at is a fair number now of 32 individuals, and these were post‑transfusion or post‑dialysis cases that were negative for all the known viral markers.  And the percentages there go to 22 percent.
So if we can have the next table, please, the P values on that become fairly important.  Let's look at the top one first, yes.  You can only arrange these sample sets in a series of progression in terms of increasing risk for hepatitis.
If you do that, you can get 1 degree of freedom for your chi‑square test, and you can see then that we end up with P values and chi‑square values that are impressive, a P value of less than .001 when compared to the normal population, that is for a progression in blood transmission.  And you can lump the various groups of those bottom four together, groups three, four and five, or groups two, three, four and five, and the numbers still hold for you in terms of the statistical significance.
So we have already said we have tools to work with, and I just heard Terry Rice talk about emerging diseases.  We have laid one out for you.  The ocean is a spawning ground.  These things occur in tremendous antigenic and pathotypic variability.  They are an RNA virus.  The quantity species concept is alive and well.  Genomic scatter is phenomenal.  PCR will not get you there at this point in time because of those factors.
And so I think the last point I would want to make is that this concept of emerging problems in industries such as yours is not just an ephemeral concept.  There are things out there going on right now that we can talk about.
And now that I have given you just a small piece of the bad news, Dr. Iversen has come with me, and he is from AVI Biopharma, and wants to talk to you about what in my mind is an entire paradigm shift in terms of what you really do in terms of detection and prevention in some of these issues.  And I do thank you.
DR. IVERSEN:  Well, thank you for the opportunity to address this committee.  I guess I drew some things on the top of that that don't show up very well.  Is that true?  Okay, they don't.  Maybe they rubbed off.
Well, let me just point out that we're a company that makes an antisense strategy towards inhibition of gene expression, and I've been working in this area for about 12 years.  Our company has been working on this area for 20 years.  The research has led to what we believe is an improved approach to synthetic DNA analogs which are capable of binding to messenger RNA and preventing gene expression.  This is a very specific form of therapy.
And we met with Al Smith because we were interested in a virus that would be able to be the same virus in our testing systems, that is, a zoonotic type of infection where you could treat an animal that has the exact same virus as does a human, for the process of development.  How little did we know that it would be found so broadly that animals who eat shellfish, for example, can obtain the infection, and people who then subsequently eat those domestic animals can also gain this infection.
And so we have set about trying to find an inhibitor for the expression of the Calicivirus, and what I am showing here is a Western blot.  The Calicivirus capsid protein is at about 60 kilodaltons, and when we add our antisense sequence, as you can see, we suppress the expression of that capsid protein.  We show a control in there of the 40 kilodalton actin protein as a loading control, to show that we loaded our blots in an equivalent manner.
And at the bottom, in that same set of experiments, we looked at the viral titer, and you can see we can reduce the viral titer at 1 micromolar concentration of viral oligomers, we can reduce viral titer to about between 60 and 80 percent.  This is a highly reproducible result, and the reason for reducing only 80 percent is that our ability to deliver the oligomer in cell culture to cells is only about that efficient; it's about 80 percent efficient.
When we look at electron microscopy, we do see that we do not change the infection in cells that we do not deliver the oligomer to, but that when we do successfully deliver the oligomer, we almost entirely eradicate the infection.
What turns out to be very interesting from these observations is, however, that when this chemistry which has a neutral backbone, which we now have in clinical trial for targeting c‑myc, and we are developing a drug strategy for the treatment of restenosis following angioplasty, that clinical trial has demonstrated that we can go GLP toxicology, we do have GMP manufacturing of this material, and the interesting observation was that when this unique neutral chemistry binds to the RNA, rather than all of the other approaches that have been tried to date, this does not cut the RNA.
And that is a very important observation, that when the oligomer pairs, the cell will actually degrade the RNA on either side of that duplex that is formed, and that duplex is so stable that the cell will actually export that, and we can detect that in blood and urine.  This means that we have a scheme to not only inhibit the virus but also detect our success or detect the presence of virus by detecting the duplex, and we think that this has broad implications in use in improving the quality of the blood supply.
Thank you.  I would be glad to answer any questions.
DR. HOLLINGER:  Thank you, Dr. Iversen.
Is there anyone else from the public that wants to make a comment?
[No response.]
DR. HOLLINGER:  If not, we're going to take a 15‑minute break.  We'll meet back here in 15 minutes and start the next session, where we will take up on the Blood Action Plan.
[Recess.]
DR. SMALLWOOD:  We are ready to reconvene.  May I ask all committee members to return to their seats?
I would just like to make an announcement to clear any confusion.  Dr. Tabor had stated that a copy of his algorithm would be available.  That will not be available today.  However, you may retrieve it from our web site; my understanding, that it has been placed on the web site so that you may look there to get a copy of the algorithm.  Unfortunately, I do not have the correct web site address, so I do not want to misdirect you, but I'm sure that you will be able to find it, as I know you can.  Thank you.
DR. HOLLINGER:  We are going to begin with the Blood Action Plan:  Supply Issues.  This is informational, and we have asked Dr. Mary Gustafson or Captain Mary Gustafson to tell us about this.
CAPTAIN GUSTAFSON:  Thank you.  The title of this is "Implementation of the Blood Action Plan:  Initiatives to Promote Blood Availability."
The Blood Action Plan has been presented to the BPAC before.  However, there are several new members who may not be aware of the Blood Action Plan.  It's a plan that was undertaken in 1997, and is a collection of initiatives in the blood area supported by the Department of Health and Human Services.  The initiatives, many of which require interagency coordination, include activities related to recommendations from various oversight groups, including congressional committees, the General Accounting Office, the Inspector General, and the Institute of Medicine.
The true beauty of the action plan is that it publicizes the work being performed and prioritizes the work efforts, which helps to ensure that the work efforts will result in a finished product.  The complete action plan is available for viewing on the CBER web page.
Today I'm going to review with you the most recent addition to the Blood Action Plan.  This addition includes initiatives to improve blood availability.  The Blood Action Plan amendment on monitoring and increasing the blood supply resulted from a report requested by Dr. David Satcher, our Surgeon General and Assistant Secretary for Health, who also serves as the Blood Safety Director.
Dr. Satcher requested that a report addressing strategies to increase the blood supply be developed in light of two major developments.  One was our recommendations that donors living in the United Kingdom for a cumulative period of six months from 1980 through 1996 be deferred, with an estimated nationwide decrease in blood collections of 2.2 percent.  The second was a report from the National Blood Data Resource Center comparing 1997 blood collection and utilization data to data from 1994, with a projection that if everything remained the same, blood demand would overcome supply sometime in this year 2000.
A report was developed by an ad hoc interagency task group‑‑some of you on the BPAC were members of this group‑‑working under the auspices of the PHS Working Group on Blood Safety and Availability.  This report was developed during the summer of 1999 and was presented publicly to the PHS Advisory Committee on Blood Safety and Availability at its August meeting.  The report contained recommendations in five areas.
These recommendations were considered by Dr. Satcher's Blood Safety Committee.  Next overhead, please.  The Blood Safety Committee is a committee that is comprised of PHS agency heads.  The Blood Safety Committee recommended that the recommendations in the report be made part of the existing Blood Action Plan.  Incorporation of the recommendations into the Blood Action Plan was approved by the department in November of 1999.  Next overhead.
The five areas of the monitoring and supply area of the Blood Action Plan are:  first, to monitor the blood supply; second, to encourage more donations by eligible donors; third, improve donor relations as part of recruitment and retention; four, remove restrictions to safe donation; and, five, address economic issues facing the blood industry.  We'll go through these, the high points of these five elements.
In terms of monitoring the blood supply, the National Heart, Lung and Blood Institute of the National Institutes of Health on December 10th contracted with the National Blood Data Resource Center to conduct monthly surveys.  This effort will proceed under contract for some time.  By October of the year 2001, the Public Health Service will determine if one of the public health agencies should have long‑term responsibility for this effort.
Jane, if I could have, there is a clear overhead that Dr. McCurdy, BPAC member from NHLBI, provided to me to give you a sample of the type of data that's being collected.  The data collection began with data from October, November and December, which was collected retrospectively after the contracts were let, and the January data which was more real time data, and these data were submitted to the NHLBI in February.
I don't think you can see a whole lot in terms of trends, but this was total red blood cells released during this four‑month period, released and made available for transfusion, with the total number of units and then broken down by O positive and O negative, which are the types that are generally more in short supply.  Although there was a dip in November‑December, there is a fairly constant rate of O positive and O negative.
Now, whether these are adequate supplies, we will need to see.  This is only one element.  We also have data that is being collected on outdating, bimonthly collection of data representing inventories, and the program will move to collecting data on utilization for comparison purposes.  Okay, we can go back.
The second part of the supply and monitoring area of the Blood Action plan is to encourage more donations by eligible donors.  The department offered the support to industry to participate in public service announcements, and it's my understanding that Dr. Satcher has filmed several PSAs in the area of blood supply.  I don't know that any of these have hit the airways yet.
In addition, the National Heart, Lung and Blood Institute sponsored a workshop on February 28th entitled "National Strategy to Increase Blood Donations."  It was attended by corporate representation, blood center directors, blood donor recruiters, and was an important first step in forming a national message concerning blood donations.
The FDA has committed to publish a donor incentive guidance by June 30, 2000.  This will be in the form of a compliance policy guide, and will represent what has been allowed according to our regulations as they are written now.  It's not a gold standard on the desirability of donor incentives.  That area requires more work, more studies.
The NHLBI is sponsoring studies in this area.  At present we don't have a lot of data, but a lot of strong opinions on the use of donor incentives.  And also the NHLBI will explore the feasibility of initiating studies on development of educational programs to encourage blood donation as a civic responsibility by June 30th of this year.  Next.
The next part is to improve donor relations as part of recruitment and retention.  The FDA has committed to a draft guidance on recruitment practices by the end of this year.  In order to do this, we are‑‑well, it's more than possible, I think we're planning now to have a workshop on donor recruitment by the end of the summer, and we're seeking co‑sponsorship of this workshop.
Additionally, we plan on providing guidance on what we have approved in licensing for computer interviews by September 30th, and we will initiate simplification and abbreviation of the donor questionnaire by January 1, 2001.  You may have heard at this meeting there's a lot of enthusiasm for this one element by the industry and by consumers.
The next is to remove restrictions to safe donation.  FDA is to issue guidance for the use of therapeutic hemochromatosis donations by May 31, 2000.  I am beginning to worry a bit about this date, not because we don't have a policy; we do.  It was in a memo from Jane Henney, our Commissioner of the Food and Drug Administration, to David Satcher last August.
We also have been approving, on a case‑by‑case basis, requests to allow use of therapeutic hemochromatosis donations without the labeling, the disease state labeling that made it undesirable, and to allow the collections at more frequent intervals than every eight weeks.  We have approved several of these; we have several in‑house to review.
The issue on the guidance is trying to generalize what is a fairly easy operation, case‑by‑case, to a guidance document that can be used industry‑wide.  In addition, we are looking into having workshops to review some of the donor deferral criteria to see which ones are useful anymore.  However, in our discussions, most prefer to have NAT implemented before we tackle this, and so the workshops will be in the year 2001.
The last element is to address the economic issues facing the blood industry.  I think Dr. Nightingale told you this morning that in August the PHS Advisory Committee on Blood Safety and Availability heard discussions on safety measures and cost implications.  Their April 2000 advisory committee meeting will continue to discuss reimbursement issues related to safety measures, and by June 1st the Department will clarify policies on reimbursement.
And that's the plan and our status thus far.  Do you have questions?
DR. HOLLINGER:  Any questions of Doctor Captain Gustafson?  Yes, Dr. Schmidt?
DR. SCHMIDT:  I don't understand how it's in the mission of the Food and Drug Administration to tell people how to recruit donors or help them recruit donors.  I mean, I'm very glad they are.  Everybody should be helping.  But if blood is really a drug and we think of parallels to other drugs, it doesn't make sense for me to divert FDA funds into promoting donor recruitment.
Of course, to take away some of the barriers for accepting donors, but the concept of donor publicity or whatever is going to be in this‑‑you said you were going to publish a donor, FDA would publish a donor incentive guidance.  This, to me, I just don't understand it.
CAPTAIN GUSTAFSON:  Well, part of having a safe blood supply is also having an available blood supply.  We view that safety and availability are very much intertwined.  And yes, it does go beyond where FDA has gone in product jurisdiction issues, but we think it is important.  We think blood is a national resource, and we think having an available supply from our donors is very, very important for the public health.
DR. HOLLINGER:  Yes, Ms. Knowles?
MS. KNOWLES:  Could you give me just a little clarification on point number three under improved donor relations, where it says FDA guidance on computer interviews, please?  Thank you.
CAPTAIN GUSTAFSON:  Yes.  NHLBI has funded studies on having donor interviews with an interactive computer.  They also had funded a study back in the 1980s looking at the best way to interview donors, and part of the information that came out of that study was that a computer assisted donor interview would be useful.
We have approved at least one application using the computer‑assisted interview, and I think there are others that will be coming in for us to review, but we would like to make more public what we have approved so that others may pick up on the initiative.
DR. HOLLINGER:  Okay.  Thank you, Dr. Gustafson.
CAPTAIN GUSTAFSON:  Thank you.
DR. HOLLINGER:  We are going to now go into a discussion on donor deferral issues, but Dr. Smallwood has something she would like to put up first in regards to this issue.
DR. SMALLWOOD:  This is the web site that you may obtain copies of the information that was provided to the committee, and my understanding is that the information that we had provided to us prior to this meeting is already present on the web site.
The other announcement I wanted to make is that for this discussion concerning xenotransplantation issues, we will have joining the committee as a temporary voting member, Dr. Jonathan Allan, and we will also have as a guest of the committee, Dr. Louisa Chapman.  Thank you.
DR. HOLLINGER:  Are they here?  We are going to go ahead, then, and start the discussion.  This is on donor deferral issues related to xenotransplantation.  It comes on the heels of a subcommittee meeting that was held recently to discuss these issues, and the introduction and background is going to be given by Dr. Andy Dayton.  Andy?
DR. DAYTON:  Could I have the first slide?  The title to this talk is the implementation of precautionary measures to reduce the possible risk of zoonoses by blood and blood products from xenotransplantation product recipients and their contacts.  I have updated this committee in the not‑too‑distant past on xeno issues.  I will just focus on a few basic definitions to jog people's memories and to help the members of the public who aren't as familiar with xenotransplantation issues.
Zoonoses are infectious diseases of animals that can be transmitted to humans through exposure to or consumption of animals.  Xenotransplantation is any procedure that involves the transplantation, implantation, or infusion into a human recipient of either live cells, tissue or organs from a non‑human animal source, or human body fluids, cells, tissues or organs that have had ex vivo contact with live non‑human animal cells, tissues or organs.
Xenotransplantation products include live cells, tissues or organs used in xenotransplantation.  By way of exceptions, biological products, drugs or medical devices sourced from non‑living cells, tissues or organs from non‑human animals, including but not limited to porcine insulin and porcine heart valve, are not considered xenotransplantation products.  So, for instance, vaccines are generally not considered xenotransplantation products, even though they overlap in many characteristics with xenotransplantation products.
Because transplantation necessitates disruption of the recipient's usual protective physical and immunologic barriers, xenotransplantation may facilitate transmission of known or as yet unrecognized zoonotic agents to humans.  So it's not just a problem of getting animal viruses, it's also a problem of getting adapted viruses, and xenotransplantation in many cases theoretically can favor adaptation.
Some xenotransplantation product sources, particularly pigs, are being genetically modified in ways that may foster adaptation of zoonoses to human receptors.  I discussed some of the details of these technologies the other year, and the critical take‑home is just to remind you that there are many factors in xenotransplantation which predispose to adaptation.  Some of them involve in this case genetic manipulation of the donor animal, and others involve things like immunosuppression of the human recipient.
Some xenotransplantation procedures maintain a barrier between host and foreign tissue, and it depends on the particular technology used.  This barrier can be involved in transplants or implants into a recipient.  It can also be involved in ex vivo exposure.  But even when such barriers are non‑permeable for virus, the barriers can fail, and therefore situations such as this do represent a risk that requires serious consideration.
Now the risks of zoonotic transmission to xenotransplant recipients and their contacts remain undefined in many cases.  I should say the outer limits of risk remain undefined.  Some risks are well known.  And of course the history of introduction of HIV into the human populations from simian sources, not even‑‑and HTIV‑‑not even involving xenotransplantation situations, makes us doubly wary of the unknown.
We also have to balance our worries about the risks of xenotransplantation with the immediate risk to public health of blood or plasma becoming unavailable.  Certainly this committee needs no reminding of that.  Withdrawal of plasma derivatives to address even small numbers of unsuitable donations could cause serious product shortages.
Now, how many xenotransplantation recipients are there?  Okay, these are very iffy numbers, and they won't add up, and the reason they don't add up perfectly is because they are so iffy.  Probably there are about 1,000 or less than 1,000 in the U.S.  It's not 10,000; it's probably not 3,000; probably under 1,000.
Of these roughly 1,000, probably 550 have had autologous transplants of cells grown for long periods of cells grown for prolonged periods on a monolayer of a well characterized murine tissue culture line.  The product in particular considered in our minds here is the Epicel.  Probably about 500‑‑there are only probably about 50 or 100, very rough numbers again, of the classic xenotransplantation recipients.  And I point this out to you so you'll have a handle on how big a threat in numerical terms xenotransplantation is to the blood supply.
Just to highlight some of the recent chronology of events related to this talk, on December 23rd of '99 we published the draft guidance document, which is the precautionary measures to reduce the possible risk, etcetera, etcetera.  This is a draft guidance document.
On January 13th of this year the subcommittee, the Biological Response Modifiers Advisory Committee Subcommittee on Xenotransplantation, or for short, Xeno Advisory Committee, met.  There were several members of this committee participating in that committee.  And they discussed the highlights‑‑for that committee we discussed the highlights of the draft guidance document and voted on several recommendations.
In general, in rough terms, the Xeno Advisory Committee felt it was in its purview to address the scientific issues, and they had a general preference to have the implementation issues devolve to this committee, the Blood Products Advisory Committee.
Now I'm going to go through the votes that that committee made, because I think they are a very excellent way of summarizing the nature of the discussions, the results of the discussions, and also how unanimous or split the decisions, the recommendations were.  There are about 10 or 11 different questions here they voted on.
First, should xeno recipients be indefinitely deferred?  And that was a very easy one.  That was unanimously "yes".
Now, the draft guidance document said‑‑had discussed what to do with close contact of xeno recipients.  The Xeno Advisory Committee felt that the "close contacts" was too broad a definition to deal with in terms of contacts relevant to deferral issues, so they decided to limit contacts of significance for deferral and withdrawal policy to "intimate" contacts as opposed to "close" contacts.  Now, again there was pretty strong sentiment for this.  "Yes" was nine, "no" was one, "abstain" was three.
But it's very important to realize that "intimate" was never defined.  In fact, it was said, "Well, we all know what `intimate' means."  So we are not sure that we know what "intimate" means even yet, but we're going to try later on perhaps a further definition of it than we got that day.
Then, using the undefined "intimate" contacts, should we defer intimate contacts if xenotransplantation product recipients.  It was somewhat split, but the vote was in favor of that, nine yes, seven no, to defer intimate contacts.
Now, the issue of‑‑in the guidance documents, draft guidance documents, we had recommended to defer health care workers who had had percutaneous or mucosal exposure.  After discussion of whether health care workers who have had exposure to xeno recipients should be deferred, the committee did vote unanimously "no".  However, we probably‑‑we feel that there should be some reexamination of this issue, and I'll get back to that later in my talk.
Then, should we allow case‑by‑case exceptions for deferral, such as when exposure has been to well characterized cell lines?  Well, again, case‑by‑case gives us a lot of leeway, and the committee was unanimously in favor of that.
Should we withdraw whole blood and unpooled blood components for donation by a xeno recipient, for example, unpooled plasma, source leukocytes?  This was‑‑the committee was unanimously in favor of that.
Now, should we withdraw plasma derivatives, such as pooled plasma, for donation by a xeno recipient?  And again this is the xeno recipient, not the contact.  And again it was felt unanimously "yes".
Now, when you get to pooled plasma, the issues got a little more complicated.  Should we withdraw plasma derivatives, pooled plasma, for donation by an intimate‑‑I'm sorry.  When we get to intimate contacts, it gets a little more difficult.  Should we withdraw plasma derivatives or pooled plasma for donation by an intimate contact of a xeno recipient?  And here it was somewhat split.  Only four voted in favor of it.  A majority, though, nine voted against it, with three abstentions.
The committee also decided, for the issues of pooled plasma and intimate contacts, not to distinguish between a xeno situation which had been involved in non‑human primate or any other animal.  The original draft guidance document had suggested handling the two differently, but they had identical votes to handle them this way.
Should there be case‑by‑case exceptions to withdrawal of pooled products for exposure ex vivo, for example, to well characterized cell lines or across a physical barrier, again case‑by‑case?  And the vote was "yes" unanimously.
Now, an issue which we're going to be discussing today was brought up, should we add‑‑and I'll show you what I mean‑‑about the series of xenotransplantation questions to the donor deferral questionnaire.  In the guidance document we had recommended an admittedly fairly complex set of questions to be added to the donor questionnaire, and there was a lot of sentiment against that, as there often is to adding questions to the donor questionnaire, and particularly complicated ones such as we presented, and the committee voted unanimously against that set of questions.
Now, I'm just going to preview the questions that you're going to be asked, that we're asking you to vote on‑‑of course, you can add to that or modify it‑‑basically to give you a heads‑up so that you can follow some of the proposed changes we're proposing‑‑some of the changes we're proposing for the draft guidance document.
And what you will actually be given later on is, we have proposed language concerning, and I'll give you that language, xenotransplantation deferral issues to be added to educational material required to be read by donors before donation, and the question will be:  Does the committee agree that donors should be required to read this before donation?
And then the second question, we have proposed modifying the blood donor questionnaire to intercept xenotransplantation recipients and their intimate contacts, and we will be asking you:  Does the committee agree with the proposed modification in the questionnaire?
And with that preview, let me now go into the key changes that we have proposed to make to the draft guidance document which are based on our interpretations of the sentiment of the Xeno Advisory Committee.  Several of these slides will have "old" on the left and "new" on the right.  "Old" is perhaps not the best nomenclature.  That refers to the draft guidance document that is published, draft guidance.  "New" is referring to changes that we propose to make to it, or what's going to be new.
And instead of the old definition of "close contacts," we will simply remove the definition of "close contacts" and insert a definition of "intimate contacts."  And this definition of "intimate contacts" includes persons who have engaged repeatedly in activities that could result in intimate exchange of bodily fluids with a xenotransplantation product recipient, for example, sexual partners, household members who share razor blades or toothbrushes, and health care workers or laboratory personnel with repeated percutaneous, mucosal or other direct exposures.
In the draft guidance document, the older document, we had called for deferral of close contacts.  The new one will call for deferral of intimate contacts.  The key take‑home there is that the definition of contacts to be deferred has been narrowed considerably, going from "close" to "intimate."
Now, in the old guidance document we had suggested deferral for health care workers with percutaneous or mucosal exposure.  Now, with the new definition of intimate contacts, health care workers are included in the definition of intimate contacts, so they would be deferred.  However, and this was a consideration discussed by the Xeno Advisory Committee, what's important to remember is that under this definition, yes, they are included, which they weren't before, but only if the exposure has been intimate and repeated.  So that takes you to a fairly restricted set of health care workers.
Below on these slides I've listed some of the relevant votes from the‑‑and I believe you have copies of that in your handout‑‑from the Xeno Advisory Committee.  Those are the same votes that I just read out to you individually.
In the new guidance document, again following the suggestions of the committee, we're calling for withdrawal of plasma derivatives or pooled material for donation by any xenotransplantation product recipient.  There will be certain exceptions.  And no withdrawal of plasma derivatives for donation by intimate contacts of xeno recipients.  Again, there is‑‑the primary consideration here was the threat to the plasma supply of having to withdraw possibly a small number of donations which could have serious repercussions.
And, again, this is not terribly different from the old document, but I remind you that we have allowed ourselves to have case‑‑in the new guidance document‑‑we allow ourselves to have case‑by‑case exceptions to deferral and/or withdrawal for donation by xenotransplantation product recipients when the exposure has involved only well characterized cell lines, or when the exposure occurred only across a physical barrier.  The emphasis here is on case‑by‑case, and also that we‑‑such situations may be considered.
Now, this doesn't show well on the slide because it is fairly involved.  I think it is worth reading out because it is an implementation issue, which is one of the two questions here.
What is here on this slide, and also you have a copy in your handout, is the proposed modification of the reading material that donors will be asked to read or required to read before they donate.  Our staff has done a wonderful effort of bringing the‑‑of taking the level of the language to a level that can be understood, I think it's what, a fifth or seventh grade level you have to make it understandable to, and they've done a very good job of bulletizing the key information here.  And I'm going to read through this with you because it's one of the voting questions.
We want to include the following information in the educational material presented to donors before donation:
"Do not donate blood or blood products if you have ever been exposed to animal organs, tissues or cells during a medical procedure or treatment.  An individual may be exposed to animal organs, tissues or cells by one of the following medical procedures or treatments:  receiving a transplant of a living organ, tissues or cells from an animal; having blood or other body fluids removed from your body, passing it through a machine or procedure which exposes your blood or body fluids to living organs, tissues or cells from an animal, and then returning it to your body."
"Do not donate blood or blood products if you have ever had intimate contact with an individual who has been exposed to animal organs, tissues or cells during a medical procedure or treatment.  Examples of intimate contact activities include sexual intercourse; sharing of needles, toothbrushes, or razor blades; laboratory or health care workers who may experience repeated direct injection or mucosal exposure to body fluids."
We're going to ask you to vote on whether you want this added or not, and if you do, we also welcome comments to modifications of the language, etcetera.
Now, the next issue is again a key implementation issue, and this involves a voting question, and this involves modification of the questionnaire.  Now, in the old guidance document‑‑and you have that before you, but there is, as I mentioned, a fairly complicated series of questions, we are proposing to modify‑‑we are proposing to get rid of those and to do a much simpler modification to the questionnaire.  And what we want to focus on, is we want to modify the current AABB standard donor questionnaire question on transplantation and transfusion.
And up here I have listed how the question currently reads.  The question currently reads"  "In the past 12 months, have you received blood or had an organ or tissue transplant or graft?"  On the next slide I'll show you how we want to modify that.
First, what we want to do is to change that question so that it will now read:  "In the past 12 months, have you received blood or had an organ or tissue transplant or graft from a human?"  We feel that's a very straightforward and simple modification, and not overly complex.
Then after that question we would insert a nested set of questions, and this one underlined here is the key one to consider because that's‑‑if it doesn't pertain to you, you don't get into the more complicated nested questions.  And the question here that is supposed to capture the people we want is, "Have you or anyone you know ever been exposed to animal organs, tissues, cells or transplants as part of a medical treatment?"  So if that doesn't apply, then you're out of the xeno questions; you don't get into any of the complications.
Now, of course, what does it mean if you know someone?  Well, if you know someone who is a xeno recipient, then you get into these subset questions, these nested questions which we have also tried to keep fairly simple.  And to read that:  "If the answer to this question A. here is yes, were you the one who received the medical treatment?"
And if the answer to that were‑‑well, then there is a subcategory to that:  "If the answer to II.A.1. above is no, did you engage with the treated individual in behaviors which could involve the repeated exchange of body fluids, such as sexual intercourse, or sharing of razors or toothbrushes, or were you repeatedly exposed to cells, tissues, organs, or body fluids from such individuals through your mouth or eyes or open wounds or sores?"
Again, that gets pretty complicated at that point, but there are two things to take into consideration here when you worry about the complication of that question.  First of all, it's a nested question.  Most people won't get to it.  We specifically designed it so that these two very simple questions will intercept most of the people, will take most of the people away from the more complicated questions.
Secondly, although this is a complicated question, donors will have been required to read the material I quoted you before explaining what these issues meant and going into these in detail.  We feel that between the two instruments, the addition to the educational material and this nested subquestion, we should be able to effectively capture the people we want to capture without making the questionnaire overly complicated for the vast majority of people who answer it.
And then the guidance is that prospective donors answering yes to any of the questions above should be deferred.
I want to just come to a close, again to reexamine or to get back a little bit to the health care worker issue, and there are important factors distinguishing exposure of health care workers to xenotransplantation product recipients from people such as abattoir workers and veterinarians who get exposed to animals.  The reason I bring this up is because this was discussed at the Xeno Advisory Committee, but we felt at this point needed emphasis or reemphasis.
And please remember that the xenotransplantation product recipient represents generally a long term, intimate apposition of xenogeneic tissue.  Not always necessarily long term, but in the classic case, yes, long term.  Even something like Epicel is fairly long term.  This apposition is generally under conditions of host immunosuppression or even a lack of an immune system, which may allow abnormal amounts of xenozoonotic replication, thereby favoring adaptation.
And, finally, in some xenotransplantation scenarios, as I have mentioned, genetic modifications of the transplanted material may pose the risk of additional avenues of xenozoonotic adaptation.  So, again, the health care worker's and laboratory worker's situation is very different than the abattoir, slaughterhouse worker's or veterinarian's or farmer's.
And now, Linda, I am going to stop here, and then we have‑‑the next two slides are the questions, but I guess there should be a discussion first?  How do we do that?  And then if you want the questions, they're on the slides.  So I'll turn it over to you.
DR. HOLLINGER:  Yes.  Dr. Epstein?
DR. EPSTEIN:  Andy, could I get you to clarify one apparent inconsistency.  In the proposed donor educational material, in the second highlighted sentence, you say, "Do not donate blood or blood products if you have ever had intimate contact with an individual who has been exposed to animal organs, tissues or cells during a medical procedure or treatment," whereas the actual deferral recommendation is only if you have had repeated contact.  So I'm just asking whether that is a deliberate inconsistency or something that should be corrected before the discussion.
DR. DAYTON:  I think when we originally wrote the sentence, we felt that the explanatory material would go into repeated, but if it doesn't, we should change that so it does.  That's a fair point.
DR. EPSTEIN:  I mean, I think it would be reasonable for the question to the donor to ask about ever, and then there could be follow‑up query whether it was repeated.  But to up front defer or suggest that donors self‑defer for isolated single time exposure would be inconsistent with the proposed deferral.
DR. DAYTON:  Well, it may be‑‑first of all, if you look carefully here, for the health care workers and laboratory there is‑‑"repeated" is mentioned.  For sharing needles, for instance, maybe we don't want to emphasize the repeated nature of that, or even for sexual intercourse.  Again, if it's going to lead to self‑deferral, I don't think we're going to lose many people.  So I think to be correct we should have the repeated in but, you know, this is not something that's necessarily going to lead to withdrawal, which is the big issue, big worry.  We could modify that
DR. EPSTEIN:  Well, I think the committee could discuss whether we want an over‑inclusive self‑deferral, but I think for purposes of the committee discussion we ought to propose them as consistent; so, in other words, revise the‑‑
DR. DAYTON:  We can just‑‑we could change.  I know where that came from.  It was getting away from the 12‑month concept that is seen in human transplantation, and we could change that.  You know, "Have you had repeated intimate contact," that's very easy to do.
DR. HOLLINGER:  Yes?
DR. SIMON:  I want to ask a question.  I didn't go to this workshop and I'm not up on this field, and I've asked a couple of people about this since I got the material.  But from what I'm told by them, something like a porcine heart valve was not meant to be covered, and yet the way the question is phrased, if you had a porcine heart valve‑‑now, people who have porcine heart valves ordinarily wouldn't be donors, but their sexual contacts might be.  How are we dealing with that issue, as to what's okay in terms of animal tissue and what's not?
DR. DAYTON:  Well, the way this is written, it specifies "living."  We might have to add language excepting things like that.  That's a good point.  People are going to be confused on that.  Again, it's very hard to write this‑‑ and we absolutely invite comments like this‑‑it's very hard to write this at a level that's very easy for non‑sophisticated laymen to understand.  Certainly in all of our guidances we say "living" and we mention that issue specifically, and we welcome comments on how to make this language simplified.  Because I don't think a standard person who had had a porcine heart valve, they may not know whether it was living or not.
DR. SIMON:  Yes, and it says any individual who may be exposed, if you have ever been exposed to animal organs, tissues or cells, is the way you start it.  Now, you do have in the bullet‑‑well, someplace I guess you have "living".
DR. DAYTON:  Yes, yes.  No, but it's a fair point.  That's a fair point.
DR. SIMON:  Okay.
DR. HOLLINGER:  We're going to move on.  We're going to have questions you can ask Dr. Dayton in just a second, but I want to go to the open public hearing first, and then we'll come back to the questions and Dr. Dayton will be glad to answer any questions you have.
Yes?  First I want to call on Dr. Louis Katz, who is going to speak for both the AABB and ABC, I believe.
DR. KATZ:  We had in fact as organizations not prepared specific statements for this meeting.  You have the AABB's written comments on the docket in your packet, I believe, and I do want to emphasize some of the high points in that.  In addition, I have had discussions with representatives of the American Red Cross, and what I am going to say is consistent with their position, although I am not an official representative of the Red Cross.
Our organizations recognize the important potential risk of transmitting zoonotic pathogens to patients by this route, and agree that xenotransplant recipients as defined are unacceptable donors of allogeneic blood and tissue.  Parenthetically, because of donor restrictions regarding medication used in general health, virtually no xenotransplant recipients as defined would be qualified blood donors at this time.
The theoretical risk of zoonotic transmission was well articulated in the August '96 document entitled "The draft Public Health Service (PHS) guideline for infectious disease issues in xenotransplantation," which states specifically, and I quote:  "Consent forms should stated clearly that xenograft recipients should never, subsequent to receiving the transplant, donate whole blood, blood components, source plasma, source leukocytes, tissue, breast milk, ova, sperm, or any other body parts" if they have any left‑‑it doesn't say that‑‑"for humans."
The language appropriately recognizes, and this is we think a key point, the primary responsibility of the transplant community for the apprisal of their patients about these zoonotic risks.  We believe strongly that this aspect of the Health and Human Service guidance should be implemented, even pending formal implementation of the draft guidance from 1996.  FDA can insist on inclusion of such information in consent procedures as a condition for acceptance of clinical protocols for xenotransplantation.  And I would hope that Dr. Dayton or somebody from FDA can tell us whether that is ongoing at this point or not.
Blood collection facilities can reinforce the prohibition on donation by including xenotransplant exclusions in our written materials to blood donors as required study before each donation.  This would avoid the issue of time‑consuming and, in all due respect to Dr. Dayton, we believe still confusing and certainly unvalidated FDA questions to the donor interview.
The written materials that we already provide to donors prior to donation include the following information:  an admonition not to donate in order to receive test information; description of the signs and symptoms of AIDS and the behaviors that are associated with the risk of HIV infection; a statement to the effect that you'll be tested for, and then a long list of I believe seven agents that we're looking for now; a statement that they will be deferred if positive in infectious disease testing; a statement apprising them that the relevant public health authorities will be notified if required; and a request that they call after donation if they recognize problems that they didn't recognize at the time of donation.
Now, that's the written material they get already.  Okay?  That's not the donor screening interview, which is already lengthy and complex.  The AABB Uniform Donor History sanctioned by FDA contains 32 separate elements that include inquiries into highly sensitive personal areas, including sexual activity and drug use and references to such rare diseases as babesiosis, transmissible spongiform encephalopathies, etcetera.  The FDA proposes to add what we would consider an additional complex set of nested questions to this process.
The REDS investigators, Williams, et al. in JAMA in '97 reported that approximately 2 percent of anonymously surveyed accepted blood donors admit to deferrable risk on anonymous interview, and it is our suspicion that a substantial proportion of this is due to the length and complexity of the donor interview.  Our concern is that increasing the complexity of the donor screening process for theoretical risks may detract from its efficacy for documented risks like traditional viral transfusion associated infections and malaria.  The result could be a paradoxical decrement in transfusion safety.
We maintain that the proposed donor questions in the draft we have seen today remain arcane, and suspect that their addition to the current donor screening process will produce confusion.  At a minimum, we would ask that additional questions proposed by FDA for the reduction of a theoretical risk be validated for sensitivity, specificity and predicted value‑‑predicted value may be hard at this point‑‑before being added to the donor interrogation process.
The requirement for deferral of contacts at this point is unsupported by evidence of transmission of potential or unrecognized pathogens to contacts after xenotransplantation.  Again, the database is small.  We are still concerned, however, that this is a slippery slope from deferral of such donors to disqualification of large populations with very significant occupational animal exposure, including abattoir workers, farmers, veterinarians, medical researchers working with large animal models.  My concern is acute because I run a blood center in Iowa.
We suggest that a risk assessment be undertaken amongst those with close contact to the relevant species for evidence of potentially transfusable disease associations that would support zoonotic transmission of disease‑causing organisms.  Given the small number of xenotransplants currently being performed in this country and the potentially very large populations with contact in non‑human primates and swine, these epidemiologic studies can be carried out long before xenotransplantation becomes prevalent and constitutes a significant zoonotic threat via the contacts of xenotransplant recipients.
Thank you for your attention.
DR. HOLLINGER:  Dr. Katz, do you know for a fact, do you have data that suggests that the reason they didn't answer those questions was because of the length of the question, or are you just making an assumption on that?
DR. KATZ:  That's basically personal communications with the REDS people that did that study and their speculation.  I think that's an important point.
DR. HOLLINGER:  But that was unlinked, if I remember right.
DR. KATZ:  Yes.
DR. HOLLINGER:  That, they couldn't account for it.
DR. KATZ:  Yes, it remains speculation.  And I guess the other anecdotal source of information on this is the questions that we get from our donors during and after screening, that indicate pretty clearly that some of the more complex questions are not really very well understood.
DR. HOLLINGER:  I think, Dr. Shapiro, you had a comment?
DR. SHAPIRO:  Yes.  Along this line‑‑
DR. HOLLINGER:  Can you state‑‑
DR. SHAPIRO:  Yes.  Ariel Shapiro.  I work at Life Service Blood Services in Chicago.  I would, because of the opportunity for confusion among the donors, and I work very closely with them, I think it would be very important to put up front on the proposed screening procedures, that you indicate "do not donate blood or blood products if during a medical procedure or treatment" if that's the intent, and then go on to the exposure to animals.  Because we have a fair number of donors that I have been called on, that have animal bites, or they have injected themselves, they have accidentally injected themselves, like giving the cats insulin or the dogs insulin.  So I think if we want to try to make this more specific, we need to really drive home that this is during a medical procedure.
DR. HOLLINGER:  Thank you.
Could you just please‑‑
DR. CHAMBERS:  Yes, Linda Chambers.  I'm a senior medical officer for Red Cross.
I would like to first verify that Red Cross endorses the statement you heard earlier from Dr. Katz, and I would like to just read into today's discussion the highlights of the official Red Cross statement on the issue that was brought to the Xenotransplantation Subcommittee meeting in January:  the highlights being that the American Red Cross agrees that a deferral policy for xenotransplantation is appropriate; however, believes that only donors need be deferred, that close or intimate or otherwise defined contacts should not be considered within the scope of the deferral; and that specifically donor questions to address the issue are unnecessary.
I would like to expand on that, not as an official representative of the Red Cross but with my own personal comments, and that is that I think it's important to appreciate in the big picture that there are a number of ways of implementing a new expectation for donor eligibility and a new donor eligibility criterion.  They run the gamut from a question on the questionnaire, the information provided to the donor, and the instructions given to the person evaluating the health history of the donor.
I believe it's important to reserve the specific questions to the donor and the information that's in the "what you must know" document that goes with the donation for those components of donor eligibility that require specific attention on the part of the donor and are the most important.  In other words, I think there's a limited amount of time and attention, and it's important to take your best shot at eliciting from the donor the kinds of health history and behavior parameters that will most substantively affect the safety of the transfusion.
In earlier discussions in talking about the post‑donation information as regards plasma recalls, this was touched on briefly, but I think is relevant to this discussion as well:  When you look at circumstances where donors call back with new donation information, and that's all reported to FDA, those are all accidents or errors that are available to be analyzed and evaluated, you will find that there is information that is relevant but not all that important.
For example, the donor that might call back and say in fact they had hepatitis when they had EBV at age 15, that's interesting but probably not substantively important for the safety of the blood products.  And then there are donors that call back after their 15th donation and only then report that they were an IV drug user, or the sexual partner of an IV drug user, or a man who had sex with another man since 1977, or something where you have a behavior that you know not only captures significant known pathogen risk but also covers what we believe to be major routes of exposure for perhaps emerging or unidentified or untestable yet blood transmissible pathogens.
Not all those reports are donors who have a broad streak of denial, and I would speculate, and I think it's as speculative and as valid a speculation as the concern about xenotransplant recipients having transmissible agents, that the failure of those questions to be answered properly with the earlier donations comes from donors who are overwhelmed by the information and overwhelmed by the process of the blood donation.  Which means that anything added into the donor information, in the form of the health history questions specifically or the information they have to read, seriously runs the risk of distracting the donor's attention from what we know to be important questions.
So I would personally endorse strongly the concept that anything new to be added to either of those documents be verified before it's put into use as not a question that's going to divert attention and adversely affect the accuracy or completeness of questions that we know are more important in terms of the ultimate blood safety.  Thank you.
DR. HOLLINGER:  Thank you.  Any‑‑yes?  Please state your name and your organization.
MR. HEALEY:  Sure.  My name is Chris Healey and I'm with ABRA.  We agree with many of the comments you've already heard.  We also agree that xenotransplantation recipients should not be blood or plasma donors.  However, we think the current donor screening procedures already exclude these donors.  Donors are currently asked whether they're under a doctor's care, whether they have had any major medical procedures in the last year, whether they have received organ or tissue transplants, blood transfusions.  So we think these donors are already being excluded.
A piece of information that I think hasn't been addressed or presented to the committee, that might help inform the decision‑making process, is the types of care and selection and cell line treatment that the donor animals receive.  At the Biologics Response Modifier Subcommittee meeting I think there was a representative from one of the xenotransplantation communities, and he characterized the donor animals as being, you know, very carefully selected, and cell lines as being purified and so forth.  So I don't have any personal knowledge about that, obviously, but I think that is some information that the committee could use in its deliberation.
DR. HOLLINGER:  Thank you.  Anyone else in this session on the public hearing?
[No response.]
DR. HOLLINGER:  If not, we're going to close the public hearing.  We'll now open it up for committee discussion.  Perhaps, before we do, we should have the questions that you want us to look at, Andy.
DR. DAYTON:  Okay.  This is the first question.  How do you want to do it?  Do you want to just discuss, or do you want to have the questions or‑‑the next slide has the next question, so do you want me to read this question?  Okay.
We have proposed language concerning xenotransplantation deferral issues to be added to educational material required to be read by blood plasma donors before donation.  That's that bulletized document you have.  The question is:  Does the committee agree that donors should be required to read this material before donation?  And if you are interested in this kind of material being added but would like to make comments on what we have actually suggested, we would request committee members wishing to modify the proposed language to submit revised language to the FDA within the next two weeks.
DR. HOLLINGER:  Okay.  I think we'll look at this issue here, what I think Andy's talking about, what is on page 5, basically, of your handouts.  Well, it's the second page 5 there.
DR. DAYTON:  The top of it says "Proposed Modification of Screening Procedures," Roman numeral I.
DR. HOLLINGER:  Thank you, Andy.  It's the second set at page 5, on planned changes to guidance.  Okay, and I think that's the issue that's brought up here.  It's asking about the educational information, not about the information to the donor at the time of screening.  This is the stuff that you get prior to donating.  So I'm going to open this up now for discussion.  Yes, Dr. Macik?
DR. MACIK:  One problem is, how does the donor differentiate between what's an organ, tissue, fluid?  Rarely used, but an example would be porcine Factor VIII, and in particular a person who acquires Factor VIII deficiency might get porcine Factor VIII, completely clear that disorder, and 10 years later be wanting to donate blood and say, "Well, I got something from the pig one time."  How are they able to distinguish these things?
So I think there's some need for clarification, you know, on just what these things are.  I find it still confusing to try to put this into perspective, confusing even for me on some levels, and I think for a donor it would be even more confusing.
DR. HOLLINGER:  You're saying that perhaps there ought to be some exclusionary things?  This does not‑‑well, I mean, for example, like you're talking about, like insulin possibly?
DR. MACIK:  They might know, "I got insulin from a pig," or "My doctor said this is bovine or pig," or you know there's a lot of products now that are out there.  Depending on the level of sophistication of the patient, they may even actually know a little bit too much and add more confusion.  "I got a recombinant product that was made from a hamster kidney cell.  I was exposed to an animal product."  So I think there's some issues here that need to be refined a little bit.
DR. HOLLINGER:  A vaccine from E. coli or something.  Yes, Dr. Schmidt?
DR. SCHMIDT:  Of course I wasn't at the meeting where all of this was thrashed out, and I have some specifics, but sort of a philosophical statement on this, the whole question of where bugs come from.  There was smallpox and tuberculosis and influenza and AIDS, and there's that whole sea of waterfowl off South China, and that's all in the background.
And going back a long time, in the 19th century it was parasites and bacteria for which we can sterilize and we have vaccines and chemicals, and in this century antibiotics for bacteria; and the 20th century was the century of viruses, for which we can sterilize and have vaccines but we have not been able to cure a single one.  And this, at least the Nobel Prize Committee says, is the century of prions, for which we can't sterilize, we have no vaccines, and we have absolutely no cures.
And I think we have to keep that in mind and not talk about the old stuff.  I think this came up earlier.  But we don't know, this is the first meeting of this committee in the 21st century, and I think we have to look ahead rather than look back.
And then just some comments on what the day‑to‑day‑‑I think what I was hearing Jay talk about was the problem of "ever" had intimate contact and down below with the health care workers it would be "repeated."  Well, those two things are incompatible, those statements, "ever" versus "repeated," and I think I heard Jay leaning towards having both of them as sort of "repeated" contact, where I would want to take the position, if you have ever had intimate contact, and for a health care worker it wouldn't have to be "repeated."  I mean, one shot is what's going to do it.  So in this text, as we go along, I'll submit in writing the proposal that it's not a question of "repeated."
The other thing in here is this problem of sexual intercourse.  We're reading now that many young people don't consider some things as sexual intercourse.  Maybe that all could be changed to "sexual contact" and not use the word "intercourse," but a sexual contact.  That's broader.  Maybe it's too broad, but I will send that proposal in anyway.
DR. HOLLINGER:  Yes, Dr. Linden?
DR. LINDEN:  I have noted the same thing that Toby did.  On the first statement, it's overly broad to say if you have ever been exposed to organs and tissues because it would include some of these other things, as Gail mentioned.
But I also share Linda Chambers' concern that this is just too long and too complicated, and it's going to divert from people really understanding the material.  We know a lot of the donors don't really read the brochure now, anyway.  So I think if you're going to have anything, it should be limited to one or two very succinct sentences, and if they have any questions they can ask about it.  But this material, I'm concerned, is just too long and detailed and it's just going to confuse the issue, and the way it's phrased is also, it's overly broad, so two concerns.
DR. HOLLINGER:  Thank you.
Dr. Mitchell?
DR. MITCHELL:  Yes, I agree that it should be limited to two, maybe two, maybe as much as three sentences, but not more than that.  And also I think that a lot of the issues should be part of the training for the staff, and the staff should be able to answer questions about insulin and vaccines and tissue and that kind of things, rather than having it in either the questionnaire or the educational materials.
On the first sentence, I think that the specifics, I would not talk about either "ever" or "repeated," I would just take it out and just say, "have you ever had," and I think "been exposed to" is also very confusing.  So I would just say, "Have you ever received a transplant or a graft of animal organs, tissues," blah, blah, blah, and to me that's much more simple.  But I'll put something in writing for the specifics, but my point is that I think there should be one question, one question that's asked of everybody, and maybe the nested questions but‑‑
DR. HOLLINGER:  Now, Mark, we're just going to deal here with the educational aspect now.  These are not the questions to the donors.
DR. MITCHELL:  Right.  Okay.
DR. HOLLINGER:  So this section here is just on the material that they get before they even go and get the questions that they have for that.
Yes, please?  Excuse me just a minute, Mark.  Jay
DR. EPSTEIN:  Yes.  I just have a concern that, a little bit, it might be better to take the issue of the donor question before the issue of the educational material, for the following reason:  One of the proposals on the table is not to use a donor question but to utilize donor education and self‑deferral in lieu of a specific donor question.  And my concern is that if we deal with the comments on the educational material first, we're looking at the fact that, should the committee vote against a donor question, you might view the educational material in a different light.  You might want more of it; you might want it more expansive.  And some people may not feel influenced one way or the other, but others might.
DR. HOLLINGER:  How does the committee feel about this?  Do you want to deal with the question first, the issue about the question first?  I see a lot of nods.  Or not?  Okay.  All right, so we'll deal with the question first, then, that Mark had started addressing‑‑now you can come in there, Mark‑‑that he started addressing his question about.  So that's on the next page.
DR. DAYTON:  Do you want me to read the second question?
DR. HOLLINGER:  You could read that, yes.
DR. DAYTON:  Okay.  We have proposed modifying the blood donor questionnaire to intercept xenotransplantation product recipients and their intimate contacts.  Does the committee agree with the proposed modification to the questionnaire?
DR. HOLLINGER:  And that's on the next page, basically, with several parts to it.  So go ahead, Mark.  Why don't you go ahead with your‑‑
DR. MITCHELL:  Okay, and so I would say that the first thing, I would leave the original question about blood and organ or tissue transplant as it is.  I think it confuses if you say "from a human."  Then people will say, "What do you mean, from a human?  As opposed to what?"  And it will throw people off.  And, you know, people normally assume that it's from a human, so I don't think that there's a reason to‑‑I think it adds more confusion than it adds clarification.
Then the specific question that would have to do with xenotransplantation I believe should be similar to the statements that are made previously, and I believe that it should ask, "Have you ever received a transplant or a graft of animal organs, tissues," blah, blah, blah, and then may say something about intimate contact either as a second sentence in that same question or‑‑because I think if you say, "Have you or anyone you know," It is still very, very broad.  And so I would say, you know, that again as part B of that or maybe even a separate question, you would ask about intimate contacts, and then I think you can get into some of the nested questions.
But I think that you should only have one question, maybe two, that ask about the initial exposure through receiving a transplant or graft of tissues or cells and intimate contact with someone who has had that exposure.
DR. HOLLINGER:  Dr. Linden?
DR. LINDEN:  I have a comment and a question.  Then I'll have another comment after the answer.
For the people who weren't at the meeting, one of the issues discussed was the fact that a lot of the people who may have these procedures, particularly children, may not know of the risk and they may not know that they need to inform their sex partners.  So that you can ask, "Have you ever had sex with somebody who got an animal graft?" and they're not going to know that because the person hasn't told them.
So that I think the committee really felt pretty strongly that the most effective way to address this problem is to tell the recipients at the time, and their parents if they're children, that there is a risk of getting pathogens, whatever you want to call them, from these tissues or organs, and it is important that you, your child, not donate and tell sex partners that they shouldn't be donating blood, and that that really is probably the most effective way to go.
Dr. Dayton, given that the committee voted 16‑0 in favor of not having any questions, and opposition from all the blood banking organizations, could you explain, elaborate a little bit why the agency really feels it's important to have questions?
DR. DAYTON:  That's a fair question, of course, and we did give this a lot of thought before approaching it.  We felt that what they were largely focusing on was the very bulky‑‑they weren't focusing, the discussion did not focus entirely on the bulky set of questions, but we felt that the questions that we had proposed at that time were very bulky and cumbersome and confusing, in retrospect, and we felt that that was a major obstacle to putting them in, and we felt that the negative reaction to them was based largely on an inadequate design.
We felt that what we have come back with is considerably more simple, although by no means perfect, and we felt that there was a sufficient improvement in the simplicity of the questions that it was worth reconsidering in that light.
DR. HOLLINGER:  Yes.  Dr. Chapman has been asked also to join us as part of the discussion here from the CDC, so Dr. Chapman?
DR. CHAPMAN:  I just wanted to mention that when you're discussing rephrasing the informational material or the questions, you may want to refer back to that definition of xenotransplantation, because while it's true that it's clearer to say "have you received animal tissue" than "have you been exposed to," one of the components of the definition is that one of the ways in which xenotransplantation products are currently being used is as a sort of biologic dialysis for people in acute hepatic failure, and those people do not receive animal hepatic tissue, in the way that renal failure patients do not receive kidney dialysis machines; they are exposed to animal tissue the way that renal failure patients are exposed to kidney dialysis machines.
That may not influence, still, your recommendations on simplicity of wording, but you need to be consciously aware of that and refer to that definition when you make those recommendations to FDA.
DR. MITCHELL:  Could I respond?
DR. HOLLINGER:  Thank you, Dr. Chapman.
Yes, please, Dr. Mitchell.
DR. MITCHELL:  They are really not exposed.  Their blood is exposed, or their body fluids are exposed, and I don't think that people would perceive themselves as being exposed under those conditions.
DR. HOLLINGER:  Dr. Schmidt, and then I'll come back to you.
DR. SCHMIDT:  I saw something, I forgot exactly, but it relates to this, about physical barriers, and I don't know what the physical barrier to a prion is.
DR. HOLLINGER:  Dr. Boyle?
DR. BOYLE:  Thank you.  Since I ask questions for a living, I want to take this chance to make some observations.  Number one, if you can't ask the question simply, don't ask the question, because all you're going to get is a lot of error and a lot of confusion.  And if you're self‑administering this thing to a million or more people per year, the potential loss of people who are confused and say "yes" or "not sure" is a serious issue, given what we've been through recently.
Secondly, it is appropriate to have a committee of M.D.'s and Ph.D.'s agree about whether we should ask a question.  It is not appropriate to have them frame the question, at least in my experience, because they don't necessarily write very good questions.
Number three, if you are going to ask a question and you're going to administer it to a million people a year, please go through a process of cognitive testing to make sure that the average person who gets it can read and understand the question the way that you plan to do it, because it will save a lot of grief for a lot of people who will be reading those questions.
DR. HOLLINGER:  Dr. Epstein
DR. EPSTEIN:  Yes, I wanted to follow up on Dr. Linden's question.  I think that part of the agency's bias in putting back the proposal for a specific donor question comes from our experience with AIDS‑related behavioral risk questioning.  When we first introduced exclusion of donors based on AIDS‑related risk, it was done only through education to the donor and then donors were only asked if they had read and understood the material, and they later signed a statement that if any of the information pertained to them, that they wouldn't donate.
And what we learned over time was that that was a lot less effective at eliciting deferrable risk than following up with a question to the donor about their actual risk.  And, yes, that was belt‑and‑suspenders, but we did have actual experience that it made a difference.  And as I recall, Paul, you were one of the people that had studied that at a later time over the issue of whether direct questions about behavioral risk, including sexual behavior, would be a big put‑off to donors and whether it would be tolerated.
So, you know, we spent a lot of time agonizing over whether to move to direct questions, and what we learned was, (a) we could do it without putting off donors, as long as the rationale was clear, and (b) that it was important in making the self‑deferral into effective deferral.  That's not to say there was no utility of self‑deferral, only that it got better.
So that's an up‑front bias which I want the committee to acknowledge.  I also think that we could perhaps simplify the debate if we suggest that the real question for this committee is whether FDA ought to develop an appropriate question, rather than getting us bogged down in trying to design it here today.
We put in front of you our most recent effort to simplify a question.  I think we can take to heart the message that, you know, more scientific methods should be applied to doing it, but really the issue on the table is, should the appropriate deferral strategy include a direct question, one or two questions, well designed, and that that would be a better issue for the committee to cut on.
DR. BIANCO:  Mr. Chairman?
DR. HOLLINGER:  Yes?
DR. BIANCO:  Celso Bianco, America's Blood Centers.  I would like to make a couple of observations about this issue.  I was at the meeting of the Xenotransplantation Committee, and I think those are critical issues because they affect‑‑we should look at them as part of the forest, not each individual tree, and xenotransplantation is a tiny little plant in the middle of everything.
First, Dr. Boyle, it's 13 million volunteer blood donors, and a similar number of units collected from source plasma, and so the number is much bigger.
The second thing, there is a very big difference between risk questions, risk behavior questions that we ask to pick up somebody that may have been exposed to a virus through use of drugs or sex, and addressing a population of individuals that today are maybe less than 1,000, 2,000 in the country.  They are all part of clinical trials.  They are all known to the sponsors of the clinical trials.  Everybody has a name, has an address, has a physician.  We are choosing to ask 20 million people a question to find these thousand, instead of just going directly to these thousand people and telling them that they cannot donate blood and that their sex partners cannot donate blood.  I cannot see the logic of that.
And, finally, as an observation, even if it is very important, like CDC has pointed out, the issue of exposed to transplanted and all that, those are issues, but I can guarantee that somebody in liver failure, using dialysis with baboon liver, is not going to show up at the blood center to donate blood.  Thank you.
DR. DAYTON:  Blaine, can I make a comment?
DR. HOLLINGER:  Go ahead.  Yes, please, Andy.
DR. DAYTON:  There are several things I want to address here.  First of all, the complexity of the language in both the question and the proposed educational material.  I think Jay really did focus on what we should really be addressing, is do we want to ask a question or not.  I think you should realize that we certainly understood how complex this material is to question people.
The approach we took and suggested was, we know we're not going to catch them all on the educational material, we know we're not going to catch them all on the questions.  Let's make it very simple, and hope that the redundancy does the best job that it can.  So that, in terms of whether or not you want to ask a question, I want you to take that into consideration, that there are ways to handle it even if it's fairly complex, and they may not be perfect but they may be reasonably effective.
Now, the other point I wanted to address is, there have been‑‑numerous people have brought up the point that xeno recipients go through an informed consent, and there's every reason to believe that you can, except for juveniles who may not be aware that they have had a xenotransplantation product, transplant, there is every reason to believe that they can be effectively deferred from donation, but informed consent is not effective at reaching their contacts, and that's something we need to remember.
The point has also been made that, okay, it has not really been shown that their contacts are at risk and anything is going to happen, but it's very important to realize that one of the major factors behind this issue is, we don't know what is out there.  We don't want to end up with another epidemic like HIV.  If there is something there that's going to get out, that's where it's going to get out, because if it's going to be a threat to the population, it probably would be easily transmissible by intimate, close contacts, or intimate contacts.
So that was our thinking in going in these directions, and I hope you will remember those key points.  That's all I wanted to put in at this point.
DR. HOLLINGER:  Yes, Dr. Simon?
DR. SIMON:  Yes.  I would like to focus, then, on the question of whether there should be a question, and there is obviously an industry point of view here, and I guess as the industry representative you're not surprised that I'm supporting it, but I would argue against a question at this time.  While I think we shouldn't focus on the language, I don't believe the FDA would have come here without putting quite a bit of effort into framing a good question, and you can see how difficult it has been, so I think it's going to be very difficult to frame a good question.
I think this also runs counter to another major effort of the agency which Captain Gustafson told us about, which is to look at the donor questionnaire and try to shorten it and reduce it, to focus on the major issues.  And I would hope that that could go forward without‑‑with limited tinkering with the questionnaire in the interim because this is, you know, I think a process that has been used over the years, is that somebody has expressed concern about a risk and it's been noted by the agency and made its way into a question, and the questionnaire itself has never really been validated to determine that it actually leads to safety.
So I would hope that that effort could go forward and this effort be put on the back burner, particularly, I mean I think one wouldn't be reticent if one thought there was a risk there, but particularly since the committee was unanimous that we didn't need a question.  And on this issue of the intimate contacts, while I certainly understand the logic, the committee was very divided as to whether it was even important to defer intimate contacts at this time.
So I think there are a whole variety of reasons to argue against a question, or there are a whole variety of reasons why we should not adopt a question at this time to be added to the questionnaire.
DR. HOLLINGER:  Okay.  Dr. McCurdy?
DR. McCURDY:  I would like to second a couple of comments made by others.  Number one, I think if you need the information, you have to ask the question.  I became aware a number of years ago of a colleague who donated blood in a number of different blood centers around the country, ostentatiously took the pamphlet that he was supposed to read and stuck it in his pocket, and not once was he called by the blood center personnel that, hey, you're supposed to read that before you put it down.  So I think educational material, I agree with Jay that it has limits.
I also think that it would be highly desirable to get question writing people to help write the questions, and it would almost certainly be desirable to do some field testing before you put it in.  Now, if it's important to defer both xenotransplant recipients and particularly their intimate contacts, then I think you have to move forward and not wait until you review the entire questionnaire.
DR. HOLLINGER:  Yes, Dr. Chamberland?
DR. CHAMBERLAND:  A couple of thoughts.  I also want to re‑echo some of the comments that have been made, but in a little bit of a different direction.
I'm concerned that, as Dr. Simon said, that no matter how hard folks at FDA and others work with them, it's going to be extremely difficult to distill down into a simple question a very complicated situation.  And we've heard a number of people on the panel and in the open committee, open public hearing, bring up for instance the porcine insulin question, the porcine valve question.  Not only will it be extremely difficult and complicated to ask the question, but I think it's going to be very challenging to educate the people in the mobiles and the donor collection sites that have to then engage in a back‑and‑forth with the donor to really get to the heart of it.
I personally, and my colleagues in the Malaria Branch, for example, are getting questions from Mary Smith:  "I'm at mobile in Des Moines, Iowa"‑‑that's not really the place, Lou‑‑"but I've got a donor in front of me, and she's going back and forth about countries in Africa, and are these Group O countries?"  And it's very black and white:  "These are the countries that pertain.  Your person comes from a different country, hence I don't think we have a match here."  So just on something that we perceive to be fairly straightforward, in a field situation ends up I think sometimes being more complicated than we anticipate.
So because I think it's a very complicated question, and because I really do believe that our primary focus at least at this point should be on the xeno recipients themselves, which is, as has been stated, an extremely small population at present, although growing, likely to be deferred because of other questions that are asked in the history‑taking session, and because the transplant programs should be, through informed consent and other processes, informing these recipients, that that's probably a better way to go.
I would suggest two things.  One is, perhaps FDA or others‑‑I'm assuming that these transplant centers are fairly small in number.  Maybe I'm wrong, and I would appreciate anybody giving me some correct information.  But I would suggest that FDA perhaps, if they haven't already, consider going to these transplant centers or a sampling of them to see what currently is being done.  With what rigor are recipients being given information about the need not to donate?  Or if you want to extend that, their intimate contacts, etcetera, and examine that.
And then, secondly, sort of along the lines of what we do with new variant CJD, because I think there is a legitimate concern that's being expressed that we're really only on the beginning of a learning curve in terms of accumulation of epidemiologic and laboratory data, we're at a very early stage, that maybe as a sort of interim measure that there be sort of a systematic reassessment of the data every six months, every year, whatever people think that's a reasonable interval, like we're doing for new variant with an ad hoc working group, so that there is some sense that this is being actively looked at.  But I would say that maybe we're not quite ready yet for a question or maybe an information in a donor brochure.
DR. HOLLINGER:  Thank you.
Dr. Koerper?
DR. KOERPER:  I agree.  I think this is a very complex issue.  I myself am having trouble sorting out whether Recombinant Factor VIII made from baby hamster kidney cells is a‑‑you know, does that mean the recipient of Recombinant Factor VIII has been exposed to something?  I mean, it's complicated for us, as well as for the patients.
However, I do agree with comments that individuals don't read those brochures that they're handed.  I think there needs to be a statement in the brochure for those rare individuals who read it, but I don't think we can count on people reading it.
I also agree with Dr. Boyle's point that the questions need to be written and field‑tested.  For instance, this question II.A here is really two questions.  It's not one question.  And people are going to get so confused over "has anyone you know ever," and they're sitting there, "Well, was it Aunt Suzy, or was it my first grade teacher," that they're going to forget the point that they are‑‑you know, the first important point is, "Have you ever had this?"  So I personally feel that there does need to be one or two well crafted questions, but they have to be much simpler than this nested set of questions that we're seeing here.
I also agree with Dr. Mitchell's point that adding "from a human" to that first question is just going to also set off a whole train of "What are they talking about?" that people will then be diverted from the point of the question.
So I think we need questions.  I think they need to be extremely carefully worded.
DR. HOLLINGER:  Dr. Macik?
DR. MACIK:  Well, for one, if you look at the way the original question, the question that currently exists, you know, we don't have "human" there.  But I think one thing you just have to be very careful with and very simplistic is to say, have you been infused with, you know, have you gotten anything?
Why are you separating out human from animal?  If they've gotten a blood transfusion or had a surgery or had a transplant or had‑‑you know, do you have to specify was it animal or human?  Because you're going to be deferred regardless of the source, of where it came from, and it would take away maybe some of the confusion from that standpoint.
I just don't know if I want this to be a question or not.  I think at this point I'm so confused about‑‑I would find it very difficult to say whether I wanted a question or didn't want a question, having listened to a lot of things that are going on.
You know, I like the idea that we're being very prospective, we're thinking of some new risk that right now is very small but might some day be very big, and how do we get this‑‑how do we attach this early on in the process, before we find out when it's 500,000 people have had this and all of a sudden there's an infection, you know, to look at these issues early on.  But maybe we're going a little bit too early, getting back to the idea that most of the people who have xenotransplants, probably a very small group and probably already too sick to donate blood, and what risk do we really have from their intimate contacts?
I would also think it very unlikely that people who were being dialyzed on‑‑say a liver failure patient, that the discussion of whether or not they would donate blood ever even comes up in that informed consent or any discussion of their management at that time.  The critical situation you're addressing at that point, you're not going to think about later talking about donating or your wife donating.
DR. BIANCO:  Dr. Hollinger, I would like to make‑‑I would like to support the suggestion made by Dr. Chamberland.  Celso Bianco again.
And I would like to go one step ahead and suggest that the most effective way that FDA could deal with xenotransplantation issues and the potential risks of transmission of disease would be to establish requirements for all the sponsors of clinical trials that are related to xenotransplantation, that they provide an educational program to all recipients, their families, their contacts, and that show them the risks‑‑because we say "intimate contact" but we don't know if this couldn't be transmitted by aerosol, it is just an assumption that it would be transmitted like HIV‑‑that they should be very careful because that possibility exists.
It would be much more effective, and we could, since we know who these people are, we know where they are, if such a campaign, pamphlets, appropriate informed consents, appropriate discussions, an 800 number for xenotransplantation recipients and their families.  There are so many things that would be so much more effective than just putting a question to donors.  I really would like to support that proposal.
DR. HOLLINGER:  Mr. Rice, did you have a question?
MR. RICE:  Well, yes.  It may sound strange coming from me, but I kind of support Dr. Bianco and Dr. Chamberland.  I support Dr.  Mitchell, Dr. Linden, Dr. Boyle.  I think all of them had important points.
I think that, like somebody who may be exposed to CJD, this population, xenotransplant individuals, are pretty much well known.  We know where they are, and it may be more effective to target, as others have said, those particular avenues that we can identify the patient and basically educate there.
I think it would be quite difficult that someone who has had some sort of contact with someone who is a xenotransplant person, I mean, it isn't the first thing you say to somebody, "By the way, I'm a xenotransplant patient."  I mean, frankly, I'd ask some other questions before I'd ask that question.  And so here you've had sexual contact, you've gone on for three or four years, and now you're reading a question.
I mean, I think that maybe at some point a question could be designed, because I think that that is the‑‑ultimately the fail‑safe is that those are the people, that maybe the xenotransplant person hasn't really discussed this with everybody they meet in their lives‑‑that that could go on at some point in time.  But I think the merits of that question right now are‑‑well, I don't think there's any consensus.
DR. HOLLINGER:  Yes, Dr. Boyle?
DR. BOYLE:  I think I have a simple solution.  The critical question here is whether we need the question on the questionnaire to be able to identify these people.  We don't know whether we need it or not, and we're having to decide on this.
The simple solution is, have the FDA administer 50 of the blood donor questions to 50 people who have been through the transplant process.  If in fact they all fall out on one of the other characteristics, you know that.  If in point of fact half of them don't indicate anything else, then you know you've got a problem.  And if it's one or two one way or the other, I don't know, but at least we would have some real data, and it should be fairly simple to do.
DR. HOLLINGER:  Thank you, John.
Colonel Fitzpatrick?
DR. FITZPATRICK:  Dr. Chamberland said everything I was going to say.  I don't think we need a question right now, because of the complexity involved and all the questions that those questions lead to.  And the other is that when interviewing donors, of which I have done several thousand, a lot of them are going to say "I don't know," and then we are faced with how do we address that donor, and what FDA guidance are we going to get about the donors that say "I don't know"?
And I was at the advisory committee meeting, and my recollections from that is that there was a great deal of discussion about the ex vivo expansion portion of the xenotransplantation definition.  And I recall, and I don't have my notes with me, that the FDA was going to take those comments into consideration and consider refining the ex vivo portion of that definition, and I don't see that here.  And there were even discussions there about in vivo fertilization and exposure to animal cells during in vitro expansion in fertilization, and that's a whole area that is so broad that it's very difficult to put into a question or define.
And one more comment, and I'll be done, that I think it's all well and good to say we need to tell the FDA to go develop a question, but as we have heard over the past few years, there is not a process for question development for blood donor questionnaires.  So they don't have a process to go to, and we've seen them go back to our historic process of beating questions around the bush, bringing them to the committee, and then going back and trying to work it over, and we don't know if that works or not.
So we need a process to have a valid questionnaire, that we see whether it's effective or not, with pilot studies and random groups and with the appropriate set of questions in them.  And that's an even broader thing, but if you're going to go do a question, then you need a proper process to make the question.
DR. HOLLINGER:  All right.  I'm going to call for the question, then.  I'm going to call for the question here, Mark, if I can.  Oh, Jay, do you want‑
DR. EPSTEIN:  I just wanted to answer Colonel Fitzpatrick, that the question of ex vivo expansion was addressed by the Xeno Advisory Committee and a strongly voted recommendation was made that the agency could exempt both from donor deferral and product withdrawal, conditions where there was exposure to well characterized cell lines derived from animals.  So the situation you're talking about falls into the case‑by‑case exemption policy which is part of the current guidance proposal.
DR. FITZPATRICK:  But that's really hard to define in a question to 12 million donors
DR. EPSTEIN:  I understand that, but I think there's a little bit of confusion going on here:  Where does the sorting out come?  I think the concept is that if the donor has a positive history for some question asked, you then have the medical director sorting out whether that's a relevant history for deferral or not a relevant history for deferral, and FDA would be providing guidance and/or the FDA could be queried on a case‑by‑case basis.
We don't really expect the question to the donor to do all that sorting out.  I mean, that would be my answer also for issues like heart valves and, you know, porcine Factor VIII and recombinant made in BHK.  You might elicit those histories, but then the doctors sort it out, not the donors.
DR. HOLLINGER:  Mark?
DR. MITCHELL:  Yes, I think that the issue here is, you know, that xenotransplantation itself has a potential for developing new diseases.  Now, if we see the diseases, they're probably going to happen in the recipients first before they happen in any household contacts to those recipients.  It's a relatively risky procedure right now because we don't know and we have such small numbers.
And, you know, it seems that the approach would be better to actually track these people until we have good‑‑people who have received xenotransplantations‑‑until we have enough confidence in our abilities and in the safety of xenotransplantation, and then perhaps, you know, because it is so rare, perhaps‑‑I guess I've changed my mind‑‑I think that we should not have a question on that on the questionnaire, since again if we're tracking the individuals who are most likely to get disease, we will have some time to react if there's a disease that does develop among that group.  But I think it's important, so I think that, you know, maybe there should be something in the literature but not a question.
DR. McCURDY:  I think that we're not probably concerned with the recipients, although I could be wrong, because they're going to be relatively sick or have been relatively sick and probably not show up with donors, but I think we do have to be concerned about the intimate contacts.
And I think also that if there's anything that can be learned by a number of the things that have happened in the last 15 years or so, it's that the public wants us to fall down on the side of safety.  And if we are acting with insufficient information, that's fine, but the public in various different forms wants you to come down on the side of safety and not delay until you actually have things happening and hitting you in the face.
DR. HOLLINGER:  Okay.  David?
DR. STRONCEK:  One short comment:  When we brought this up, what, six months ago, I thought it was crazy to ask this question, but the more I thought of it, I agree with Paul.
And a couple of reasons:  One, if you don't ask the donors directly, you're never going to know.  They won't read the pamphlets.  At the time of the surgery and the transplants, too much is going on to worry about donating.  So I think the question is the only way to get at it.  And, yes, we have a problem with the donor questions, but that's a whole huge issue.  That doesn't mean we shouldn't ask the right questions.
DR. HOLLINGER:  Okay.  I'm going to call‑‑
DR. MITCHELL:  I want to clear up one point, though.  When we talked about this six months ago, we said that over half of the people were skin graft recipients, and those people aren't particularly sick, and so this is in fact something that the recipients may in fact want to go and donate blood.
DR. HOLLINGER:  I think the committee, if I remember right, the subcommittee voted actually that that particular group could donate.  That's not an issue.
I'm going to call for the question that's up there, at least for right now, and the question is:  Does the committee agree with the proposed modification to the questionnaire?
And this is the proposed modification that you have in your handouts here, the part I, part II, II.A., II.A.1.  So the question is, do you agree with those proposed modifications to the questionnaire, not whether there should be a question or anything of that nature, but do you agree with the proposed modification as it is stated?
All those in favor of‑‑all those that agree with the proposed modification to the questionnaire, raise your hand.
[A show of hands.]
DR. HOLLINGER:  All those opposed?
[A show of hands.]
DR. HOLLINGER:  Those abstaining?
[No response.]
DR. HOLLINGER:  And I would like to ask our industry representative and our consumer representative how they would vote.  Ms. Knowles?
MS. KNOWLES:  I'm going to abstain.
DR. HOLLINGER:  Okay, and‑‑
DR. SIMON:  Opposed.
DR. HOLLINGER:  Opposed.
Linda, could you read the results?
DR. SMALLWOOD:  The voting results for the question:  Does the committee agree with the proposed modifications to the questionnaire?  There were two votes which agreed with the proposed modification.  There were 10 votes against the proposed modification.  The consumer representative abstained from commenting, and the industry rep agreed with those that opposed.
DR. HOLLINGER:  Paul?
DR. McCURDY:  I'd like to make one quick comment about my apparent inconsistency.  I don't think I like the questions the way they are now, but I think a question should be asked, and I think it ought to be wordsmithed by people who know what they're doing.  I think that the institute, the NHLBI, would certainly be willing to talk about doing some field testing in some of the REDS centers.  I can't guarantee that we would do it, but certainly we'd be willing to talk about it.
DR. HOLLINGER:  Let me ask the committee, then, let me just throw out another question, then, for the committee.  I'd just like to see how the committee feels at this time.  And that would be something to the effect, does the committee agree with excluding any specific donor question on xenotransplantation at this time?  I'm not saying for the future, but at this time.  Would the committee agree with excluding any specific donor question on xenotransplantation at this time?  I'd like to see‑‑
DR. BOYLE:  Don't you mean adding?  You don't mean excluding, do you?
DR. HOLLINGER:  Adding, yes.  Well, it could be excluding.  Okay, that's right, it couldn't be excluding.  Does the committee agree with adding any specific donor questions on xenotransplantation at this time?  I'd like to just see how the committee feels about that, so all those who agree with‑‑let's see‑‑yes, all those who agree with adding a specific question or specific questions on xenotransplantation at this time, I'd like to see you raise your hand.
[A show of hands.]
DR. HOLLINGER:  And those opposed?
[A show of hands.]
DR. HOLLINGER:  And those abstaining?
[A show of hands.]
DR. HOLLINGER:  Okay, and Dr. Simon?
DR. SIMON:  Opposed.
DR. HOLLINGER:  And‑‑
MS. KNOWLES:  Abstain, again.
DR. HOLLINGER:  Okay.  This is not official.  I just wanted to get the feeling here.  Go ahead.
DR. SMALLWOOD:  The question being asked was:  Does the committee agree with adding any specific donor questions on xenotransplantation at this time?  The results of voting are:  Five agreed with adding questions; four were in opposition; three abstentions.  The industry rep agreed with those that opposed, and the consumer representative abstained.
DR. HOLLINGER:  Well, I think that gives the FDA at least some‑‑Andy, I think you may be up here as long, maybe, as Ed Tabor will be.
Okay, I think this concludes this session here.  We're going to take a break until‑‑
DR. SIMON:  What about the issue of adding information to‑‑
DR. HOLLINGER:  Oh, sorry.  Toby is right.  Thank you.  I would like to then see, unless there is some discussion on this, about adding educational information to the packet that a donor has, that a donor receives at the time of donation.  That's really what the issue will be dealing with.
Mary?
DR. CHAMBERLAND:  I guess I just wanted to make the observation, I was glad that Lou Katz went through in outline form what is currently in the brochure, and I guess I was struck with what I felt was kind of a disparity.  The information that's in the brochure, that several people have said is barely read or largely ignored, seemed to be pretty important stuff.  And to add to the brochure information about xenotransplants just seemed to me a little out of sync in terms of prioritization, and I think that was along the lines that Linda Chambers from the Red Cross spoke.  So I guess I just wanted to put that out at this point, my sort of reaction to all that.
DR. HOLLINGER:  Are you saying you thought it was more overwhelming than what the other information that was being asked, or not enough, or what?
DR. CHAMBERLAND:  I guess I felt that the brochure should be reserved for the most critical, important information, trying to get at the highest risks that you're wanting people to really think hard about, and admittedly it seems to be mostly focused on HIV, and by default a lot of that would overlap with hepatitis B and C, the current known viral pathogens that people are, continue to be‑‑you know, that we're worried about.
And to add to that xenotransplant as a possible concern, and you need to know this and you might need to defer yourself, I was just struck with to me what I thought was kind of a disparity, that going from situations or behaviors that we're very concerned about wanting to exclude donors because of known or emerging pathogens, and then to drop down to xeno where we're still struggling with trying to identify what the risk is to the recipients themselves, and then into these concentric circles of intimate contacts or health care workers, etcetera, I just‑‑it may not be the first thing I would want to put in the brochure.
DR. HOLLINGER:  Yes, Dr. Simon?
DR. SIMON:  Yes, just to amplify, as you know and I've sent you, that we and many others in the plasma industry use a video to inform donors, and it's much the same issue as we're dealing with in the questionnaire.  We're really trying to emphasize the significant risk factors of male sex with male, ever use drugs intravenously, and so on.  And the more of this sort of thing that you have to get in there, that's complicated to explain, I think the more potentially dilute the important message.
So certainly, again I guess I'm agreeing with Mary, that the state that we're in and the state that the committee was in, I would favor leaving things as they are.  And then as we revisit the issue, if the importance of it begins to come up to a level where it's more important, then we have to go ahead and make these revisions.
DR. HOLLINGER:  On the other hand, I guess, Toby, you know part of the time it takes to do things in getting blood from patients, processing it, obtaining, collecting it, is the actual collection process and asking the questions.  You sit there for a long time in the donor room waiting, sometimes, to go and have your blood collected, and therefore there is time to sit and actually read the document or look at your video or things like this.  And that doesn't take out time from anybody else, because you're there waiting to‑‑
DR. SIMON:  Right.  I would agree it's not as critical an issue as it is with the questionnaire.  I would certainly agree this would be a less intrusive thing to do than the questionnaire, so if you're going to do one or the other, I would agree with supporting this.  On the other hand, it is the same issue, though, that you really want people to focus, and the more you put in there, the potentially less focus you get.
DR. HOLLINGER:  Any other comments about the educational material?
[No response.]
DR. HOLLINGER:  I'm going to bring this, then, to a vote also.  I guess one should, without getting into the proposed language that was placed in there, I guess the question really should be, does the committee agree that donors should be required to have information on xenotransplantation as educational material before their donation.  Is that a fair phrase of what the issue is here?
So those of you who are in favor of having educational material on xenotransplantation before donation to be given to the donor, so signify by raising your hand.
[A show of hands.]
DR. HOLLINGER:  Those opposed?
[A show of hands.]
DR. HOLLINGER:  And those abstaining?
[No response.]
DR. HOLLINGER:  Okay, and Ms. Knowles?
MS. KNOWLES:  Abstain.
DR. SIMON:  Opposed.
DR. HOLLINGER:  Linda?
DR. SMALLWOOD:  I'm sorry, I'm going to have to ask you to vote again because I'm coming up one short on those that are eligible to vote.
DR. HOLLINGER:  Those who are in favor of having educational material on xenotransplantation, raise your hand.
[A show of hands.]
DR. HOLLINGER:  Okay.  Those opposed?
[A show of hands.]
DR. HOLLINGER:  And abstaining?  No one?
[No response.]
DR. HOLLINGER:  And you are staying the same, one opposed, one abstain.  John, you can't vote.
Okay, could you read those, please?
DR. SMALLWOOD:  I'm trying to repeat the question as best as I was able to:  Does the committee agree that donors should be required to have educational material on xenotransplantation before donation?  And the results of voting:  There were five that agreed.  There were seven that opposed.  The industry rep agreed with those that opposed and the consumer rep abstained.
DR. HOLLINGER:  Thank you.  Well, I think FDA has their work cut out for them, as does the blood banking community.  So we're going to take a break until 1:45.  I would like you all back here at 1:45, and then we're going to get into the session on the site visit.  Thank you.
[Recess.]
DR. SMALLWOOD:  We're ready to reconvene.  May I ask all advisory committee members to please return to your seats?
Dr. Hollinger, if you're ready, we are ready.
DR. HOLLINGER:  Thank you, Dr. Smallwood.
The committee is sitting today on an important issue, and that is to review the information from an intramural site visit.  It's one of our responsibilities to approve or disapprove or modify information that is given to us about these site visits for the various laboratories or divisions of CBER, and this is one such intramural site visit.
We were hoping that Dr. Kagan, who is on our committee, was supposed to be here to go over the assessment that the committee made, or Dr. Allan, who is the chairman of this committee.  Neither one of them are here, so I'm going to have to read for you just a short portion.  I have sort of redacted this, if you will, what's going on here.
But we have some introductions and overview about what this site visit was about and what the issues are, so Dr. Goldman is going to give us an introduction and overview, to be followed by John Finlayson, Mark Weinstein, and then Basil Golding, and somewhere in here we're probably going to have the presentations from Dr. Scott and Dr. Alayash.  Yes?
DR. SIMON:  Just a question for a new member.  The packet we received had what looked like the materials that were given to the site visitors, but I didn't see that we got the site visitors' report.  Is that correct?
DR. SMALLWOOD:  Yes, I can answer that.  Only those committee members that were permitted to participate in the closed session received that information, and unfortunately your position on the committee would not permit that.  That's why you did not receive that information, but you may participate in the open discussion that we're going to have now.
DR. SIMON:  So other people on the committee got the report of the site visit?
DR. SMALLWOOD:  Yes.
DR. SIMON:  And I specifically didn't.  Okay.
DR. HOLLINGER:  It's exclusive.  No, it's not, really, but I think that's the issue.  But, please, we would like your input on the information.
DR. GOLDMAN:  Okay?
DR. HOLLINGER:  Yes, please.
DR. GOLDMAN:  Thank you, Dr. Hollinger.  Good afternoon.  I am Neil Goldman.  I am the Associate Director for Research at CBER, and I would like to actually begin by thanking you for the valuable role that you all play in the quality control of our research programs at the Center.
And I thought for the next approximately 5 to 10 minutes I would give you just sort of the abridged version of the importance of research at the Center, based on responsibilities that the Center has, as well as the critical need for oversight of our research programs.  And of course following me you will hear presentations from the Office of Blood, from the Division of Hematology, and also from the members of the Laboratory of Plasma Derivatives, who I think will provide you a more focused view of the needs for research to support the regulatory issues.
So if I could have the first obligatory slide, and I say this is obligatory since we always customarily start all of our talks with this.  The mission of CBER, of course, is to protect and enhance the public health through regulation of biological and related products, including blood, which is why you have a committee here for the last two days; vaccines; biological therapeutics; and also, by the way, devices, and of course we handle some of the blood transfusion or collection devices, and now some new devices.  These are new devices that are composed of new biotechnology products in conjunction with new biomaterials.
Next slide.  The regulation of these products is founded on science and law to ensure their purity, potency, safety, efficacy and availability, and to fulfill this mission we conduct research as an essential element of our science based decision‑making on regulatory issues.  Thus, we see that research in fact is the linchpin to our other areas of regulatory responsibility, as you see up here, and they include review of product submissions, development of regulatory policy, product surveillance, and that entails such things as our lot release testing, our inspections, and adverse event monitoring.  And of course, lastly, manufacturer compliance, and of course all the enforcement aspects that go along with that.
Next slide.  Now, just historically, we were mandated back in 1955 by a PHS order that we, CBER‑‑we were not CBER at the time‑‑shall conduct research on problems related to the development, manufacture, testing and use of vaccines, serums, antitoxins and analogous products, including blood and its derivatives.  We shall conduct other studies to assure safety, purity and potency of biologic products, to improve existing products, and to develop new products.  In fact, these mandates have been broadened quite a bit over the last 45 years to include a whole host of new products, some of which you talked about today in terms of xenotransplantation, but then as well some others that you mentioned like the Recombinant Human Factor VIII.
Next slide.  Now, this is the current organizational structure of CBER, and the currently the Director of CBER is Dr. Kathryn Zoon, and underneath the Office of the Director there are seven offices.  And the site visit report that you will be listening to later, and I apologize, some of you may not be able to make it to the closed session, but that site visit report in fact will involve investigators in the Office of Blood.  And you will see in the Office of Blood that there are three divisions.  Two of these divisions in fact are laboratory‑based divisions, and the laboratories, the two investigators are in laboratories in the Division of Hematology, and they are in the Laboratory of Plasma Derivatives.
Next slide, please.  Now, currently at CBER we have approximately 440 lab‑based scientists, and approximately 72 of them are what we refer to as permanent career appointment principal investigators, and there are about 57 who are what we refer to as conversion track investigators.  This is similar to what you will recognize in academia as your tenure track investigators.  Now, most of this staff who are in this latter category are either Service Fellows or Commission Corps Officers.
Next slide.  Just a few words about our Service Fellows.  CBER has a Service Fellow program where a research scientist comes in at a journeyman‑like level, and usually these researchers have approximately seven years of postdoctoral experience under their belt, and as they scientifically develop, they themselves will be given additional research support, in particular their own postdoctoral fellows and technical support.
Service Fellows also have regulatory responsibility that progressively increases each year.  It's usually about 20 to 30 percent in the first two years, and on average about 30 to 50 percent later on.  The two investigators that will be discussed here, and who actually the site visit is about in fact, spend probably at least 50 percent of their time doing regulatory work.
Next slide.  In CBER all researchers are fully integrated into the review process.  Their regulatory duties include the review of INDs and BLAs, development and presentation of regulatory policies, meeting with manufacturers as well as meetings with the advisory committees, as you have already had‑‑I know Dot Scott presented already‑‑and they also participate in biennial and prelicense inspections, as well.  In total, this is what we refer to as the researcher/reviewer model.
Now, as I have put down in that box in red at the bottom, it was pointed out by our External Committee for the Review of CBER Research, and I'll get into that committee in just a couple of minutes, but this was a large committee that came in to review all of CBER's research, they commented that they felt that the researcher/reviewer model is essential to providing CBER with top level expertise in a regulatory culture.
Next slide.  Now, the types of research at CBER which are considered mission‑related include, number one, research on a specific product, including for example such aspects as mechanism of action, potential toxicity, or surrogate measures of efficacy; and, second, research on a specific policy issue, and this may be related to a particular product class, a disease area, or a therapeutic modality; and, third, and of course probably of major importance to a regulatory agency like ours, research associated with the development of methods and standards to maintain product safety and quality, and I think you are going to hear briefly, at least, some of what the site visit team had heard presented to them by Dr. Alayash and Dr. Scott, and I think you will see how each of these aspects play into the type of research that they do.
Next slide.  Now, actually, as Dr. Hollinger just mentioned, and I'm sure you are intimately aware of the varied roles of the product advisory committees, you certainly provide technical advice on products and product classes, advice on appropriate design of clinical trials, as well as advice on surrogate markers and choices of endpoints, and of course advice on how to interpret many of these clinical protocols, as well as you talked about this morning, in terms of xenotransplantation, advice on risk assessment.  But, lastly, of course, as Dr. Hollinger had mentioned, your last responsibility is to assist us in the peer review of our intramural research programs, and of course the research scientists involved in them.
Now, this accomplished by use of a site visit team, and this team is usually a subgroup of this particular Blood Advisory Committee, and therefore the Blood Products Advisory Committee is in fact the parent committee of now this subgroup, this site visit team.  The site visit teams is usually composed of at least one member of the advisory committee, and in this case Dr. Kagan was that member.  Dr. Alving was chosen as the Chair of the committee, but in addition there were other ad hoc members.  These are experts in the field of the individual being reviewed, so that the committee is usually‑‑usually brings in at least two to three additional, per person, per individual being reviewed, an additional two to three people who are experts in that field.
Next slide.  The charge that was given to the site visit team was to assess, and that was to assess both the strengths as well as the weaknesses, the quality and appropriateness to the regulatory mission of the research being conducted.  That includes relevance, scientific rationale, validity of approaches, creativity, design and solution, as well as level of sophistication.
Can I have the next one?  We also ask the site visit team to evaluate the accomplishments of the individual scientist, which includes demonstration of his or her abilities in experimental design and performance, independence of effort, originality, stature and recognition amongst his or her peers, and productivity.
Next slide.  In addition, we ask the site visit team to provide us advice on the current direction of the research program, whether new direction should be considered, any changes in the way the research program is administered or the level and utilization of resources in that program.  And, lastly, we solicit advice on promotion of the staff member being reviewed, or whether or not conversion of a candidate to a permanent position, for example, as a principal investigator is appropriate at this time.
Next slide.  Now, finally, after the site visit team has had an opportunity to actually review each researcher and their program, there is an oral summary at the end of the day that is provided by the team and is provided to the management at CBER.  This actually gives CBER sort of a preliminary picture of the team's observations and conclusions.
Now, the Chair of this site visit team, of course with the help of the ad hoc members, goes on to prepare a written report.  Now, that is the report that actually was given to the members of the committee here, and again, this report certainly reflects, as was in the previous slides, an evaluation of the research program, the individuals in the program, the resources being utilized in that program, as well as any recommendations for, for example, personnel actions.
Now, this report then is presented in closed session, and that's what will happen after this open session, and is usually presented by the site visit Chair.  In this case, this site visit Chair could not be present, so Dr. Hollinger has been kindly willing to take on that responsibility.  And it is presented to the entire product advisory committee for your review and your approval.
Now, after approval, this final report will be sent back to the Center director, who then will send it back down the chain of command, and it will eventually go down to the investigator who was actually reviewed.  Any responses to comments that are made in the final report are then prepared, and these responses are in fact forwarded back to the appropriate advisory committee to show that in fact we do respond when questions do come up.
Next slide.  Now, you may or may not be aware, but I think most are probably aware that we actually at CBER maintain visual and oversight and quality control of our research programs by actually utilizing three independent mechanisms:  First by our periodic in‑depth site visits of our laboratories which occur every four years.  Each laboratory is site visited on a four‑year cycle.
The second mechanism is by internal prioritization of the research programs which is performed annually by our senior management based on a number of criteria.  And the criteria include not just scientific quality and mission relevance but also the public health impact on product availability; the unique position of CBER to address critical safety issues pertaining to a particular product; or relevant regulatory research that would not be done elsewhere, in relation to a particular product area.
The third mechanism in fact for our oversight has been by a high level review of the Center's entire research program, which was in fact carried out in February of 1998 by an external blue‑ribbon panel that was composed, in fact, of highly regarded scientific experts from academia, from industry, and from other government agencies.  This was a very successful review and a very positive one, and will probably occur now every 8 to 10 years.  This will be true of all of the Centers in FDA.  Each will be reviewed as an entire Center approximately every 8 to 10 years.
Last slide.  Now, just to give you a flavor, this blue ribbon panel, and we referred to this as our Subcommittee for Review of CBER Research, as it called itself, this by the way was a subgroup that was in fact a subcommittee of our FDA Science Board.  So they acted like our site visit team does to you, where you are the parent committee.  The parent committee for our Subcommittee for Review of CBER Research was in fact a subgroup of the agency's Science Board.
This subgroup provided us quite valuable suggestions and insightful recommendations about our research programs, and I thought I would provide you one example right here:  For our industry to receive prompt and appropriate reviews, and for our regulatory agency to respond to urgent needs, it is of utmost importance that the scientists in CBER have research capabilities at the cutting edge that allows them to understand the rapidly expanding methodologies, to evaluate vaccines and biologics, but also so that they can interact with their colleagues in industry on a knowledgeable scientific and technologic basis so that the appropriate recommendations can be made.
I think actually from the discussions I heard here today around this table, I would most agree, especially for those from industry, that it is very important for us to be able to see how you feel about these various issues that come up before the FDA.
Well, again I would like to thank you for the important role that I think you may or may not realize you play in this whole process, and if there are any questions before I turn this over to Dr. Finlayson, I would certainly be willing to answer any.
[No response.]
DR. GOLDMAN:  No?  Okay.
DR. FINLAYSON:  Thank you very much, Neil, and good afternoon.  I am going to be very brief, in fact uncharacteristically brief.
The site visit was carried out on December 8, 1999.  Sorry, Toby.  You voting members have a copy of the report, and so I am just going to begin by reiterating what Dr. Hollinger said, namely, what is it that you are expected to do?  And some of you have been through this before but many of you have not, so I think a little redundancy is in order.
You, as the parent company‑‑company, that's very good, think industrial‑‑as the parent committee of the site visit team, are being asked to endorse the report.  And you have, as Dr. Hollinger pointed out, three options.  You can accept it, you can reject it, or you can modify it and accept the modified form.
Now, you heard from Dr. Goldman the general procedure for these reviews that take place on a rotating basis, so that a given laboratory unit is reviewed every four years, and you heard that the usual thing is to review a laboratory at a time.  "Laboratory" in this case does not mean a room, and we'll get to that in just a moment; it means an operating unit, an administrative unit.
This particular site visit was an exception to that, and I will tell you why.  As you heard from Dr. Goldman, if someone comes in on a conversion track, he or she has a life span of seven years, and Dr. Dorothy Scott joined the organization in 1993, and if you do the subtraction, you will see we are coming up on the seven‑year point here.  So it was very important, as we reached the end of 1999, that in order for her to be proposed for conversion to permanent status, we had to have a current site report.
At the same time, Dr. Alayash, whom both of these people you will meet very shortly‑‑actually, you met Dr. Scott this morning because she made a presentation about CJD‑‑Dr. Alayash joined the organization in 1989 and was converted to permanent status in 1996, but in order for him to be proposed for promotion, we needed also for him a recent site visit report.  So, accordingly, these two people were reviewed on an ad hoc basis, not as part of an entire laboratory review.
Fortunately, however, to make things convenient, they both are in the same laboratory, which is the Laboratory of Plasma Derivatives.  And if I could have the first overhead, if it looks familiar to you, it's because it should look familiar to you.  The committee has handouts.  For those of you in the audience, this can be obtained on CBER's external web site.
As I look at this, I am always impressed by the fact that it looks like the things, when you take these courses in audiovisual aids, the things they show you what not to do.  And I say this is, admittedly is a ridiculously busy slide, but if I may be so bold as to say, CBER is a ridiculously busy Center.
If you can read the first line of little boxes going across there, you will see the third one from the left is the Office of Blood Research and Review, the next one is the Office of Vaccines Research and Review, and the next is the Office of Therapeutics Research and Review.  These are the three offices with large laboratory components.  There are also other laboratory activities throughout the Center, but these are the ones in which the lion's share of the research is conducted.
Now, if I can have the next one, I will expand the Office of Blood Research and Review, and you will see there is the immediate Office of the Director, there are two staffs off to the right, and down at the bottom you will see we have the three divisions.  The one on the far right is the Division of Blood Applications.  This is largely a review and administrative division.  The two on the left, Division of Emerging and Transfusion Transmitted Diseases‑‑I'm learning to say that because they have just introduced the word "emerging" into it, and I have to condition myself to put the "e" into it‑‑and the Division of Hematology, in the middle of which Dr. Mark Weinstein, from whom you will hear in just a moment, of which Dr. Weinstein is the Director.
Now, if we look at the next overhead, we are expanding that Division of Hematology, and you will see that there are four groups under that, of which three are laboratories.  And this is what I meant when I said a laboratory not as a room but as an administrative or operating unit.  The third box from the left is the Laboratory of Plasma Derivatives, of which Dr. Basil Golding is the laboratory chief.  It is in this box that both of the people from whom and about whom you will hear today reside.  They are both in the Laboratory of Plasma Derivatives.
And I think that I have probably said enough, unless there are any particular questions that I can answer.
DR. HOLLINGER:  Thank you, John.
Dr. Weinstein?
DR. WEINSTEIN:  Well, you have heard from Dr. Goldman and Dr. Finlayson about the importance of research in CBER, the position of the Division of Hematology in the organizational structure of CBER, the part that this committee plays in reviewing the progress of our scientists, and the role that science plays in the regulation of blood products.
Now, following my presentation, you will hear from Dr. Golding about where Dr. Scott and Dr. Alayash are in the Division of Hematology, but I would like to‑‑and also you will hear from Drs. Scott and Alayash about their specific research program‑‑but I would like to concentrate on the regulatory activities that these two outstanding individuals have achieved.
First in regard to Dr. Scott, as many of you know, scientists at the FDA have the opportunity to pursue two full‑time careers at once.  Dr. Scott began her review career at the FDA under extraordinary circumstances.  She had been here approximately six months when the lead reviewer on a major and highly publicized submission had to withdraw from the review process because of ill health.
Dr. Scott took up the burden of reviewing this difficult submission, and came to the correct conclusion that the data submitted was inadequate to recommend approval.  Although the manufacturer was not able to market the product as quickly as they desired, Dr. Scott worked with the company to develop an appropriate study plan that eventually led to the approval of the product.
Since that time, Dr. Scott has had the lead on many PLAs and INDs, including that for RH immune globulin intravenous, and other immune globulin products.  In fact, with her immunology background and the fact that she is a practicing rheumatologist in a clinic which she attends on a half‑day per week basis, she is the person that we go to in the division for the review of INDs involving autoimmune and neurological disorders.
Another very important assignment that Dr. Scott has had in the FDA has been to help develop our CJD policy.  She wrote the first draft of our revised CJD guidance document, and then integrated the numerous amendments and comment into the 35 subsequent drafts that were prepared before this document was sent out for public notice and comment.  She is the point of contact in the agency who handles inquiries about this document.
To improve understanding of CJD guidance, she co‑organized a workshop on CJD policy that was attended by representatives of industry, PHS and other regulatory agencies, and she has done an exceptional job in presenting our CJD recommendations at national and international meetings.  You were the benefits of one such presentation this morning.  She has presented before the PHS Advisory Committee on Blood Safety and Availability, and an international conference of drug regulatory authorities in Berlin last year.
In sum, she has made exceptional contributions in the area of regulatory review and policy development, while at the same time carrying out her second career as an outstanding scientific investigator.
Next, I would like to turn to the regulatory accomplishments of Dr. Alayash.  Dr. Alayash is in a different regulatory arena compared to Dr. Scott and most other reviewers in the Division of Hematology.  His area of expertise is in blood substitutes.  There are no licensed blood substitute products; all are in the developmental IND stage.  Thus, the standards for assessing the quality of these products are not yet established.
Currently, Dr. Alayash is the lead product reviewer on nine blood substitutes in clinical trials.  A major focus of Dr. Alayash's regulatory work has been to evaluate the safety of these products and to determine what the critical elements are that should be considered to assure safety.  Recently Dr. Alayash led a team of CBER reviewers that investigated the likely cause of one blood substitute's failure in a Phase III clinical trial.
Among Dr. Alayash's accomplishments has been to organize workshops on blood substitutes that have helped to inform the FDA and the public about current state‑of‑the‑art of these products.  He assisted in organizing workshops in 1990 and 1994 that dealt with the safety and efficacy of hemoglobin and fluorochemical‑based products.  He then helped draft points to consider documents on blood substitutes that were published in the Federal Register.
Yesterday you heard from Dr. Lee about the outcome of another workshop held last year that dealt with the safety and efficacy of these products.  Dr. Alayash chaired and organized the steering committee for this meeting.
In sum, Dr. Alayash is the product expert at the FDA on blood substitutes.  He is the person whose knowledge and judgment we rely upon to assess the quality and safety of these products.  He is internationally recognized as an expert in this field, and his research work is directly relevant to his review competence.
FDA has recognized Dr. Alayash's outstanding contributions by awarding him the agency's highest scientific award this year for excellence in laboratory science.  His FDA citation reads:  "For studies that contributed fundamentally to current understanding of hemoglobin toxicity and potentially to the design of safer second generation blood substitutes."
Thank you.
DR. HOLLINGER:  The final presentation, then, is by Dr. Golding from the laboratory in which the two people we are going to be reviewing reside.
DR. GOLDING:  My job is to give you some idea of how the Laboratory of Plasma Derivatives is organized.  We have four sections.  Each section has a section head.  Abdu Alayash is head of one of the sections related to hemoglobin‑based substitutes.  We have a physical biochemistry section, a biosafety section, and an immunology section.  Dr. Scott has been a senior staff fellow in the immunology section of the laboratory for several years now.  This is her seventh year.  I would like to point out that all these section heads have already been promoted to the GS‑14, except for Dr. Alayash, who is the most recent section head to be appointed.
I don't want to go into too much detail, but just to concentrate on the groups that we are‑‑in terms of the people that are being reviewed today, Dr. Alayash is a section head.  He has several people working in his group, so he has developed a program.  As you have heard, he has developed a program to do research on hemoglobin substitutes which is very critical for assessing the safety and efficacy of these products.  And, in addition to that, he is a mentor for people who will then learn how to be involved in the review process, and this will provide continuity and ability for them to deal with these products as some of them start to become licensed and as the work load increases exponentially over the years to come.
Okay.  In the Laboratory of Immunology, as I have pointed out, Dr. Scott is a senior staff fellow in this section.  She came to the laboratory and set up her own independent research program to look at various aspects of immune responses, TH1, TH2 responses, looking at immune globulins and their subclasses, and also looking at dendritic cells and their responses to bacterial products.  She has worked most closely with Ko Ti Huang, who has a master's degree, but she has also supervised several people in the laboratory, and is an integral part of the laboratory in terms of providing ideas and in propelling all of the research projects in the laboratory.
This is the Viral Safety Group headed by Dr. Yu, and I'll just kind of mention briefly some of the important products that we regulate.  I have highlighted the products that are regulated by Dr. Alayash.  You have already heard several times that he is the point person in relation to both the review and the research on hemoglobin‑based blood substitutes.  And Dr. Scott is involved with review and research on immune globulins, both general and specific.
So these are the‑‑finally, I am just showing you a slide on the various research projects that are currently being carried out in the Laboratory of Plasma Derivatives.  Again, I have highlighted the important ones in connection with what your work is today.  This is the project in Dr. Alayash's lab, "Investigation of the Safety and Efficacy of Hemoglobin‑Based Blood Substitutes," and these are the projects that Dr. Scott is involved in, "Development of an Anti‑HIV Therapeutic Vaccine, Class and Subclass Responses," "Studies of Cytokine Regulation in Human and Murine Immune Responses," and "Studies on the Safety and Efficacy of Immune Globulins," and I would include the "Study of Dendritic Cells and the Effect of Bacteria on the Migration and Secretion of Cytokines by the Dendritic Cells."
Thank you.
DR. HOLLINGER:  Thank you, Dr. Golding.
At this time we're going to ask Dr. Alayash and Dr. Scott if they would mind just coming up here and maybe spending five or so minutes telling us just a little bit about the exciting work that they're doing, so that the committee can sort of hear about that.  Are they here?  Let's have Dr. Alayash first.
DR. ALAYASH:  Can I have the first slide, please?  Actually I will have about 10 minutes just to give you a very brief outline of what we do in terms of research.  The focus of the lab is basically to try to understand the mechanisms of toxicity of hemoglobin‑based blood substitutes, with some emphasis on finding ways and means, if possible, to control some of the unwarranted and unfavorable side reactions of hemoglobin.
This figure basically shows you the different approaches used by industry to modify hemoglobin and the other components, the synthetic compounds.  In fact, we have two classes of these compounds, fluorochemical‑based compounds and hemoglobin‑based compounds.  I'm not going to talk about these.  They are basically synthetic compounds.
The hemoglobin‑based compounds are largely derived from outdated human blood or animal blood.  Hemoglobin is isolated, purified extensively, and‑‑I'm sorry‑‑the hemoglobin derived from the red cells, outdated red cells, either chemically modified, either cross‑linked to stabilize the tetrameric form of hemoglobin.  In some instances the hemoglobin is degraded with some non‑protein components.
In some examples here, the protein is actually polymerized to increase the size of the protein and to increase the retention of the protein in circulation.  In some instances the protein is actually encapsulated with the liposomes to mimic the red cell.  And all of these approaches are presented in what we have, what we deal with in terms of product.
If you want to summarize what we really‑‑as we start now, in terms of what is there in the open literature in terms of clinical experience with these proteins, these are the sort of things you will encounter when these proteins are infused:  vasoconstriction and hypertension seen in humans; GI distress, which is basically localized spasm of the GI; and of course in one or two instances we had excess mortality in patients with ischemic stroke, more recently in trauma patients.  Both of these published studies belong to Baxter, primary product the DCLHB, and incidentally this particular product has been withdrawn from the market, and of course Baxter now working on the second generation product.
There are basically two issues that we deal with, our work sort of, you know, focus on, and these are really issues or rather problems that we encounter because of the uniqueness of this product.  One of them, one of the primary problems is really we are dealing with a rather unique product.
Hemoglobin, once you take the hemoglobin out of the red cells, you can't really control it.  That's primarily because the hemoglobin, unlike any plasma‑derived product, contains an active product which is the heme or rather the iron.  These are transition metals.  They continually change, undergo changes, so the hemoglobin that we really would like to keep in circulation of course is the ferrous functional form, the iron in two states.
Hemoglobin outside the red cells will uncontrollably go to the ferric, non‑functional form.  The heme now turns into the ferric form or the 3+.  In some instances where there are oxidants in the tissue, hemoglobin can even turn to even higher oxidation state, the ferryl, which is rather toxic.  In brief, the hemoglobin, this particular product can go from functional to non‑functional and in some instances downright toxic.
The other issue that we deal with, because of the uniqueness of this product, is the locality or the neighborhood where the hemoglobin actually finds itself, blood cells, and that is primarily the vasculature.  And what I'm showing you here, basically a cartoon section of the vascular wall.  This is the inside of the blood vessels.  This is the vessel wall.  And all we have learned in recent years about the endothelial cells that line the blood vessels, generate an important factor which is endothelial relaxing factor, which we know is a simple nitric oxide.  And this nitric oxide activate a number of enzymatic reaction, ultimately lead to relaxation of blood vessel.  That's under normal conditions.
Other, additional important things that transpire from research in recent years, that nitric oxide, besides its vasodilatory action, it actually has some antioxidant property.  In conditions where the vasculature is compromised, in conditions such as diabetes or hypertension or a number of other conditions, and/or when you have hemoglobin floating around close to the vascular system, close to the nitric oxide's production side, the reaction is of course immediate and very rapid.  That would lead to vasoconstriction instead of vasodilation, and of course the hemoglobin now has to face these unwanted oxidants which normally the nitric oxide suppressed when we have a higher level of nitric oxide.
This is the hemoglobin molecule, and really I am showing this just to show you where we are focusing in terms of research.  And we wanted to know, or rather to define, the interplay between the hemoglobin and these oxidants or antioxidants, or we define them as ligands.  The area that we focus, of course, is where the heme resides in the protein.  We call it the heme pocket, where the actions take place; all these reactions actually take place here.
But also, the second reason is that when you modify the hemoglobin as they do, the manufacturers, even if your reagent is here or on the surface, you are influencing this very crucial area.  So we spend a great deal of time and energy, really, to look at these dynamics and the chemistry of the heme pocket and whether we can actually influence the reactions there at that level.
This is just two close‑ups of the heme pocket.  I am showing you in normal hemoglobin, this is the heme, this is the oxygen, a number of key amino acids.  So we have reason, we said if we can actually in some instances make it a little bit more crowded or more space for ligands to get in, we can actually control some of these reactions.
And what we did, basically we use a variety of prototypes, variety of proteins.  The major proteins that we use are simpler components than the hemoglobin, which is the recombinant, in collaboration with a number of outside people, particularly Rice University, and we were able to change key amino acid in the heme pocket, and we were able to see actually some reduction in the rate of hydrogen peroxide reaction and nitric oxide reaction.
We also use chemically modified hemoglobin.  In fact, some of these example of hemoglobin that we have taken directly from industry.  They were kind enough to give us very little of those compounds.  And we have also looked at the dynamics in respect of these unique chemical modifications on these reactions.
We have also developed an endothelial cell model that these reactions can be tested, and our hypothesis, that if we can genetically engineer or chemically alter the heme pocket, we can influence the reaction at the level of endothelial cells and consequently the toxicity.
In brief, what we did over the years, over the last nine years or so, we determined length between the redox chemistry of a given protein and its toxicity.  We have also developed ways and means to actually suppress and control some of the side reactions of hemoglobin.  We developed a number of endothelial cell models that mimic ischemia or perfusion, an important phenomena in particularly those patients who receive blood substitute, and also we developed endothelial cell model in which to mimic the lowered antioxidant capacity of the individual, such as what you encounter particularly in those patients that receive these candidate products.
And some of these, as a final outcome of what we have done, some of these suggestions that we publish in the literature luckily found itself in the second generation of blood substitutes, and of course this is quite pleasing and rewarding, and also in the fact that that will also give us, based on that, a little bit know‑how and a nitty‑gritty type of knowledge of what the genetic engineering or chemical modification of second generation hemoglobin might entail.
And I think that's all I have in my time, which is 10 or so minutes.  Thank you.
DR. HOLLINGER:  Are there any questions of Dr. Alayash?
[No response.]
DR. HOLLINGER:  Okay.  Dr. Scott?
DR. SCOTT:  Abdu and I want to thank you for staying to listen to us, because I know it's getting late.  I'm just going to briefly give you an overview of one of my projects, and quite briefly, in a whirlwind fashion, summarize some of the others that I've been working on in the lab.
The first one is involving antibody subclass efficacy in specific immune globulins.  Just to remind you, we regulate a number of human specific immune globulins which are used to prophylax against infectious agents, and I have just listed them here for you.  We're expecting a couple of others to come down towards us in the next year.
And the question that I got interested in finding out the answer to was, could we develop techniques to assess whether or not the activity of specific immune globulins resides within a particular subclass of IgG?
Just to show you a snapshot of the different subclasses of IgG, all of these are contained in most immune globulins, except that some processing removes a lot of IgG4, and these are the subclasses IgG1, 2, 3 and 4.  And what you can notice is that they have somewhat different structures, different numbers of disulfide bonds.  There are other differences which aren't reflected here, and especially IgG3 has this long hinge region which makes it very susceptible to proteolytic degradation.  They have different chemical characteristics, and based on these, they can be separated from a preparation of immune globulin.
So there are some potential regulatory implications or at least some efficacy implications if there is a selective subclass that works against some of these pathogens.  First of all, if you knew that there was a particularly efficacious subclass, you might want to select donors that had that best antibody subclass against the pathogen.  And in cases where donors were to be immunized for a specific immune globulin, you might wish to select an immunization method or an adjuvant which resulted in production of the best antibody subclass.  Also, in manufacturing one may be able to enrich for an antibody subclass, and certainly one would wish to avoid processes that removed the desired subclass.
It's going to be a little difficult, but you can leave off the top.  What I started with was HIV immune globulin.  We had access to these preparations through NIH.  And this is just almost a prototype of the sort of project that I would like to continue, and I used protein A Sepharose and a pH gradient to sequentially elute the IgG subclasses and then tested these for binding of viral antigens in the solid phase, and also in bioassays, in collaboration with Hanna Golding's lab at FDA, which looked at neutralization of HIV, both HIV as a free virus and neutralization of cell‑to‑cell viral transmission.
You have the data, I think, in the package you received, but I'm just going to summarize the two major findings.  And one was that all of the IgG subclasses that we looked at, which were 1, 2 and 3‑‑this preparation has a chromatography step which removes almost all of the IgG4, which is a very minor component anyway‑‑all of the other subclasses bound well to HIV antigens in ELISA and on Western blot, and the rank order of binding was, IgG1 was often slightly better than or similar to the total preparation, and both of those bound better than IgG2 an IgG3 in ELISAs.  However, even though IgG3 typically was the worst at binding in ELISA, and even by Western blot, it was superior in preventing infection by cell‑free virus and in preventing cell‑to‑cell transmission of HIV.
So, very briefly, I just want to emphasize that now we have the ability to separate antibody subclasses.  We have been able to develop this, and I have shown you at least in one case that there is evidence for selective efficacy of a particular subclass.  And we have also looked at RSV immune globulin with Judy Beeler, and it appears that in that case IgG1 by far is the most effective in bioassays.  And, as I pointed out, we may be able to enhance efficacy of specific immune globulins just by knowing the subclass, how well the subclass functions, although obviously this isn't an in vivo challenge, and we plan to study other specific immune globulins.
Also, I would just note that there was a discrepancy between binding to solid phase antigens, such as in ELISAs, and bioassays.  And to us this stresses the importance of selecting biologically relevant tests which predict efficacy in the case of specific immune globulins.
And for HIV immune globulin in particular, one could imagine that you could take some of this information, it would be nice to test it in an in vivo model first, but this has some implications because one might improve its efficacy by enriching and stabilizing IgG3, which only comprises about 4, 2 to 4 percent of that total preparation.  And also I would point out that one might wish to change the dosing interval if you really thought that IgG3 was by far more important than the other subclasses, because IgG3 has a very short in vivo half life.  It's only 7 days, compared to the others which are 21 days.
So this is just to illustrate how such findings might be applied in the future.  I'm just not quite finished with that.  Thanks, though.  I wanted to say that right now I'm pursuing studies to determine whether the IgG efficacy in the HIVIG is due to preferential recognition of important HIV neutralizing epitopes, or whether it's due to the IgG3 hinge structure, and I think I set that out also in the report, but I'd be glad to talk about it.
The other major project that I've been working on is understanding immune responses to inactivated Gram‑negative bacteria, and the preparation I use is a heat inactivated or a heat killed Brucella abortus, but this represents sort of a class of immunogens which have both toxic effects but also may be used in a way as a vaccine adjuvant.  And so really there are two kind of separate arms to this study, and one is understanding the toxicity of these inactivated bacterial components.
And the reason I would like to do that is that it enhances my expertise in understanding inflammatory responses to bacterial constituents, and this might be very relevant to the side effects that occur from products containing trace levels of inactivated bacteria.  And we already know that, for example, immune globulins contain bacterial DNA, which is a known immune stimulant, and they often may contain very low levels of LPF, certainly lower than the amount that is specified as a cutoff.
What I have been able to show is that such microbial preparations induce proinflammatory cytokines like TNF and IL‑1, but in particular and most recently, interleukin 12, and this interleukin 12 comes from dendritic cells.  They also cause migration of dendritic cells to T cell areas of spleens, and all of the preparations that I have looked at seem to elicit to a greater or lesser degree an anti‑inflammatory cytokine as well, interleukin 12, and they are toxic in vivo to mice who are deficient in IL‑10.
So I'll go to the next one.  Besides understanding the proinflammatory responses to these, it's also possible to harness the immune responses to microbial substances, because in our case, the ones that we have looked at, and in particular the heat‑killed Brucella but some others can do this, as well, induce potent T and B cell responses to antigens that are covalently linked to them.  So these can be used as vaccine adjuvants, if you can get over the proinflammatory initial response.
And it has been shown by myself and by Dov Golding that you can use such an adjuvant to induce certain subclasses of complement fixing antibodies in mice, and we believe on several lines of evidence that this could be achieved in humans, as well.  And so understanding the adjuvant activity of such preparations is potentially useful in promoting subclass specific responses for the generation of specific immune globulins, which relates back to what I talked to you about a minute ago.  And also the studies that I've done in IL‑10 suggest that it might be useful to evaluate the induction of IL‑10 as a safety factor for adjuvants that might be given to humans.
And finally, just to very briefly say I do have a third project that I've been working on, which is the study of proinflammatory cytokine release, particularly, IL‑6, IL‑1 and TNF, by immune globulins, and by what mechanisms this may occur.  And I've been able to develop an in vitro model which demonstrates that many immune globulins from different manufacturers can reliably cause release of TNF by human cells, and I'm very interested in finding out how this works.
The final project that I have just begun to begin is one where I would like to look at the induction of tolerance in prevention of Factor VIII inhibitor antibodies in hemophiliac mice which we have just gotten and we are breeding to be able to address this in a mouse model.
So that's a summary of the research projects that I've been working on, and I think you'll find as an add to this package that we have a list of our recent publications.
DR. HOLLINGER:  Thank you, Dr. Scott.
Any questions of Dr. Scott?
[No response.]
DR. HOLLINGER:  If not, that really concludes the open public portion of this review, and we are now going into closed committee deliberations, so I'll have Linda tell us what we have to do at this point.
DR. SMALLWOOD:  For this particular session, only those members of the committee that are permitted to participate in a closed session and the members of the FDA with their identifying identification are permitted to remain here in the room.  We would ask those other individuals, that we thank you for your participation, and if you could move swiftly and quietly, we can proceed.  Thank you.
[Whereupon, at 2:45 p.m., the Open session was adjourned.]